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Sensitivity of human herpesvirus 6 and other human herpesviruses to the broad-spectrum antiinfective drug artesunate
Abstract
Antiviral therapy for HHV-6 infection with conventional anti-herpesviral drugs is problematic so novel drugs are required. Artesunate is a well-tolerated drug approved for malaria therapy which possesses antiviral activity.
The artesunate sensitivity of HHV-6 was analyzed and compared to that of several other human herpesviruses.
Cultured human cells were productively infected with strains of HHV-6 or other human herpesviruses to measure artesunate inhibition of viral protein synthesis (Western blot analysis) or viral genome replication (qPCR), and to determine IC(50) values by immunofluorescence or plaque reduction assays.
Sensitivity of HHV-6 to artesunate was demonstrated with an IC(50) of 3.80+/-1.06microM. This is in a range similar to IC(50) values for HCMV and EBV. Artesunate treatment of HHV-6-infected cells significantly reduced viral early and late protein synthesis that occurred in the absence of drug-induced apoptosis or necrotic cytotoxicity. HHV-6A genome replication was markedly reduced by artesunate.
Artesunate possesses anti-HHV-6 activity in vitro and may be useful for treatment of HHV-6 infections.
... Artemisinin and its derivatives from the plant Artemisia annua, in particular artesunate, have potent inhibitory effects against double-stranded DNA viruses, including CytoMegaloVirus (CMV), Herpes Simplex Virus 1 (HSV-1), Human Herpes Virus 6A (HHC-6A) and Epstein-Barr Virus (EBV) [229,230]. ...
... Effert et al. [228] showed that artesunate strongly inhibited HSV1 in vitro, with no effect on cell viability. In the same vein, Canivet et al. [230] showed an improved outcome of HSV1-induced encephalitis in mice treated with combination of artesunate-valacyclovir compared to valacyclovir monotherapy. The authors also described a decrease in proinflammatory cytokines (IL-1β, IL-2, IL-6, IFN-γ) and chemokines (CCL2, CCL4, CCL6) with the combined treatment compared to valacyclovir alone. ...
... Data on the activities of artemisinin and its derivatives on Human Herpes Virus 6 (HHV6) are inconclusive. Some authors described an inhibitory effect of artemisinin on HHV-6A replication and early and late protein synthesis with an IC50 of 3.80 ± 1.06 µM with no drug-induced apoptosis or necrotic cytotoxicity [230], while such an observation was not found in another study on HHV-6A and HHV-B [236]. Hakacova and al. [237] described a case of a decreased HHV-6B DNA in endomyocardial biopsies of a child with HHV-6 myocarditis and an improvement in clinical status after artesunate treatment, with no adverse effects of the molecule. ...
Traditional remedies have been used for thousand years for the prevention and treatment of infectious diseases, particularly in developing countries. Of growing interest, the plant Artemisia annua, known for its malarial properties, has been studied for its numerous biological activities including metabolic, anti-tumor, anti-microbial and immunomodulatory properties. Artemisia annua is very rich in secondary metabolites such as monoterpenes, sesquiterpenes and phenolic compounds, of which the biological properties have been extensively studied. The purpose of this review is to gather and describe the data concerning the main chemical components produced by Artemisia annua and to describe the state of the art about the biological activities reported for this plant and its compounds beyond malaria.
... It was determined that artesunate (4) causes changes in the reproductive system of Fasciola hepatica [144]. Antiviral activity of artesunate is displayed against the hepatitis B virus [157] and the hepatitis C virus [158], the herpes virus (HHV) type 4 and type 6 [159,160], human cytomegalovirus (HCMV) [161][162][163], including therapy-resistant mutants of human cytomegalovirus [164]. Artesunate (4) is prepared by reaction of dihydroartemisinin (2) with succinic anhydride in basic conditions (Scheme 35) [152]. ...
... Artesunate (4) is prepared by reaction of dihydroartemisinin (2) with succinic anhydride in basic conditions (Scheme 35) [152]. [157] and the hepatitis C virus [158], the herpes virus (HHV) type 4 and type 6 [159,160], human cytomegalovirus (HCMV) [161][162][163], including therapy-resistant mutants of human cytomegalovirus [164]. Artesunate (4) is prepared by reaction of dihydroartemisinin (2) with succinic anhydride in basic conditions (Scheme 35) [152]. ...
... Dehydration and deprotection resulted in phenol 204, which formed a series of compounds 205 by reaction with derivatives of carboxylic and sulfonic acids [165]. hepatitis В virus [157] and the hepatitis C virus [158], the herpes virus (HHV) type 4 and type 6 [159,160], human cytomegalovirus (HCMV) [161][162][163], including therapy-resistant mutants of human cytomegalovirus [164]. Artesunate (4) is prepared by reaction of dihydroartemisinin (2) with succinic anhydride in basic conditions (Scheme 35) [152]. ...
The biological activity of organic peroxides is usually associated with the antimalarial properties of artemisinin and its derivatives. However, the analysis of published data indicates that organic peroxides exhibit a variety of biological activity, which is still being given insufficient attention. In the present review, we deal with natural, semi-synthetic and synthetic peroxides exhibiting anthelmintic, antiprotozoal, fungicidal, antiviral and other activities that have not been described in detail earlier. The review is mainly concerned with the development of methods for the synthesis of biologically active natural peroxides, as well as its isolation from natural sources and the modification of natural peroxides. In addition, much attention is paid to the substantially cheaper biologically active synthetic peroxides. The present review summarizes 217 publications mainly from 2000 onwards.
... It has been described that ART inhibits the replication of human cytomegaloviruses in several cell lines (Efferth et al. 2002;Schnepf et al. 2011). In addition, ART displays a potent antiviral effect against hepatitis B virus (Romero et al. 2005) and human herpesvirus-6 (Milbradt et al. 2009). Furthermore, ART can also inhibit the replication of Epstein-Barr virus and human JC polyomavirus dose-dependently in cells (Auerochs et al. 2011). ...
... However, treatment with ART or DHA profoundly inhibited the genomic RNA synthesis and N mRNA transcription of RABV, leading to inhibition of RABV replication. ART-mediated inhibition of viral gene expression has been documented in human cytomegaloviruses, herpesviruses and Epstein-Barr virus (Efferth et al. 2002;Milbradt et al. 2009;Auerochs et al. 2011). Therefore, here we propose that ART and DHA may execute the antiviral action by blocking the viral gene expression of RABV, thereby inhibiting the synthesis of viral proteins and consequently preventing the onset of subsequent steps of the viral lytic replication cycle. ...
Rabies is caused by infection of rabies virus (RABV) and remains a serious threat to the global public health. Except for the requirement for cold chain and high cost of human rabies immune globulin, no small molecule drugs are currently available for clinical treatment of rabies. So, it is of great importance to identify novel compounds that can effectively inhibit RABV infection. Artesunate (ART) and dihydroartemisinin (DHA), two derivatives of artemisinin, are widely used for treatment of malaria in adults and children, showing high safety. In this study, we found that both ART and DHA were able to inhibit RABV replication in host cells at a low concentration (0.1 μmol/L). The antiviral effects of ART and DHA were independent of viral strains and cell lines. Pre-treatment with ART or DHA for 2 h in vitro did not affect the viral replication in host cells, implying that ART and DHA neither reduced the viability of RABV directly nor inhibited the binding and entrance of the virus to host cells. Further studies revealed that ART and DHA inhibited RABV genomic RNA synthesis and viral gene transcription. Treatment with ART or DHA (5 mg/kg) by intramuscular injection improved, to some extent, the survival rate of RABV-challenged mice. Combination treatment with derivatives of artemisinin and mannitol significantly improved the survival rate of RABV-challenged mice. The results suggest that ART and DHA have a great potential to be explored as new anti-rabies agents for treatment of rabies.
... AS was effective at a low micromolar range against Epstein Barr virus (EBV) in both epithelial cells and lymphocytes [50]. Antiviral activity against human herpes virus-6 (HHV-6) was demonstrated not only in vitro [51] but also in a child affected by HHV-6B-associated myocarditis. AS treatment was associated with a decrease in the levels of HHV-6B DNA in the myocardium [52]. ...
... Among the ART derivates, some showed strong activities against viruses, such as AS against HCMV, ART, and AS against HBV and HCV, and AS against HPV and HPyV, whereas data regarding the activity against HIV are uncertain. Sulfonamides in vitro [182] HCMV Artemisinin in vitro [16] Artesunate in vitro [10,11,16,17,[24][25][26][27][28][29][30][31][32][33][34] Arthemeter in vitro [61,62] HHV-6 Artesunate in vitro [51,53] HHV-6B Artesunate in vitro [52] KSHV Doxycycline in vitro [183] HSE Artemisinin in vivo (mouse) [35] Dihydroartemisinin in vitro [16] KSHV Sulfonamides in vitro [183] RCMV Artesunate in vivo (rat) [11] Polyomaviridae BKPyV Artesunate in vitro [55] JCPyV Artesunate in vitro [54] Mefloquine in vitro [71] Hepadnaviridae HBV Artemisinin, artesunate in vitro [17] Papillomaviridae HPV Artemisinin in vitro [18] Dihydroartemisinin in vivo (dog) [19] Doxycycline in vitro [177] [187,188] Dihydroartemisinin in vitro [63] HCV Artemisinin in vitro [20][21][22] Artesunate in vitro [57] Chloroquine in vitro [148][149][150] ZIKV Mefloquine in vitro [130,131] Chloroquine in vitro [140,141] Amodiaquine in vitro [140] Atovaquone in vitro [166] DENV Quinine sulfate in vitro [66] Mefloquine in vitro [131] Halofantrine in vitro [134] Doxycycline in vitro [168,178] Amodiaquine in vitro [162] CHIKV Doxycycline in vitro [169] Chloroquine in vitro [37,138,139] Atovaquone in vitro [166] Togaviridae SFV Halofantrine in vitro [134] Rhabdoviridae VSV Doxycycline in vitro [170] Orthomyxoviridae IAV Quinine sulfate in vitro [70] In vivo (mouse) [67] Mefloquine in vitro [70] Doxycycline in vivo (mouse) [171] Chloroquine in vitro [159] [145][146][147] Picornaviridae Enteroviruses Chloroquine in vitro [160] Chloroquine in vitro/in vivo (mouse) [161] Filoviridae EBOV Chloroquine in vitro [142,143] in vivo [142] Artesunate, amodiaquine in vivo [58] Mefloquine in vitro [132] Retroviridae HIV Artemisinin in vitro [23] Doxycycline in vitro [23] Mefloquine, toremifene, posaconazole in vitro [132] Chloroquine in vitro [151,157,158] in vivo [155] Chloroquine, hydroxychloroquine in vitro [152][153][154]156] Phenuiviridae SFTSV Amodiaquine In vitro [163] Among the aryl-aminoalcohols, the use of MQ in the treatment of JCPyV infection has been extensive, although with contradictory outcomes. Among the aminoquinolines, both CQ and hydroxyCQ showed promising results in reducing the replication of some emerging viruses, such as DENV and ZIKV. ...
In recent decades, drugs used to treat malaria infection have been shown to be beneficial for many other diseases, including viral infections. In particular, they have received special attention due to the lack of effective antiviral drugs against new emerging viruses (i.e., HIV, dengue virus, chikungunya virus, Ebola virus, etc.) or against classic infections due to drug-resistant viral strains (i.e., human cytomegalovirus). Here, we reviewed the in vitro/in vivo and clinical studies conducted to evaluate the antiviral activities of four classes of antimalarial drugs: Artemisinin derivatives, aryl-aminoalcohols, aminoquinolines, and antimicrobial drugs.
... Artemisinin, its semisynthetic drug artesunate and related chemical derivatives represent promising antiherpesviral lead compounds, which have first been investigated by our group Chou et al., 2011;Efferth et al., 2002Efferth et al., , 2008Fröhlich et al., 2017;Held et al., 2017;Hutterer et al., 2015;Reiter et al., 2015aReiter et al., , 2015bShapira et al., 2008;Sharma et al., 2014aSharma et al., , 2014bWolf et al., 2011) and also by other researchers (Arav-Boger et al., 2010;Barger-Kamate et al., 2016;Cai et al., 2014;Flobinus et al., 2014;Germi et al., 2014;He et al., 2013He et al., , 2011He et al., , 2012Ho et al., 2014;Roy et al., 2015;Stuehler et al., 2015;Zeng et al., 2015). In addition to its antimalaria activity, artesunate possesses a relatively broad antiviral activity that extends over HCMV to other herpesviruses and even human pathogenic viruses from other families Efferth et al., 2008;Jana et al., 2017;Milbradt et al., 2009;Morere et al., 2015;Paeshuyse et al., 2006;Qian et al., 1982;Romero et al., 2005Romero et al., , 2006Sharma et al., 2014a;Sharma et al., 2014b). The very promising potential of the entire group of artemisinin compounds (chemical class trioxanes/sesquiterpenes) has been confirmed by demonstrating the increase of antiviral efficacy when applying the chemical hybridization concept Tsogoeva, 2010). ...
... The determination of cytotoxic effects was performed as described earlier (Milbradt et al., 2009). Cells were seeded in triplicates in 96-well plate format and incubated 24 h with increasing concentrations of the compounds. ...
Human cytomegalovirus (HCMV) is a major human pathogen and is associated with severe pathology, such as life-threatening courses of infection in immunocompromised individuals and neonates. Currently, antiviral therapy is still hampered by a considerable toxicity of the available drugs and induction of viral resistance. Recently, we and others reported the very potent antiviral activity of the broad antiinfective drug artesunate in vitro and in vivo. Here, we investigated further optimized analogs including monomeric, dimeric and trimeric derivatives belonging to this highly interesting chemical group of experimental drugs (sesquiterpenes/trioxanes) and compared these to the previously identified trimeric artesunate compound TF27. We could demonstrate that (i) seven of the eight investigated monomeric, dimeric and trimeric artesunate derivatives, i.e. TF79, TF85, TF87, TF93.2.4, TF111, TF57a and TF57ab, exerted a strong anti-HCMV activity in primary human fibroblasts, (ii) the EC50values ranged in the low to sub-micromolar concentrations and indicated a higher antiviral potency than the recently described artesunate analogs, (iii) one trimeric compound, TF79, showed a very promising EC50of 0.026 ± 0.002 μM, which even exceled the antiviral potency of TF27 (EC500.04 ± 0.01 μM), (iv) levels of cytotoxicity (quantitative measurement of lactate dehydrogenase release) were low in a range between 100 and 30 μM and thus different from antiviral concentrations, (v) an analysis of protein expression levels indicated a potent block of viral protein expression, and (vi) data from a NF-κB reporter cell system strongly suggested that these compounds share the same antiviral mechanism. Taken together, our data on these novel compounds strongly encourages our earlier concept on the oligomerization and hybridization of artesunate analogs, providing an excellent platform for the generation of antiherpesviral drugs.
... Artesunate (ART), a semisynthetic compound derived from the natural product artemisinin, is commonly used in the treatment of severe malaria. In addition, ART and chemical ART derivatives exert a very interesting profile of antiviral activities both in vitro and in vivo (Arav-Boger et al., 2010;Auerochs et al., 2011;Cai et al., 2014;Chou et al., 2011;Efferth et al., 2002Efferth et al., , 2008Flobinus et al., 2014;He et al., 2011He et al., , 2012He et al., , 2013Kaptein et al., 2006;Milbradt et al., 2009;Reiter et al., 2015aReiter et al., , 2015bSharma et al., 2014aSharma et al., , 2014b. To date, a limited number of clinical antiviral treatments (name patient programs, mostly HCMV) have been conducted with ART, in some cases leading to an efficient control of viral infection (Germi et al., 2014;Shapira et al., 2008), but in other cases showing poor benefit or even treatment failure (Lau et al., 2011;Wolf et al., 2011). ...
... The broad spectrum of antiviral activities of ART, spanning a number of alpha-, beta-and gammaherpesviruses and other DNA viruses (e.g. human polyomaviruses BK and JC; Sharma et al., 2014aSharma et al., , 2014b has been illustrated by numerous studies (Efferth et al., 2002DeMeritt et al., 2006;Kaptein et al., 2006;Milbradt et al., 2009;Arav-Boger et al., 2010;Auerochs et al., 2011;He et al., 2011He et al., , 2012He et al., , 2013Cai et al., 2014;Flobinus et al., 2014;Ho et al., 2014;Reiter et al., 2015aReiter et al., , 2015bRoy et al., 2015). Here we compared the antiviral activity of a selection of animal pathogenic betaherpesviruses, namely cytomegaloviruses of rats (RCMV), guinea pigs (GPCMV), mice (MCMV) and humans (HCMV). ...
Infection with human cytomegalovirus (HCMV) is a serious medical problem, particularly in immunocompromised individuals and neonates. The success of standard antiviral therapy is hampered by low drug compatibility and induction of viral resistance. A novel strategy is based on the exploitation of cell-directed signaling inhibitors. The broad antiinfective drug artesunate (ART) offers additional therapeutic options such as oral bioavailability and low levels of toxic side-effects. Here, novel ART-derived compounds including dimers and trimers were synthesized showing further improvements over the parental drug. Antiviral activity and mechanistic aspects were determined leading to the following statements: (i) ART exerts antiviral activity towards human and animal herpesviruses, (ii) no induction of ART-resistant HCMV mutants occurred in vitro, (iii) chemically modified derivatives of ART showed strongly enhanced anti-HCMV efficacy, (iv) NF-κB reporter constructs, upregulated during HCMV replication, could be partially blocked by ART treatment, (v) ART activity analyzed in stable reporter cell clones indicated an inhibition of stimulated NF-κB but not CREB pathway, (vi) solid-phase immobilized ART was able to bind to NF-κB RelA/p65, and (vii) peptides within NF-κB RelA/p65 represent candidates of ART binding as analyzed by in silico docking and mass spectrometry. These novel findings open new prospects for the future medical use of ART and ART-related drug candidates.
... Antiviral assays. Antiviral assays were established for a selection of human and animal viruses used for the infection of a set of different primary and immortalized cells types as described earlier (13,20,22,(24)(25)(26)(27). Specifically, a green fluorescent protein (GFP)-based viral replication assay was performed with HCMV AD169-GFP in HFFs as previously described (13). ...
... Cytotoxicity and cell proliferation assays. Assays measuring distinct parameters of cytotoxicity and/or cell proliferation were performed as described earlier (25,27). In brief, a trypan blue exclusion assay was performed with cultured cells seeded in 24-well plates and incubated with increasing concentrations of antiviral compounds (range, 0.1 to 50 M) for the durations indicated. ...
Protein kinases represent central and multifunctional regulators of a balanced virus-host interaction. Cyclin-dependent protein kinase 7 (CDK7) plays crucial regulatory roles in cell cycle and transcription, both connected with the replication of many viruses. Previously, we developed a CDK7 inhibitor, LDC4297, that inhibits CDK7 in vitro in the nano-picomolar range. Novel data from a kinome-wide evaluation (>330 kinases profiled in vitro) demonstrate a kinase selectivity. Importantly, we provide first evidence for the antiviral potential of the CDK7 inhibitor LDC4297, i.e., in exerting a block of the replication of human cytomegalovirus (HCMV) in primary human fibroblasts at nanomolar concentrations (EC50 24.5 ± 1.3 nM). As a unique feature compared to approved anti-herpesviral drugs, inhibition occurred already at the immediate early level of HCMV gene expression. The mode of antiviral action was considered multifaceted since CDK7-regulated cellular factors that are supportive of HCMV replication were substantially affected by the inhibitors. An effect of LDC4297 was identified in the interference with HCMV-driven inactivation of retinoblastoma protein (Rb), a regulatory step generally considered as a hallmark of herpesviral replication. In line with this finding, a broad inhibitory activity of the drug could be demonstrated against a selection of human and animal herpesviruses and adenoviruses, whereas other viruses only showed intermediate drug sensitivity. Summarized, the CDK7 inhibitor LDC4297 is a promising candidate for further antiviral drug development, possibly offering new options for a comprehensive approach to antiviral therapy.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
... Though a number of drugs have been explored in vitro and in a limited number of patients, no anti-JCPyV drug with proven efficacy is yet available (reviewed in reference 3). Artesunate is recommended by the WHO for the treatment of severe malaria, in particular with multidrug-resistant malaria (27), and has shown broad antiviral activity in vitro (28)(29)(30)(31)(32)(33). Apparently, it has been successfully used to treat four transplant patients with recurrent multidrug-resistant cytomegalovirus (CMV) infection (34,35) and one child with human herpesvirus 6 infection (36), but it did not give satisfactory results in other patients (35,37,38). ...
... Similar to the 65% reduction of the extracellular BKPyV load found in RPTECs (39), 10 M artesunate reduced the extracellular JCPyV DNA load by 75%, and this correlated with a decrease in the number of VP1-expressing cells and in infectious progeny release. The EC 50 of 2.9 M was in the same range as that found for BKPyV (4.2 M) (39) and for herpesviruses (2.16 to 7.21 M) (29,31,(50)(51)(52), although different host cells were used. Artesunate affects a very early stage of herpesvirus infection, but the mechanism seems to be the inhibition of cellular pathways (50). ...
The human JC polyomavirus (JCPyV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). A growing number of patients with induced or acquired immunosupression are at risk and no effective antiviral therapy is presently available. The widely used antimalarial drug artesunate has shown broad antiviral activity in vitro but, as yet, limited clinical success. The aim of this study was to investigate the effect of artesunate on JCPyV replication in vitro. The permissivity for JCPyV MAD-4 was first compared in four cell lines, and the monkey kidney cell line COS-7 was selected. Artesunate caused a concentration-dependent decrease in extracellular JCPyV DNA load 96 hours postinfection with an EC50 of 2.9 μM. This effect correlated with a decreased expression of capsid protein VP1, and a reduced release of infectious viral progeny. For concentrations below 20 μM, a transient reduction in cellular DNA replication and proliferation was seen, while for higher concentrations, some cytotoxicity was detected. A selective index of 16.6 was found when cytotoxicity was calculated based on cellular DNA replication in mock-infected cells but interestingly cellular DNA replication in JCPyV-infected cells was stronger affected. In conclusion, artesunate is efficacious in inhibiting JCPyV replication at micromolar concentrations which are achievable in plasma. The inhibition at EC50 probably reflects an effect on cellular proteins and involves transient cytostatic effects. Our results together with the favorable distribution of the active metabolite dihydroartemisinin to the central nervous system, suggests a potential use in patients with PML.
... Recently, a patient with multidrug-resistant herpes simplex virus 2 (HSV-2) infection (22) and a child with human herpesvirus 6B (HHV-6B) myocarditis (23) were successfully treated with artesunate. In addition, antiviral activity in vitro has also been found against other herpesviruses, including herpes simplex virus 1 (17), Epstein-Barr virus (24), and human herpesvirus 6A (25), and also to some extent against nonherpesviruses, such as hepatitis B virus (26), hepatitis C virus (27), HIV-1 (17), and bovine viral diarrhea virus (28). Moreover, artesunate has been reported to be active against cancer cells and parasites (reviewed in reference 27). ...
... We calculated a SI 50 of only 0.6. Since the EC 50 was found to be in the same range as that reported for herpesviruses (1.5 to 6.4 M) (24,25,48,51), the low SI 50 mainly resulted from the low CC 50 of only 2.4 M. However, unlike most researchers, we calculate the CC 50 using the very sensitive BrdU assay. ...
Polyomavirus BK (BKV) causes polyomavirus-associated nephropathy (PyVAN) and hemorrhagic cystitis (PyVHC) in renal- and bone marrow transplant patients respectively. Antiviral drugs with targeted activity against BKV are lacking. Since the antimalarial drug artesunate recently demonstrated antiviral activity, possible effects of artesunate on BKV replication were explored in human primary renal proximal tubular epithelial cells (RPTECs), the host cells in PyVAN.At 2h post-infection (hpi), RPTECs were treated with artesunate concentrations from 0.3 to 80 μM. After one viral replication cycle (∼72 hpi), extracellular BKV DNA loads reflecting viral progeny production were reduced in a concentration-dependent manner. Artesunate at 10 μM reduced extracellular BKV load by 65%, early LT-ag mRNA and protein expression by 30% and 75%, DNA replication by 73%, and late VP1 mRNA and protein expression by 47% and 64%, respectively. Importantly, the proliferation of RPTECs was also inhibited in a concentration-dependent manner. At 72 hpi, artesunate at 10 μM reduced cellular DNA replication by 68% and total metabolic activity by 47%. Cell impedance and LDH measurements indicated cytostatic but not cytotoxic mechanism. Flow cytometry and EdU incorporation revealed decreased cell numbers in S-phase and suggested cell cycle arrest in G0 or G2. The anti-proliferative and anti-viral effects of artesunate 10 μM were both reversible. Thus, artesunate inhibits BKV replication in RPTECs in a concentration-dependent manner by inhibiting BKV gene expression and genome replication. The antiviral mechanism appears to be closely connected to cytostatic effects on the host cell, underscoring the dependence of BKV on host cell proliferative functions.
... In the last decade, it has been repeatedly reported that this class of compounds possesses additional activities against human diseases including cancer, diabetes, and viral infections [3][4][5][6][7]. The antiviral activity of ART and related compounds was particularly demonstrated for human cytomegalovirus (HCMV) [8-10], a number of additional herpesviruses [6,11,12], and even other pathogenic human viruses [7,[13][14][15][16][17]. Based on the initial promising anti-HCMV activity of ART, a 10-to 100-fold improvement in antiviral activity was achieved by applying a chemical hybridization concept to yield ART multimers, i.e., compounds that combine coupled trioxane moieties [10,[18][19][20], or conjugates of ART to other bioactive compounds [18,[21][22][23][24][25]. ...
Starting in 2019, the spread of respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated pandemic of the corona virus disease (COVID-19) has led to enormous efforts in the development of medical countermeasures. Although innovative vaccines have scaled back the number of severe COVID cases, the emergence of the omicron variant (B.1.1.529) illustrates how vaccine development struggles to keep pace with viral evolution. On the other hand, while the recently approved antiviral drugs remdesivir, molnupiravir, and Paxlovid are considered as broadly acting anti-coronavirus therapeutics, only molnupiravir and Paxlovid are orally available and none of these drugs are recommended for prophylactic use. Thus, so far unexploited small molecules, targeting strategies, and antiviral mechanisms are urgently needed to address issues in the current pandemic and in putative future outbreaks of newly emerging variants of concern. Recently, we and others have described the anti-infective potential and particularly the pronounced antiviral activity of artesunate and related compounds of the trioxane/sesquiterpene class. In particular, the trimeric derivative TF27 demonstrated strong anti-cytomegalovirus activity at nanomolar concentrations in vitro as well as in vivo efficacy after oral administration in therapeutic and even prophylactic treatment settings. Here, we extended this analysis by evaluating TF27 for its anti-SARS-CoV-2 potential. Our main findings are as follows: (i) compound TF27 exerted strong anti-SARS-CoV-2 activity in vitro (EC50 = 0.46 ± 0.20 µM), (ii) antiviral activity was clearly distinct from the induction of cytotoxicity, (iii) pretreatment with TF27 prevented virus replication in cultured cells, (iv) antiviral activity has likewise been demonstrated in Calu-3 human lung and Caco-2 human colon cells infected with wild-type, delta, or omicron SARS-CoV-2, respectively, and (v) analysis of TF27 combination treatments has revealed synergistic interaction with GC376, but antagonistic interaction with EIDD-1931. Combined, the data demonstrated the pronounced anti-SARS-CoV-2 activity of TF27 and thus highlight the potential of trioxane compounds for further pharmacologic development towards improved options for COVID-specific medication.
... The ethanolic extract of whole plants of A. annua showed potent antiviral activities with 50% effective concentration (EC 50 ) values of 34.5 (±2.6) and 39.2 (±4.1) µg/mL against the SARS-CoV-1 viral strains BJ-001 and BJ-006, respectively, with a CC 50 value of 1053.0 ± 92.8 µg/mL in a cytotoxicity assay [47]. Ethnopharmacological studies of Artemisia and its constituents have also revolved around their retroviral properties [43,[47][48][49][50], capacity to minimize the replication of herpes viruses [43,[51][52][53][54], and activity against bovine viral diarrhoea, Epstein-Barr virus, hepatitis B virus, and hepatitis C virus [55][56][57][58][59][60][61][62]. Interestingly, derivatization enhanced the antiviral activity of artemisinin as its derivatives, i.e., artesunate, artemether, and arteether, including dimer and trimer molecules, exhibited potent antiviral activities [62]. ...
As the world desperately searches for ways to treat the coronavirus disease 2019 (COVID-19) pandemic, a growing number of people are turning to herbal remedies. The Artemisia species, such as A. annua and A. afra, in particular, exhibit positive effects against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and COVID-19 related symptoms. A. annua is a source of artemisinin, which is active against malaria, and also exhibits potential for other diseases. This has increased interest in artemisinin’s potential for drug repurposing. Artemisinin-based combination therapies, so-called ACTs, have already been recognized as first-line treatments against malaria. Artemisia extract, as well as ACTs, have demonstrated inhibition of SARS-CoV-2. Artemisinin and its derivatives have also shown anti-inflammatory effects, including inhibition of interleukin-6 (IL-6) that plays a key role in the development of severe COVID-19. There is now sufficient evidence in the literature to suggest the effectiveness of Artemisia, its constituents and/or artemisinin derivatives, to fight against the SARS-CoV-2 infection by inhibiting its invasion, and replication, as well as reducing oxidative stress and inflammation, and mitigating lung damage.
... Recent clinical reports have stated the efficacy of artesunate, an antimalarial drug based on artemisinin, 15 in treating HHV infections. 16 It is necessary to compare the effectiveness of artesunate with a complex alternative mechanism of virostatic effect with traditional drugs valaciclovir and valganciclovir based on acyclic guanosine analogs with limited clinical efficacy. It has been shown that artesunate can be effective in managing herpes virus infections caused by multidrug-resistant strains 17 and chromosomally integrated forms 18 where valacyclovir and valganciclovir are usually ineffective. ...
The study aimed to compare the efficacy of valaciclovir, valganciclovir, and artesunate in treating chronic reactivated HHV‐6 and HHV‐7 associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). From 255 patients with reactivated HHV‐6 and HHV‐7 infections (blood leukocyte PCR) in 192 cases, valaciclovir, valganciclovir, or artesunate were administered at a dose of 3,000, 900, and 100 mg per day, respectively, for 3 months (study group). The control group consisted of similar 63 ME/CFS patients not taking any antiviral drugs. The significance of differences was evaluated by Student's T‐test and the non‐parametric criterion – the number of Z‐signs. Negative PCR results in HHV6 and HHV‐7 treated with valaciclovir was achieved in 26% and 23% (first), 34%, and 28% (second), 37% and 34% of cases (third month), respectively (p<0.05; Z<Z0.05). The same results with valganciclovir were obtained in 35% and 33% (first), 44% and 39% (second), 48% and 45% (third month), but with artesunate – in 44% and 41% (first), 57% and 53% (second), 68% and 63% of cases (third month), respectively (p<0.05; Z<Z0.05). Artesunate is more effective than valganciclovir and valacyclovir in ME/CFS patients with reactivated HHV‐6 and HHV‐7 infections. This article is protected by copyright. All rights reserved.
... Artesunate is a medication approved for the treatment of severe malaria which has been shown to be effectively against HHV-6 by reducing early and late viral protein synthesis at a relatively safe concentration. 84 Hakacova et al. 85 reported a case of HHV-6 myocarditis that was successfully treated with artesunate in a pediatric patient. ...
Human cytomegalovirus and Epstein–Barr virus have been recognized as potential drivers of morbidity and mortality of patients undergoing allogeneic stem cell transplantation for years. Specific protocols for monitoring, prophylaxis and pre-emptive therapy are in place in many transplant settings. In this review, we focus on the next three most frequent viruses, human herpesvirus-6, BK virus and adenovirus, causing reactivation and/or viremia after allogeneic transplant, which are increasingly detected in patients in the post-transplant period owing to emerging techniques of molecular biology, recipients’ characteristics, treatment modalities used for conditioning and factors related donors or stem cell source. Given the less frequent detection of an illness related to these viruses, there are often no specific protocols in place for the management of affected patients. While some patients develop significant morbidity (generally older), others may not need therapy at all (generally younger or children). Furthermore, some of the antiviral therapies used are potentially toxic. With the addition of increased risk of secondary infections, risk of graft failure or increased risk of graft- versus-host disease as well as the relationship with other post-transplant complications, the outcomes of patients with these viremias remain unsatisfactory and even long-term survivors experience increased morbidity.
... had earlier been reported to consist of essential phytochemicals that contribute to its inhibitory role against viruses (Bora and Sharma 2010). Before the outbreak of COVID-19, some ethnopharmacological studies on Artemisia derivatives revolved around their retroviral properties (Efferth 2018;Jana et al. 2017;Laila et al. 2019;Lubbe et al. 2012), capacity to minimize the replication of herpes viruses (Efferth et al. 2008;Milbradt et al. 2009;Naesens et al. 2006;Nagamune et al. 2007) and inhibition of hepatitis B and C viruses (Dai et al. 2016;Paeshuyse et al. 2006;Qi et al. 2013;Romero et al. 2005), etc. Noteworthily, the bioactive constituents present in A. annua have demonstrated activity against several viruses such as bovine viral diarrhoea (Romero et al. 2006 Lin et al. (2003). The presence of flavonoids, quercetin, and di-caffeoylquinic acid in the plant inhibits the activity of MERS-CoV-3 CLPro, an enzyme that is similarly produced by SARS-CoV-2 (Jo et al. 2019(Jo et al. , 2020. ...
The search for a potent anti-coronavirus therapy for severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) remains an overwhelming task since the outbreak of COVID-19. It is more evident that most of the existing antiviral and immune-boosting drugs are non-promising and ineffective for the treatment of coronavirus infected patients while the safety of a few drugs/vaccines that have demonstrated high potential remains unclear. With daily records of confirmed infectious cases across the world, it is crucial to emphasize the need for repurposed therapies with a validated ethnomedicinal base focused on well-known active medicines with traceable biochemical, pharmacological and safety profiles for viral infection management. In the present study, recent literature on Artemisia and Artemisia-based products for the management of COVID-19 are reviewed. Artemisia-based products have demonstrated a broad spectrum of biological ability including antiviral properties. Besides its antiviral activity, Artemisia annua have shown to contain appreciable amounts of minerals such as zinc, gallium and selenium among others. Graphic abstract
... Artemisinin, its semisynthetic derivative artesunate (ART) and related chemical compounds represent a promising antiherpesviral lead compound scaffold, which has intensively been investigated by our research group [14][15][16][17][18][19][20][21][22][23][24][25][26][27] and by other researchers [28][29][30][31][32][33][34][35][36][37][38][39]. While the original drug artemisinin proved to be poor in anticytomegaloviral activity, its semisynthetic derivative ART possessed a relatively broad antiviral activity that extended over HCMV to other herpesviruses and even human pathogenic viruses of other families [17,23,24,[40][41][42][43][44][45][46][47]. The very promising potential of the entire group of artemisinin compounds (a chemical class of trioxanes/sesquiterpenes) has been confirmed by an increase in antiviral efficacy when applying the chemical hybridization concept [18,19,48]. ...
Human cytomegalovirus (HCMV) is a major human pathogen associated with severe pathology. Current options of antiviral therapy only partly satisfy the needs of a well-tolerated long-term treatment/prophylaxis free from drug-induced viral resistance. Recently, we reported the strong antiviral properties in vitro and in vivo of the broad-spectrum anti-infective drug artesunate and its optimized derivatives. NF-κB signaling was described as a targeting mechanism and additional target proteins have recently been identified. Here, we analyzed the autofluorescent hybrid compound BG95, which could be utilized for intracellular visualization by confocal imaging and a tracking analysis in virus-infected primary human fibroblasts. As an important finding, BG95 accumulated in mitochondria visualized by anti-prohibitin and MitoTracker staining, and induced statistically significant changes of mitochondrial morphology, distinct from those induced by HCMV infection. Notably, mitochondrial membrane potential was found substantially reduced by BG95, an effect apparently counteracting efficient HCMV replication, which requires active mitochondria and upregulated energy levels. This finding was consistent with binding properties of artesunate-like compounds to mitochondrial proteins and thereby suggested a new mechanistic aspect. Combined, the present study underlines an important role of mitochondria in the multifaceted, host-directed antiviral mechanism of this drug class, postulating a new mitochondria-specific mode of protein targeting.
... For decades these drugs have been used as a well-tolerated first-line treatment of severe malaria (Dondorp et al., 2005). More recently, promising results have been published that demonstrate the pronounced and broad antiviral potency of ART-related trioxane compounds directed against certain human herpesviruses (Auerochs et al., 2011;Milbradt et al., 2009), especially HCMV (Efferth et al., 2008). TF27 is a trimeric derivative of ART with an anti-HCMV activity at nanomolar concentrations (Fröhlich et al., 2018a,b,c;Hahn et al., 2018;Hutterer et al., 2015;Reiter et al., 2015). ...
Human cytomegalovirus (HCMV) causes serious and even life-threatening diseases, particularly upon congenital or post-transplant infection. Treatment of HCMV infections with currently available drugs targeting viral enzymes is often limited by severe side effects and the emergence of drug-resistant viruses. To avoid this problem, novel therapeutic options directed to host proteins involved in virus replication are being investigated. Recently, we described the pronounced antiherpesviral activity of the trimeric artesunate derivative TF27 at low nanomolar concentrations in vitro and in vivo. In the present study, we report first data on the prophylactic efficacy of TF27 against human and murine CMV and the oncogenic avian alphaherpesvirus Marek’s disease virus (MDV). The main findings of this study are (i) a pronounced activity of the experimental drug TF27 against alpha- and betaherpesviruses in vitro upon prophylactic treatment and (ii) a therapeutic and prophylactic efficacy upon oral treatment in an immunocompetent mouse model. Moreover, our data highlight (iii) the tolerability of orally administered TF27 free of compound-associated adverse events and further confirms (iv) the suitability of cellular factors as primary antiviral targets. Thus, we provide evidence for therapeutic and prophylactic antiherpesviral efficacy of TF27 upon oral treatment in immunocompetent hosts and thereby underline its potential for future antiviral drug development.
... Other potentially efficient nucleoside or nucleotide analogues are currently in preclinical development or in early clinical trials (94,95,105,106). Artesunate, a derivative of artemisinin used for the treatment of malaria, has been shown to inhibit the replication of CMV and HHV-6 and was used to treat CMV infections in vivo as a compassionate use (107,108). Recently, the use of complementary immunotherapy, particularly in the context of HSCT, has been considered using polyclonal cytotoxic T lymphocytes targeted to several opportunistic viruses, including HHV-6 (28, 94). The concept of an adoptive therapy based on T-cells is very attractive, due to the possibility of circumventing drug cytotoxicity and resistance, but requires a validation in ongoing clinical trials. ...
... 92 JQ1 preferentially represses EBV+ NPC cells partially through repressing c-Myc and is therefore a promising therapeutic candidate for advanced NPC. 93 Artesunate, best known as an antimalarial drug, is known to inhibit herpesvirus replication. 94 Artesunate has been shown to inhibit EBV replication in both epithelial cells and lymphocytes. The mode of action is through a block on viral immediate early protein synthesis. ...
Epstein-Barr virus (EBV) is a ubiquitous human virus which infects almost all humans during their lifetime and following the acute phase, persists for the remainder of the life of the individual. EBV infects B lymphocytes leading to their immortalisation, with persistence of the EBV genome as an episome. In the latent phase, EBV is prevented from reactivating through efficient cytotoxic cellular immunity. EBV reactivates (lytic phase) under conditions of psychological stress with consequent weakening of cellular immunity, and EBV reactivation has been shown to occur in a subset of individuals with each of a variety of cancers, autoimmune diseases, the autoimmune-like disease, chronic fatigue syndrome/myalgic encephalitis and under other circumstances such as being an inpatient in an intensive care unit. Chronic EBV reactivation is an important mechanism in the pathogenesis of many such diseases, yet is rarely tested for in immunocompetent individuals. This review summarises the pathogenesis of EBV infection, EBV reactivation and its role in disease, and methods which may be used to detect it. Known inhibitors of EBV reactivation and replication are discussed, including drugs licensed for treatment of other herpesviruses, licensed or experimental drugs for various other indications, compounds at an early stage of drug development and nutritional constituents such as vitamins and dietary supplements.
... Reported EC 50 values for artesunate were relatively low, with data available for CMV (3.7 μM), EBV (1.5-7.21 μM), and HHV-6A (3.8 μM), but no data were available for HHV-8, HSV-1, HSV-2, and VZV (Appendix I(Kaptein et al., 2006;Marschall et al., 2012;Milbradt et al., 2009)). ...
Background:
Double-stranded (ds) DNA virus infections often occur concomitantly in immunocompromised patients. We performed a systematic search of published in vitro activity for nine approved and investigational antivirals to understand the spectrum of in vitro activity against dsDNA viruses.
Methods:
A literature search was performed (PubMed and the WoS Core Collection) using keywords related to: 1) targeted approved/developmental antivirals (acyclovir, artesunate, brincidofovir, cidofovir, cyclopropavir (filociclovir), foscarnet, ganciclovir, letermovir, and maribavir); 2) pathogenic dsDNA viruses; 3) in vitro activity. We summarized data from 210 publications.
Results:
Activity against ≤3 viruses was documented for maribavir (cytomegalovirus, Epstein-Barr virus), and letermovir, while activity against > 3 viruses was shown for ganciclovir, cidofovir, acyclovir, foscarnet, cyclopropavir, artesunate, and brincidofovir. The EC50 values of brincidofovir were the lowest, ranging from 0.001 to 0.27 μM, for all viruses except papillomaviruses. The next most potent agents included cidofovir, ganciclovir, foscarnet, and acyclovir with EC50 values between 0.1 μM and >10 μM for cytomegalovirus, herpes simplex virus, and adenovirus.
Conclusion:
Most of the identified antivirals had in vitro activity against more than one dsDNA virus. Brincidofovir and cidofovir have broad-spectrum activity, and brincidofovir has the lowest EC50 values. These findings could assist clinical practice and developmental research.
... [45][46][47] HHV-6 has been shown to be sensitive to Artesunate and was used for the first time in a recent case study to treat a child with HHV-6 associated myocarditis. 48,49 Artesunate is a drug already approved for the treatment of malaria and is widely available in Africa and could present a good drug candidate for future pilot trials looking at treating HHV-6 positive FSE in this population. ...
Background
Human herpesvirus 6B (HHV‐6B) is the causative agent of Roseola infantum, and has also been suggested to play a role in the pathogenesis of febrile seizures in young children, a percentage of whom go on to develop febrile status epilepticus (FSE), but existing data is conflicting and inconclusive. HHV‐6A is a distinct species, rarely detected in most parts of the world, but prior studies suggest a higher prevalence in febrile African children. We describe a case control study comparing the frequency of HHV‐6A and/or HHV‐6B infections in children with febrile seizures (including febrile status epilepticus) and a control group of febrile children without seizures.
Methods
We recruited children aged 6‐60 months admitted with a febrile illness with (cases) or without (controls) seizures presenting within 48 hours of commencement of fever. 3mls of whole blood was centrifuged and plasma stored at ‐80oC for pooled screening for HHV‐6B and HHV‐6A by Taqman Real Time PCR.
Results
102 cases and 95 controls were recruited. The prevalence of HHV‐6B DNA detection did not differ significantly between cases (5.8% (6/102)) and controls (10.5% (10/95)) but HHV‐6B infection was associated with febrile status epilepticus (OR 15; 95% CI, [1.99‐120]; p=0.009). HHV‐6A was not detected.
Conclusion
Prevalence of HHV‐6B was similar among cases and controls. Within the febrile seizure group, HHV‐6B infection was associated with FSE, suggesting HHV‐6B infections could play a role in pathogenesis of FSE.
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... This lends artesunate the ability to significantly reduce viral early protein synthesis, which cannot be accomplished with drugs targeting viral DNA polymerase. [33] Considering the tolerability, limited viral resistance, anti-inflammatory action, and good safety profile when used for malaria, artesunate should be explored as a treatment for patients who demonstrate HHV-6-associated myocarditis. [34] ...
Over the last decade, human herpes virus 6 (HHV-6) has been implicated in the etiology of pediatric myocarditis and subsequent dilated cardiomyopathy (DCM). This review provides an overview of recent literature investigating the pathophysiological relevance of HHV-6 in inflammatory cardiomyopathy. We examined 11 cases of previously published pediatric myocarditis and/or DCM associated with HHV-6 and also our experience of detection of virus particles in vascular endothelium of HHV-6 positive endomyocardial biopsy tissue by electron microscopy. The exact role of the presence of HHV-6 and its load remains controversial, as the virus is also found in the heart of healthy subjects. Therefore, the question remains open whether and how cardiac HHV-6 may be of pathogenetic importance. Quantitative polymerase chain reaction or mRNA testing allows differentiation between low level latent virus found in asymptomatic myocardium and active HHV-6 infection. Although only a small number of pediatric cases have been reported in literature, HHV-6 should be considered as a causative agent of inflammatory cardiomyopathy, especially in children under three who might be experiencing a primary infection. Future studies are needed to establish a threshold for determining active HHV-6 infection in biopsy samples, and the role of coinfections with other cardiotropic viruses.
... From these aspects, this study was focused on two key points for the discovery of new candidate substances as one of the various solutions for developing anti-Mtb drugs: first, the minimization of side effects and the safety of drugs, and second, finding novel pharmacological activity/effects of drugs causing anti-Mtb activity/effects through existing drugs which are used in other diseases. From these perspectives, new pharmacological activities/actions of artemisinin and artesunate have been consistently reported since the development of anti-malarial drugs, as follows: (1) the anti-viral activities of artesunate against human herpes viruses such as human cytomegalovirus (HCMV), herpes simplex virus 1 (HSV-1), human herpesvirus 6A (HHC-6a), and Epstein-Barr virus [21][22][23], as well as the inhibitory effect against hepatitis B virus (HBV) [24]; (2) the anti-parasitic effects of artesunate and artemisinin against the proliferation of Toxoplasma gondii [25][26][27] and the eggs of the liver flukes in an animal model [28,29]; (3) the anti-fungal activity of artemisinin against fungi, such as Cryptococcus neoformans and Aspergillus fumigates [30,31]; (4) the anti-arthritic effects of artesunate and artemisinin against rheumatoid arthritis through multi-signaling pathways in animal models [32][33][34]; (5) the anti-allergic activity of artesunate against allergic dermatitis in rat/guinea pig models [35][36][37]; (6) the anti-bacterial synergistic effects by a combination treatment of artesunate with ampicillin or oxacillin against sepsis animal models induced by Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA) [38,39]; (7) the anti-cancer effects of artemisinin, which are caused by inducing or promoting apoptosis, and by inhibiting the growth of various cancer cells such as breast, colon, leukemia, and prostate cancer cells [40][41][42][43]; (8) the anti-allergic asthma effect of artesunate in a mouse model of allergic asthma [44]. These studies have demonstrated that artesunate and artemisinin have various biological effects/pharmacological actions, as well as the potential to be used as other therapeutic agents. ...
Tuberculosis is a major infectious disease that globally causes the highest human mortality. From this aspect, this study was carried out to evaluate novel pharmacological activities/effects of artesunate and artemisinin causing anti-tubercular activity/effects against Mycobacterium tuberculosis (Mtb). The anti-Mtb activities/effects of artesunate and artemisinin were evaluated using different anti-Mtb indicator assays, such as the resazurin microtiter assay, the Mycobacteria Growth Indicator Tube (MGIT) 960 system assay, and the Ogawa slant medium assay, as well as in vivo tests. Artesunate showed selective anti-Mtb effects by strongly inhibiting the growth of Mtb compared to artemisinin, and consistently induced anti-Mtb activity/effects by effectively inhibiting Mtb in the MGIT 960 system and in Ogawa slant medium for 21 days with a single dose; its minimum inhibitory concentration was 300 µg/mL in in vitro testing. Furthermore, artesunate demonstrated an anti-tubercular effect/action with a daily dose of 3.5 mg/kg in an in vivo test for four weeks, which did not indicate or induce toxicity and side effects. These results demonstrate that artesunate effectively inhibits the growth and/or proliferation of Mtb through novel pharmacological activities/actions, as well as induces anti-Mtb activity. This study shows its potential as a potent candidate agent for developing new anti-tuberculosis drugs of an effective/safe next generation, and suggests novel insights into its effective use by repurposing existing drugs through new pharmacological activity/effects as one of the substantive alternatives for inhibiting tuberculosis.
... ganciclovir poses a risk of hematological toxicity, while foscarnet poses a risk of renal toxicity. In contrast, artesunate, an agent used clinically in the treatment of malaria, surprisingly has shown strong activity against HHV-6 in tissue culture [47], and has proven successful against HHV-6B myocarditis in a child [48] where no serious adverse side effects were noted. ...
In recent years, two outstandingly effective drugs for the treatment of multiple sclerosis (MS) have appeared on the market: Tysabri® (Biogen Idec/Elan, 2008) and Gilenya® (Novartis, 2010). Tysabri (Natalizumab) is a humanized monoclonal antibody that binds to the cellular adhesion molecule alpha-4 integrin, which is used by lymphocytes to cross vascular walls and penetrate the blood-brain barrier. Tysabri thus reduces the flux of infected or autoimmune lymphocytes into the CNS. Gilenya (Fingolimod) is an immunomodulatory drug that acts on the sphingosine-1-phosphate receptor to sequester lymphocytes in peripheral lymph nodes, thus also indirectly reducing the flux of infected or autoimmune lymphocytes into the CNS. Both drugs have great clinical promise for treating MS, but both have revealed a critical shortcoming: their use increases the risk of Progressive Multifocal Leucoencephalopathy (PML), a demyelinating disease worse than MS and quickly fatal if not controlled. PML arises in individuals whose immune function is compromised, such as patients undergoing chemotherapy for various kinds of cancer. During the early years of the AIDS epidemic (approximately from 1986-1999), the incidence of PML rose in parallel with increasing numbers of immunocompromised AIDS patients, then fell after effective combined aggressive retrovirus treatment (cART) for HIV-1/AIDS became widely available (after 2000-2001). Unfortunately, the incidence of PML is now rising again in conjunction with the increased use of Tysabri and Gilenya in treating MS. It is therefore important to identify effective treatment modalities for PML.
... Of critical importance is the high cost of ganciclovir and valganciclovir, and the perception that competing priorities are more important. The development of new [95] or cheaper generic CMV drugs and repurposing of available medicines [96] are steps in the right direction, but treatment will only become more available to low-income patient groups if trials are undertaken and if they demonstrate sufficient impact. When designing therapeutic trials for CMV, the method of diagnosis, and even the definition of CMV disease, present several challenges. ...
In Africa, human cytomegalovirus (CMV) is an important pathogen in a diverse range of patient groups. Congenital CMV infection is common, and most children undergo primary infection during the first year of life. Preliminary studies suggest that these early primary CMV infections could have population-wide effects on growth and development. In most studies of adults, CMV seroprevalence is close to 100%, but some studies have found that significant minorities of adults are seronegative. CMV is a common cause of pneumonia and meningitis in hospitalised immunosuppressed patient groups, and CMV DNAemia may be an important marker of rapid progression and poor outcomes of HIV infection, despite roll-out of antiretroviral therapy (ART). Diagnosis and treatment of CMV-related disease is broadly neglected in Africa, and no randomised clinical trials of anti-CMV drugs have been conducted to date. Autopsy is rarely performed in Africa, but identifies CMV as a frequent pathogen when it is carried out. Here we review the available literature on CMV in Africa, primarily in adult patients, and discuss this in the context of contemporary understanding of CMV as a human pathogen.
... Other potentially efficient nucleoside or nucleotide analogues are currently in preclinical development or in early clinical trials (94,95,105,106). Artesunate, a derivative of artemisinin used for the treatment of malaria, has been shown to inhibit the replication of CMV and HHV-6 and was used to treat CMV infections in vivo as a compassionate use (107,108). Recently, the use of complementary immunotherapy, particularly in the context of HSCT, has been considered using polyclonal cytotoxic T lymphocytes targeted to several opportunistic viruses, including HHV-6 (28, 94). The concept of an adoptive therapy based on T-cells is very attractive, due to the possibility of circumventing drug cytotoxicity and resistance, but requires a validation in ongoing clinical trials. ...
Human Herpesviruses 6A, 6B, and 7, Page 1 of 2
Abstract
Human herpesviruses 6A, 6B, and 7 (HHV-6A, HHV-6B, HHV-7), are members of the family Herpesviridae, subfamily Betaherpesvirinae, and genus Roseolovirus. The three viruses are genetically close to each other and to cytomegalovirus (CMV), the type-species of human betaherpesviruses. Like other human herpesviruses, they are ubiquitous and establish a lifelong latent infection which originates further reactivations and reinfections. Early after the recent discovery of the three viruses, these properties, as well as the genetic relationship with CMV, have been a potent rationale for speculating on their potential pathogenicity in the immunocompromised population. The pathogenic role of HHV-6, this term collectively referring to HHV-6A and HHV-6B, is now ascertained in immunocompromised subjects whereas the clinical impact of HHV-7 infection appears less important in this domain. However, numerous questions are still pending, regarding diagnostic as well as therapeutic approaches targeted to these three viruses. Due to their strong similarities, the three viruses will be presented together throughout the chapter and specific details will be given for each of them within the different sections when needed. Diagnostic Microbiology of the Immunocompromised Host, Second Edition
... The antimalarial agent artesunate was reported to have in vitro efficacy against human herpesvirus 6 and the closely related cytomegalovirus, and it was successfully used to treat a patient with human herpesvirus 6B myocarditis. 12,13 When constructing a differential diagnosis, physicians should be aware that human herpesvirus 6B is a potential culprit in atypical pneumonia in adults. The virus may be overlooked in populations with low seroprevalence. ...
... It has been proven to inhibit the replication of several human herpesviruses in vitro, in particular HCMV and HHV-6, and has been given to treat HCMV infections in vivo as a compassionate use. Its mechanism of antiviral activity likely involves the modulation of cellular activation pathways involving Sp1 and NF-B (212,213). Valomaciclovir, a drug developed initially against varicella-zoster virus, has also shown significant activity against HHV-6 in vitro (214)(215)(216). Other antiviral compounds have demonstrated promising experimental anti-HHV-6 activity, including the nucleoside/nucleotide analogues SS2242, A-5021, cyclopropavir, and 3-deaza-HPMPA and the nonnucleoside inhibitor CMV423 (4,(217)(218)(219)(220)(221)(222). ...
Human herpesvirus 6 (HHV-6) is a widespread betaherpesvirus which is genetically related to human cytomegalovirus (HCMV) and now encompasses two different species: HHV-6A and HHV-6B. HHV-6 exhibits a wide cell tropism in vivo and, like other herpesviruses, induces a lifelong latent infection in humans. As a noticeable difference with respect to other human herpesviruses, genomic HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6) in about 1% of the general population. Although it is infrequent, this may be a confounding factor for the diagnosis of active viral infection. The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Many active HHV-6 infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. However, the virus may be the cause of serious diseases, particularly in immunocompromised individuals. As emblematic examples of HHV-6 pathogenicity, exanthema subitum, a benign disease of infancy, is associated with primary infection, whereas further virus reactivations can induce severe encephalitis cases, particularly in hematopoietic stem cell transplant recipients. Generally speaking, the formal demonstration of the causative role of HHV-6 in many acute and chronic human diseases is difficult due to the ubiquitous nature of the virus, chronicity of infection, existence of two distinct species, and limitations of current investigational tools. The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active HHV-6 infections, but the indications for treatment, as well as the conditions of drug administration, are not formally approved to date. There are still numerous pending questions about HHV-6 which should stimulate future research works on the pathophysiology, diagnosis, and therapy of this remarkable human virus.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
... Over the past 25 years, artemisinin, an herbaceous drug, and its derivatives have been used for treatment and growth inhibition of some parasites (10). Simultaneously, antitumoral effects of this drug have been evaluated. ...
Background: Visceral leishmaniasis is the most acute form of leishmaniasis. Instead of administering usual drugs with different side effects, applying a herbal drug can put forward a novel horizon in dealing with this parasite. Artemether is one of the derivatives of artemisinin, a new anti-malarial drug, and can be activated by heme to produce free radicals which, in turn, have toxic effect on the parasite. Objectives: In this study we used artemether as a new drug for treatment of visceral leishmaniasis. Materials and Methods: In the present study, BALB/c mice infected with Leishmania infantum (MHOM/TN/80/IPI1) were treated with the most effective dose of artemether assessed with In Vitro assay. Artemether was given in parenteral and oral forms. Parasite burdens in the spleen and liver were determined by homogenizing and counting the parasite rate and were compared with those in the untreated mice. To evaluate the apoptotic properties of artemether by FACS flowcytometry, annexin-V FLUOS staining was performe. Results: IC50 of the drug on Leishmania infantum was determined to be 25 mu g/mL after 24 h. In Vivo experiments indicated that oral artemether treatment of mice, during 3 days and every 6 h (0.625 mg/kg) was more significant than parenteral (0.625 mg/kg IP) treatment. Artemether exerts its cytotoxic effect on this parasite via apoptosis-related mechanism. Accordingly, parasite burden in the current study decreased in the liver and spleen of mice by oral treatment. Conclusions: Artemether especially in oral treatment is an effective and simple method and may be used as a new method to treat visceral leishmaniasis.
... HCMV pneumonia can be treated successfully with intravenous ganciclovir in both immunocompromised (HIV-infected South African infants with confirmed HCMV infection) [28,29] and immunocompetent children [31]. There are generic anticytomegalovirus drugs in the pipeline, and antibetaherpesvirus activity has been reported for several low-cost alternatives such as artesunate [32,33] and the immunostimulant active hexose correlated compound [34]. Here we present data from a broad group of admitted children at the University Teaching Hospital in Lusaka, Zambia, with the aim of determining prevalence of betaherpesvirus DNAemia and viral loads, and identifying possible clinical associations and risk factors. ...
Background:
Betaherpesviruses are established causes of morbidity and mortality in immunosuppressed patient groups but have been little studied in sub-Saharan Africa, the epicenter of the human immunodeficiency virus (HIV) pandemic. In this region, primary infections with human cytomegalovirus (HCMV) and human herpesvirus type 6 (HHV-6) type 6 are endemic in infancy, but the clinical impact of these infections among pediatric inpatient groups is poorly characterized and assumptive, based largely on data from Western populations.
Methods:
We used TaqMan polymerase chain reaction to screen sera from a group of 303 pediatric inpatients aged between 3 weeks and 2 years, at the University Teaching Hospital in Lusaka, Zambia. We report the prevalence of DNAemia and viral loads within this patient group, and evaluate possible clinical associations/risk factors for betaherpesvirus infections in these hospitalized children.
Results:
We detected betaherpesvirus DNAemia in 59.1% (179/303) of children. HCMV was the most prevalent (41.3%), followed by HHV-6B (20.5%), HHV-7 (20.1%), and HHV-6A (0.3%). HIV infection (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.37-3.90; P = .002), being underweight (OR, 1.82; 95% CI, 1.06-3.12; P = .03), and an admission diagnosis of suspected meningitis (OR, 5.72; 95% CI, 1.07-30.5; P = .041) were independently associated with an increased odds of HCMV DNAemia. Conversely, HHV-6B and HHV-7 DNAemia were not associated with HIV, underweight, or admission diagnosis. Median HCMV viral load was moderately but significantly higher in HIV-infected children.
Conclusions:
Highly prevalent HCMV DNAemia was independently associated with HIV infection and being underweight across all age groups, and was also associated with meningitis, with previously underappreciated implications for the health and development of African children.
... Anecdotal reports have documented apparent efficacy in a very few cases but clinical trials will be required to assess the potential utility of this compound [64,65]. Efficacy has also been reported against HHV-6A with and EC 50 value of 3.8 μM [66]. A single report described the use of the drug in the treatment of a child with HHV-6B myocarditis, yet it was unclear that the artesunate therapy was related to the recovery of the patient [67]. ...
Human herpesvirus 6 (HHV-6) infections are typically mild and in rare cases can result in encephalitis. A common theme among all the herpesviruses, however, is the reactivation upon immune suppression. HHV-6 commonly reactivates in transplant recipients. No therapies are approved currently for the treatment of these infections, although small studies and individual case reports have reported intermittent success with drugs such as cidofovir, ganciclovir, and foscarnet. In addition to the current experimental therapies, many other compounds have been reported to inhibit HHV-6 in cell culture with varying degrees of efficacy. Recent advances in the development of new small molecule inhibitors of HHV-6 will be reviewed with regard to their efficacy and spectrum of antiviral activity. The potential for new therapies for HHV-6 infections will also be discussed, and they will likely arise from efforts to develop broad spectrum antiviral therapies for DNA viruses.
... Artemisinins, especially artesunate, possess strong inhibitory effects against double-stranded DNA herpes viruses including cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), human herpesvirus 6A (HHC-6a) and also Epstein-Barr virus (Efferth et al., 2008;Milbradt et al., 2009). The human CMV (HCMV) is a major cause of infections in neonates, patients with AIDS and transplant recipients (Schreiber et al., 2009). ...
Abstract Artemisinins are a family of sesquiterpene trioxane lactone anti-malarial agents originally derived from Artemisia annua L. The anti-malarial action of artemisinins involves the formation of free radicals via cleavage of the endoperoxide bond in its structure, which mediate eradication of the Plasmodium species. With its established safety record in millions of malarial patients, artemisinins are also being investigated in diseases like infections, cancers and inflammation. Artemisinins have been reported to possess robust inhibitory effects against viruses (e.g. Human cytomegalovirus), protozoa (e.g. Toxoplasma gondii), helminths (e.g. Schistosoma species and Fasciola hepatica) and fungi (e.g. Cryptococcus neoformans). Artemisinins have demonstrated cytotoxic effects against a variety of cancer cells by inducing cell cycle arrest, promoting apoptosis, preventing angiogenesis, and abrogating cancer invasion and metastasis. Artemisinins have been evaluated in animal models of autoimmune diseases, allergic disorders and septic inflammation. The anti-inflammatory effects of artemisinins have been attributed to the inhibition of Toll-like receptors, Syk tyrosine kinase, phospholipase Cγ, PI3K/Akt, MAPK, STAT-1/3/5, NF-κB, Sp1 and Nrf2/ARE signaling pathways. This review provides a comprehensive update on non-malarial use of artemisinins, modes of action of artemisinins in different disease conditions, and drug development of artemisinins beyond anti-malarial. With the concerted efforts in the novel synthesis of artemisinin analogues and clinical pharmacology of artemisinins, it is likely that artemisinin drugs will become a major armamentarium combating a variety of human diseases beyond malaria.
... Other potentially efficient nucleoside or nucleotide analogues are currently in preclinical development or in early clinical trials (94,95,105,106). Artesunate, a derivative of artemisinin used for the treatment of malaria, has been shown to inhibit the replication of CMV and HHV-6 and was used to treat CMV infections in vivo as a compassionate use (107,108). Recently, the use of complementary immunotherapy, particularly in the context of HSCT, has been considered using polyclonal cytotoxic T lymphocytes targeted to several opportunistic viruses, including HHV-6 (28, 94). The concept of an adoptive therapy based on T-cells is very attractive, due to the possibility of circumventing drug cytotoxicity and resistance, but requires a validation in ongoing clinical trials. ...
Le sixième herpesvirus humain est un Betaherpesvirus proche du cytomégalovirus infectant plus de 90 % de la population générale adulte. Agent de l’exanthème subit lors de la primo-infection, il est responsable de pathologies graves chez le sujet immunodéprimé pouvant conduire au décès des patients et nécessitant une prise en charge thérapeutique. À ce jour, seule la multiplication active du virus a été associée à des manifestations pathologiques. Or, le phénomène d’intégration du génome viral au génome cellulaire récemment mis en évidence soulève de nombreuses questions en termes de pathogénicité, réactivation et diagnostic. Lors d’une immunodépression, les marqueurs virologiques directs sont à privilégier pour le diagnostic et le suivi des infections avec, en premier lieu, la mesure de la charge virale dans le sang et les liquides biologiques. L’arsenal thérapeutique comporte des molécules agissant sur la synthèse du génome viral et s’enrichit peu à peu avec de nouvelles molécules. Cependant, aucun schéma thérapeutique standardisé n’a été établi jusqu’à présent et nous devons continuer nos recherches pour améliorer la connaissance de ce virus et de la prise en charge de ses infections.
Human cytomegalovirus (HCMV) is one of the main causes of serious complications in immunocompromised patients and after congenital infection. There are currently drugs available to treat HCMV infection, targeting viral polymerase, whose use is complicated by toxicity and the emergence of resistance. Maribavir and letermovir are the latest antivirals to have been developed with other targets. The approval of letermovir represents an important innovation for CMV prevention in hematopoietic stem cell transplant recipients, whereas maribavir allowed improving the management of refractory or resistant infections in transplant recipients. However, in case of multidrug resistance or for the prevention and treatment of congenital CMV infection, finding new antivirals or molecules able to inhibit CMV replication with the lowest toxicity remains a critical need. This review presents a range of molecules known to be effective against HCMV. Molecules with a direct action against HCMV include brincidofovir, cyclopropavir and anti-terminase benzimidazole analogs. Artemisinin derivatives, quercetin and baicalein, and anti-cyclooxygenase-2 are derived from natural molecules and are generally used for different indications. Although they have demonstrated indirect anti-CMV activity, few clinical studies were performed with these compounds. Immunomodulating molecules such as leflunomide and everolimus have also demonstrated indirect antiviral activity against HCMV and could be an interesting complement to antiviral therapy. The efficacy of anti-CMV immunoglobulins are discussed in CMV congenital infection and in association with direct antiviral therapy in heart transplanted patients. All molecules are described, with their mode of action against HCMV, preclinical tests, clinical studies and possible resistance. All these molecules have shown anti-HCMV potential as monotherapy or in combination with others. These new approaches could be interesting to validate in clinical trials.
Visceral leishmaniasis (VL) is an acute and deadly form of leishmaniasis, caused by Leishmania infantum parasite. Due to the toxicity and side effects of conventional treatment options, such as glucantime and other pentavalent drugs, finding novel drugs with fewer adverse effects is required. Artemether (ART), is one of the derivatives of artemisinin, which was shown to be effective in treating malaria and more recently, leishmaniasis. In this fundamental-applied research, we compared the effect of ART and nanostructure loaded with artemether (NLC-ART) on Leishmania infantum promastigotes and amastigotes, at different concentrations (2.5–5-10–25-50–100 μg/ml) using the MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay method after 24 and 48 h of treatment. Inhibitory concentration (IC50) values (μg/ml) of promastigote and amastigote of L. infantum to ART/ NLC-ART, after 48 h of treatment, were found to be 37.12 / 32.1 and 16.43 / 15.42, respectively. Moreover, we found that (NLC-ART), had the lowest cytotoxicity against the J774 macrophage cell line. Conclusion: The NLC-ART can be a good candidate for the treatment of visceral leishmaniasis.
Artemisia monosperma Delile is a Saharo-Arabian dwarf shrub that grows on sandy soils along coasts and in deserts of North Africa, the Arabian Peninsula and southern Levant under semi-arid and arid climates. It is a key species in these regions, dictating landscape formation and facilitating other plants, arthropods, reptiles and small mammals by ameliorating environmental stresses, and is – therefore – an important ecosystem engineer.
A. monosperma has morphological properties and physiological mechanisms that enable it to cope with exposure and burial by sand and with water limitations, to increase seed and seedling survival and to defend it from grazing. The plant contains a wide range of secondary substances that are used by traditional societies for medication, pest control and against plant pathogenic funguses. It is also used as firewood and for building shelters, fences and pens for sheep and goats.
Despite its importance for local ecosystems and for traditional societies in arid semi-arid regions, A. monosperma is exposed to anthropogenic threats caused by urbanization and recreational activities, mainly at coastal areas, by intense cutting in the deserts, and toby climate changes.
In this chapter, we review the fundamental traits that make A. monosperma a keystone species in sandy ecosystems and the current experience in A. monosperma management, mainly from studies carried out recently in Mediterranean coastal sand dunes and in the western Negev sand dunes of Israel.
Human cytomegalovirus (HCMV) infection is associated with serious pathology such as transplant rejection or embryonic developmental defects. Antiviral treatment with currently available drugs targeting viral enzymes is often accompanied with severe side effects and the occurrence of drug-resistant viruses. For this reason, novel ways of anti-HCMV therapy focusing on so far unexploited small molecules, targets and mechanisms are intensively studied. Recently, we described the pronounced antiviral activity of the artesunate-related class of trioxane compounds, comprising NF-κB/signaling inhibitors like the trimeric derivative TF27, which proved to be highly active in a nanomolar range both in vitro and in vivo. Here, we extend this analysis by presenting further TF27/artesunate-derived antiviral compounds designed for their specific use in target verification by click chemistry applied in fluorescence labeling and tag affinity strategies. Our main findings are as follows: (i) compounds TF27, BG95, AC98 and AC173 exert strong inhibitory activity against HCMV replication in cultured primary human cells, (ii) autofluorescence activity could be quantitatively detected for BG95 and AC98, and confocal fluorescence imaging revealed accumulation in mitochondria, (iii) postulated cellular targets including mitochondrial proteins were down-regulated upon TF27 treatment, (iv) a click chemistry-based protocol of target enrichment was established, and (v) mass spectrometry-based proteomic analysis, using proteins from HCMV-infected fibroblasts covalently interacting with AC173, revealed a refined list of targets. Combined, data strongly suggest a complex mode of antiviral drug-target interaction of artesunate-related compounds, now highlighting potential roles of mitochondrial, NF-κB pathway proteins, exportins and possibly more. This strategy may further promote antiviral drug development on the basis of pharmacologically optimized trioxane derivatives.
Background. TT, or Torque teno virus, is a widespread population of DNA-containing simple virus from the Anelloviridae family that can cause both chronic hepatitis and extrahepatic lesions, but is still an under-studied pathogen that lacks effective antiviral drugs. Aim of the study: to study the spectrum of clinical phenotype, immune status and efficacy of artesunate in chronic reactivated TTV infection in humans. Materials and methods. In this retrospective clinical case study, we examined the results of case histories of 67 patients aged 19 to 52 years (36 men, 31 women) with reactivated TTV infection (PCR data from blood cells) who received artesunate therapy. 38 additional patients with reactivated TTV infection with similar age, gender distribution, and clinical picture who did not receive artesunate constituted the control group. Immunological study included the study of indicators of total blood count, subpopulation composition of lymphocytes using laser flow cytofluorimetry (cytofluorometer Epics Xl, USA) and indirect immunofluorescence method with monoclonal antibodies to CD (CD3+, CD3+ CD4+, CD3+CD8+, CD3-CD19+, CD3-CD16+CD56 +, CD3+CD16+ CD56+) (Beckman Coulter reagents, USA). Phagocytosis was evaluated according to a latex test to determine the index of phagocytosis, the number of active phagocytes and phagocytic blood capacity. Serum immunoglobulin concentrations of the major classes (M, G, A) were determined by Mancini simple radial immunodiffusion. Concentration of IgE, IgD and IgG subclasses (IgG1, IgG2, IgG3, IgG4) in serum was measured by enzyme-linked immunosorbent assay (VectorBEST, RF). Serum mannose binding lectin concentration and myeloperoxidase activity were determined by enzyme immunoassay. Within 1 month of therapy, artesunate was administered at a dose of 50 mg twice a day 1 time for 12 hours orally after meals, and for 2-3 months with insufficient effectiveness of the previous course - at a dose of 50 mg three times a day 1 time for 8 hours orally after food. Statistical analysis of information was performed using structural and comparative analyzes. Methods of variational statistics were applied with the calculation of the parametric index of the Student’s T-test with the index of confidence probability p and the nonparametric criterion of the number of signs Z by Urbach Yu.V. Results of the study and discussion. Hepatic lesions were reported in only 34%, while non-hepatic forms of the disease - in 66% of cases. Extrahepatic manifestations were determined by chronic fatigue syndrome (34%), neuropsychiatric symptoms associated with temporal mesial sclerosis (32%), mononucleosis-like syndrome (16%), vasculopathy of small cerebral vessels (14%), encephalitis (5% of cases) . All patients were immunocompromised individuals. Only one case was diagnosed with HIV infection, and all other patients suffered from minor immunodeficiencies, including deficiency of natural killer T-lymphocytes (49%), natural killer cells (30%), cytotoxic T-lymphocytes (24%), IgE and/or IgD, mannose-binding lectin (15%), myeloperoxidase (12%), IgA (4%), and idiopathic CD4+ T-cell lymphopenia (3% of cases). Artesunate therapy was effective in 62% of cases (p<0.05; Z<Z0.05), providing removal of virus DNA from blood cells according to PCR for 1-3 months. In 21% of cases there was a partial and 17% - complete resistance of the virus to artesunate. This is 10-15% more effective than previously reported in alpha interferon preparations, with better tolerability and ease of use for artesunate. According to PCR, the mean number of viral particles in blood cells during therapy decreased from 97 to 11 thousand in the sample (p<0.05; Z<Z0.05). Conclusions. TTV is not exclusively hepatotropic, but a multitropic opportunistic virus that is reactivated in an immunosuppressed organism, including primary minor immunodeficiencies with damage to various branches of the immune system. Artesunate, given a three-month course of 100-150 mg/day orally, provides the elimination of viral DNA from blood cells in 62% of cases with satisfactory tolerability, so it can be considered as a new promising drug for the treatment of this infection.
Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy and hippocampal sclerosis (HS) is the most common pathological substrate of TLE. Considering the significant consequences of uncontrolled seizures (e.g., increased morbidity and mortality), epilepsy prevention remains a necessity that potentially could save many lives. Human herpes virus-6 (HHV-6) has been linked to TLE in humans. The relationship between HHV-6 and HS-TLE could be attributed to a neuro-inflammatory cascade triggered by the infection, involving direct neuronal damage and production of several pro-inflammatory cytokines under certain conditions that are still incompletely understood. Hepatitis B virus (HBV) infection is another chronic viral infection with a life-long latency. HBV infection is linked to various clinical conditions, including liver cirrhosis. There are currently three ways to fight HBV infection and its consequences; primary prevention (by vaccination), secondary prevention (by drug therapy), and tertiary prevention (by liver transplantation). Considering the similarities between the natural histories of HHV-6 and HBV infections, and also the successful strategies which are currently available to fight HBV infection and its long-term consequences, here, we propose three strategies to fight HHV-6 and its possible long-term consequence (i.e., HS-TLE): Primary prevention: by developing vaccines to prevent HHV-6 infection; Secondary prevention: by considering trials of antiviral drugs to treat HHV-6 infection, when it happens in the childhood to hopefully prevent its long-term consequences; and, Tertiary prevention: by stem cell therapy for drug-resistant epilepsy.
Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases1–4. Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge1,5 and approximately 30% of patients with DiHS/DRESS develop complications, including infections and inflammatory and autoimmune diseases1,2,5. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect human disease pathophysiology at unprecedented resolutions6, particularly in diseases lacking animal models, such as DiHS/DRESS. We performed scRNA-seq on skin and blood from a patient with refractory DiHS/DRESS, identifying the JAK–STAT signaling pathway as a potential target. We further showed that central memory CD4+ T cells were enriched with DNA from human herpesvirus 6b. Intervention via tofacitinib enabled disease control and tapering of other immunosuppressive agents. Tofacitinib, as well as antiviral agents, suppressed culprit-induced T cell proliferation in vitro, further supporting the roles of the JAK–STAT pathway and herpesviruses in mediating the adverse drug reaction. Thus, scRNA-seq analyses guided successful therapeutic intervention in the patient with refractory DiHS/DRESS. scRNA-seq may improve our understanding of complicated human disease pathophysiology and provide an alternative approach in personalized medicine. Single-cell RNA sequencing facilitates successful therapeutic treatment of a patient with a rare and severe drug-induced inflammatory skin reaction.
Human herpesviruses 6A (HHV-6A) and 6B (HHV-6B), often referred to collectively as HHV-6, are a pair of beta-herpesviruses known to cause a variety of clinical syndromes in both immunocompetent and immunocompromised individuals. Most humans are infected with HHV-6B, and many with HHV-6A. Primary infection typically occurs in early childhood, although large-scale reviews on the topic are limited. Herein, the authors explore the clinical manifestations of HHV-6-associated disease in both immunocompetent and immunocompromised pediatric patients, risk factors for development of HHV-6-associated neurologic disease, risk of autoimmunity associated with development of active or latent infection, the relevance of HHV-6-specific diagnostic tests, and the medications used to treat HHV-6. The goal of this review is to improve the current understanding of HHV-6 in pediatric populations and to examine the most effective diagnostic and therapeutic interventions in this disease state.
The association between glioblastoma (GBM) and human cytomegalovirus (HCMV) infection has been the intensely debated topic over decades for developing new therapeutic option. In this regard, the peroxides from natural and synthetic sources served as potential antiviral and anticancer agents in the past. Herein a concise and efficient strategy has been demonstrated to access a novel class of peroxides containing a spiro-isoxazoline to primarily investigate the biological activities. The synthetic compounds were evaluated for in vitro antiviral and antiproliferative activity against human cytomegalovirus (HCMV) and glioblastoma cell line (GBM6), respectively. While compound 13m showed moderate anti-CMV activity (IC50 = 19 µM), surprisingly, an independent biological assay for compound 13m revealed its antiproliferative activity against human glioblastoma cell line (GBM6) with IC50 = 10 µM. Hence, the unification of an isoxazoline and peroxide heterocycles could be a potential direction to initiate HCMV-GBM drug discovery program.
Background
Human herpesvirus 6 (HHV‐6) encephalitis is a known life‐threatening complication following allogeneic hematopoietic stem cell transplantation (allo‐HSCT). However, few studies have focused on the occurrence of HHV‐6 encephalitis in patients receiving mycophenolate mofetil (MMF) combined with a calcineurin inhibitor as prophylaxis for graft‐versus‐host disease (GVHD). This study aimed to investigate the impact of MMF administered for GVHD prophylaxis in the occurrence of HHV‐6 encephalitis after allo‐HSCT and the characteristics of this condition.
Methods and Results
We retrospectively analyzed 73 patients who underwent allo‐HSCT (83 transplants) at our hospital between April 2010 and December 2015. MMF (2–3 g/day) was administered along with a calcineurin inhibitor. Seven patients (8.0%) developed encephalitis due to HHV‐6. The median period from allo‐HSCT to the onset of HHV‐6 encephalitis was 23 days (range, 17–98 days). The cumulative incidence of HHV‐6 encephalitis on day 100 after treatment was 12% and 6% in patients who underwent cord blood transplantation (CBT) and non‐CBT (i.e., bone marrow transplantation and peripheral blood stem cell transplantation), respectively (P = 0.344). Neurological symptoms of encephalitis were more severe in non‐CBT cases than those in CBT cases. All patients diagnosed with HHV‐6 encephalitis were treated with ganciclovir or foscarnet. None of the enrolled patients died from HHV‐6 encephalitis.
Conclusions
MMF may have the potential to increase the frequency of severe HHV‐6 encephalitis in patients undergoing CBT and non‐CBT. Thus, MMF should be administered with caution, and patients should be monitored closely for HHV‐6 encephalitis even those who did not undergo CBT.
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Infection with human cytomegalovirus (HCMV) is a serious medical problem, particularly in immunocompromised individuals and neonates. The success of (val)ganciclovir therapy is hampered by low drug compatibility and induction of viral resistance. A novel strategy of antiviral treatment is based on the exploitation of cell-directed signaling, e. g. pathways with a known relevance for carcinogenesis and tumor drug development. Here we describe a principle for putative antiviral drugs based on targeting dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs). DYRKs constitute an evolutionarily conserved family of protein kinases with key roles in the control of cell proliferation and differentiation. Members of the DYRK family are capable of phosphorylating a number of substrate proteins, including regulators of the cell cycle, e.g. DYRK1B can induce cell cycle arrest, a critical step for the regulation of HCMV replication. Here we provide first evidence for a critical role of DYRKs during viral replication and the high antiviral potential of DYRK inhibitors (Harmine, AZ-191, SC84227, SC97202 and SC97208). Using established replication assays for laboratory and clinically relevant strains of HCMV, concentration-dependent profiles of inhibition were obtained. Mean inhibitory concentrations (EC50) of 0.98 ± 0.08 μM/SC84227, 0.60 ± 0.02 μM/SC97202, 6.26 ± 1.64 μM/SC97208, 0.71 ± 0.019 μM/Harmine and 0.63 ± 0.23 μM/AZ-191 were determined with HCMV strain AD169-GFP for the infection of primary human fibroblasts. A first analysis of the mode of antiviral action suggested a block of viral replication at the early-late stage of HCMV gene expression. Moreover, rhesus macaque cytomegalovirus (RhCMV), varicella-zoster virus (VZV) and herpes simplex virus (HSV-1) showed a similarly high sensitivity to these compounds. Thus, we conclude that DYRK signaling represents a promising target pathway for the development of novel anti-herpesviral strategies.
Human herpes virus 6 (HHV-6) infection, mostly due to HHV-6B, is frequently recorded after solid organ transplantation, but symptomatic infections are not common. Only 1 to 6.7% of transplant recipients have been reported to develop clinical illness or allograft dysfunction associated with HHV-6. Fever, myelosuppression, hepatitis, colitis, and encephalitis have been observed. HHV-6 has also been associated with indirect effects, such as acute and chronic allograft rejection, and increased risk of cytomegalovirus (CMV) disease, fungal infections, and other opportunistic infections. HHV-6 has an ability to integrate into the host chromosome, but the clinical significance of chromosomally integrated HHV-6 in transplant patients is not yet clear. The laboratory diagnosis of HHV-6 infection is complex due to the common asymptomatic reactivations. Laboratory diagnostics are primarily based on quantitative nucleic acid amplification tests of blood, plasma, or serum samples. HHV-6 antigens may also be demonstrated in clinical specimens by immunohistochemistry. Antiviral treatment of HHV-6 is indicated in encephalitis or other severe end-organ disease. Foscarnet, ganciclovir, and cidofovir are the drugs used for treatment.
Auteur(s) : Henri Agut Service de virologie, ER1 DETIV UPMC, Groupe hospitalier Pitie-Salpetriere, 83, boulevard de l'Hopital, 75013 Paris, France Introduction Depuis la decouverte de l'herpesvirus humain 6 (HHV-6) en 1986, se pose regulierement la question de sa pathogenicite pour le systeme nerveux central (SNC). De facon corollaire, on se demande si des methodes diagnostiques sont a mettre en œuvre pour rechercher le virus dans le SNC (si oui, lesquelles) et si [...]
Human herpesvirus-6 (HHV-6) encephalitis following allogeneic hematopoietic cell transplantation is a serious and often fatal complication accompanying reactivation of HHV-6B. Incidence varies among studies, but is reportedly 0-11.6% after bone marrow or PBSC transplantation and 4.9-21.4% after umbilical cord blood transplantation, typically around 2-6 weeks post transplant. Symptoms are characterized by memory loss, loss of consciousness and seizures. Magnetic resonance imaging (MRI) typically shows bilateral signal abnormalities in the limbic system. This complication is considered to represent acute encephalitis caused by direct virally induced damage to the central nervous system, but our understanding of the etiologies and pathogenesis is still limited. The mortality rate attributable to this pathology remains high, and survivors are often left with serious sequelae such as impaired memory and epilepsy. Despite the poor prognosis, no validated treatments or preventative measures have been established. Establishment of preventative strategies represents an important challenge. This article reviews the current knowledge of the clinical features, incidence, pathogenesis and treatment of HHV-6 encephalitis, and discusses issues needing clarification in the future to overcome this serious complication.Bone Marrow Transplantation advance online publication, 27 April 2015; doi:10.1038/bmt.2015.76.
Background Addition of artemisinin derivatives to existing drug regimens for malaria could reduce treatment failure and transmission potential. We assessed the evidence for this hypothesis from randomised controlled trials. Methods We undertook a meta-analysis of individual patients' data from 16 randomised trials (n=5948) that studied the effects of the addition of artesunate to standard treatment of Plasmodium falciparum malaria. We estimated odds ratios (OR) of parasitological failure at days 14 and 28 (artesunate combination compared with standard treatment) and calculated combined summary ORs across trials using standard methods. Findings For all trials combined, parasitological failure was lower with 3 days of artesunate at day 14 (OR 0.20, 95% CI 0.17-0.25, n=4504) and at day 28 (excluding new infections, 0.23, 0.19-0.28, n=2908; including re-infections, 0.30, 0.26-0.35, n=4332). Parasite clearance was significantly faster (rate ratio 1.98, 95% CI 1.85-2.12, n=3517) with artesunate. In participants with no gametocytes at baseline, artesunate reduced gametocyte count on day 7 (OR 0.11, 95% CI 0.09-0.15, n=2734), with larger effects at days 14 and 28. Adding artesunate for 1 day (six trials) was associated with fewer failures by day 14 (0.61, 0.48-0.77, n=1980) and day 28 (adjusted to exclude new infections 0.68, 0.53-0.89, n=1205; unadjusted including reinfections 0.77, 0.63-0.95, n=1958). In these trials, gametocytes were reduced by day 7 (in participants with no gametocytes at baseline 0.11, 0.09-0.15, n=2734). The occurrence of serious adverse events did not differ significantly between artesunate and placebo. Interpretation The addition of 3 days of artesunate to standard antimalarial treatments substantially reduce treatment failure, recrudescence, and gametocyte carriage.
Artemisinin and its derivatives are renowned for their potent antimalarial activity. They have found their way into clinical use in many areas where malaria is endemic. The in vitro concentration at which artemisinin can inhibit 50% of the growth of Plasmodium falciparum ranges from 3 to 30 micrograms/L. The fat-soluble derivatives artemether and arteether are approximately twice as active. The water-soluble dihydro-artemisinin and artesunate are 4 to 5 times more active in vitro. Artemisinin is available only for oral and rectal administration. Absorption is incomplete and elimination is fast, with and elimination half-life of 2 to 5 hours. Plasma concentrations after a single 500 mg oral dose most often exceed 200 micrograms/L. Artesunate and artemether can be considered as prodrugs. Biotransformation into the active metabolite dihydro-artemisinin occurs rapidly--almost immediately for artesunate. The reported elimination half-life of artesunate is less than 1 hour, and for artemether the figure is 3 to 11 hours. The pharmacokinetics of dihydro-artemisinin are not yet completely clear. Elimination is probably also rapid, with an elimination half-life of a few hours. Arteether, dissolved in oil for intramuscular administration, has a much longer elimination half-life of over 20 hours. The clinical efficacy of this group of drugs is characterised by an almost immediate onset and rapid reduction of parasitaemia, with complete clearance in most cases within 48 hours. Efficacy is high even in areas with multidrug-resistant parasite strains. To prevent recrudescence with monotherapy of these compounds, treatment needs to be extended beyond the disappearance of parasites. After 5 days of therapy the rate of recrudescence is approximately 10%. Alternatively, combination with other drugs can be used. Combination with mefloquine is recommended for areas with multidrug-resistant P. falciparum.
Artesunate (ART) is a semi-synthetic derivative of artemisinin, the active principle of the Chinese herb Artemisia annua. ART reveals remarkable activity against otherwise multidrug-resistant Plasmodium falciparum and P. vivax malaria. ART has now been analyzed for its anti-cancer activity against 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute, USA. ART was most active against leukemia and colon cancer cell lines (mean GI50 values: 1.11+/-0.56 microM and 2.13+/-0.74 microM , respectively). Non-small cell lung cancer cell lines showed the highest mean GI50 value (25.62+/-14.95 microM) indicating the lowest sensitivity towards ART in this test panel. Intermediate GI50 values were obtained for melanomas, breast, ovarian, prostate, CNS, and renal cancer cell lines. Importantly, a comparison of ART's cytotoxicity with those of other standard cytostatic drugs showed that ART was active in molar ranges comparable to those of established anti-tumor drugs. Furthermore, we tested CEM leukemia sub-lines resistant to either doxorubicin, vincristine, methotrexate, or hydroxyurea which do not belong to the N.C.I. screening panel. None of these drug-resistant cell lines showed cross resistance to ART. To gain insight into the molecular mechanisms of ART's cytotoxicity, we used a panel of isogenic Saccaromyces cerevisiae strains with defined genetic mutations in DNA repair, DNA checkpoint and cell proliferation genes. A yeast strain with a defective mitosis regulating BUB3 gene showed increased ART sensitivity and another strain with a defective proliferation-regulating CLN2 gene showed increased ART resistance over the wild-type strain, wt644. None of the other DNA repair or DNA check-point deficient isogenic strains were different from the wild-type. These results and the known low toxicity of ART are clues that ART may be a promising novel candidate for cancer chemotherapy.
To determine whether receipt of an investigational anti-CD3 monoclonal antibody (BC3) increased the risk of human herpesvirus
6 (HHV-6) reactivation and development of encephalitis in bone marrow transplant (BMT) recipients, persons who had and had
not received BC3 were compared. Odds of HHV-6 reactivation were higher among BC3 recipients than among control patients (odds
ratio, 2.5; 95% confidence interval [CI], 1.3–4.7). In addition, BC3 recipients were more likely than control patients to
develop encephalitis (risk ratio [RR], 3.5; 95% CI, 1.3–9.5), and this association followed a BC3 dose-dependent relationship
(P=.03, by Mantel-Haenszel χ2 test). In a multivariable model, HHV-6 reactivation and receipt of BC3 were associated with increased risk of encephalitis
(RR, 5.4; 95% CI, 1.9–15.3, and RR, 3.3; 95% CI, 1.2–9.1, respectively). In conclusion, both HHV-6 reactivation and receipt
of BC3 for prophylaxis of acute graft-versus-host disease independently increased the risk of encephalitis in allogeneic BMT
recipients. Prospective studies to better define the relationship between HHV-6 reactivation and encephalitis in allogeneic
BMT recipients are warranted.
A profound cytotoxic action of the antimalarial, artesunate (ART), was identified against 55 cancer cell lines of the U.S. National Cancer Institute (NCI). The 50% inhibition concentrations (IC50 values) for ART correlated significantly to the cell doubling times (P = 0.00132) and the portion of cells in the G0/G1 (P = 0.02244) or S cell cycle phases (P = 0.03567). We selected mRNA expression data of 465 genes obtained by microarray hybridization from the NCI data base. These genes belong to different biological categories (drug resistance genes, DNA damage response and repair genes, oncogenes and tumor suppressor genes, apoptosis-regulating genes, proliferation-associated genes, and cytokines and cytokine-associated genes). The constitutive expression of 54 of 465 (=12%) genes correlated significantly to the IC50 values for ART. Hierarchical cluster analysis of these 12 genes allowed the differentiation of clusters with ART-sensitive or ART-resistant cell lines (P = 0.00017). For exemplary validation, cell lines transduced with 3 of the 12 genes were used to prove a causative relationship. The cDNAs for a deletion-mutated epidermal growth factor receptor (EGFR) and for gamma-glutamylcysteine synthetase increased resistance to ART. The conditional expression of the CDC25A gene using a tetracycline repressor expression vector increased sensitivity toward ART. Multidrug-resistant cells differentially expressing the MDR1, MRP1, or BCRP genes were not cross-resistant to ART. ART acts via p53-dependent and- independent pathways in isogenic p53+/+ p21WAF1/CIP1+/+, p53-/- p21WAF1/CIP1+/+, and p53+/+ p21WAF1/CIP1-/- colon carcinoma cells.
Human herpesvirus-6 (HHV-6), a ubiquitous beta-herpesvirus, is the causative agent of roseola infantum and has been associated with a number of neurologic disorders including seizures, encephalitis/meningitis, and multiple sclerosis. Although the role of HHV-6 in human CNS disease remains to be fully defined, a number of studies have suggested that the CNS can be a site for persistent HHV-6 infection.
To characterize the extent and distribution of HHV-6 in human glial cells from surgical brain resections of patients with mesial temporal lobe epilepsy (MTLE).
Brain samples from eight patients with MTLE and seven patients with neocortical epilepsy (NE) undergoing surgical resection were quantitatively analyzed for the presence of HHV-6 DNA using a virus-specific real-time PCR assay. HHV-6 expression was also characterized by western blot analysis and in situ immunohistochemistry (IHC). In addition, HHV-6-reactive cells were analyzed for expression of glial fibrillary acidic protein (GFAP) by double immunofluorescence.
DNA obtained from four of eight patients with MTLE had significantly elevated levels of HHV-6 as quantified by real-time PCR. HHV-6 was not amplified in any of the seven patients with NE undergoing surgery. The highest levels of HHV-6 were demonstrated in hippocampal sections (up to 23,079 copies/10(6) cells) and subtyped as HHV-6B. Expression of HHV-6 was confirmed by western blot analysis and IHC. HHV-6 was co-localized to GFAP-positive cells that morphologically appeared to be astrocytes.
HHV-6B is present in brain specimens from a subset of patients with MTLE and localized to astrocytes in the absence of inflammation. The amplification of HHV-6 from hippocampal and temporal lobe astrocytes of MTLE warrants further investigation into the possible role of HHV-6 in the development of MTLE.
Addition of artemisinin derivatives to existing drug regimens for malaria could reduce treatment failure and transmission potential. We assessed the evidence for this hypothesis from randomised controlled trials.
We undertook a meta-analysis of individual patients' data from 16 randomised trials (n=5948) that studied the effects of the addition of artesunate to standard treatment of Plasmodium falciparum malaria. We estimated odds ratios (OR) of parasitological failure at days 14 and 28 (artesunate combination compared with standard treatment) and calculated combined summary ORs across trials using standard methods.
For all trials combined, parasitological failure was lower with 3 days of artesunate at day 14 (OR 0.20, 95% CI 0.17-0.25, n=4504) and at day 28 (excluding new infections, 0.23, 0.19-0.28, n=2908; including re-infections, 0.30, 0.26-0.35, n=4332). Parasite clearance was significantly faster (rate ratio 1.98, 95% CI 1.85-2.12, n=3517) with artesunate. In participants with no gametocytes at baseline, artesunate reduced gametocyte count on day 7 (OR 0.11, 95% CI 0.09-0.15, n=2734), with larger effects at days 14 and 28. Adding artesunate for 1 day (six trials) was associated with fewer failures by day 14 (0.61, 0.48-0.77, n=1980) and day 28 (adjusted to exclude new infections 0.68, 0.53-0.89, n=1205; unadjusted including reinfections 0.77, 0.63-0.95, n=1958). In these trials, gametocytes were reduced by day 7 (in participants with no gametocytes at baseline 0.11, 0.09-0.15, n=2734). The occurrence of serious adverse events did not differ significantly between artesunate and placebo.
The addition of 3 days of artesunate to standard antimalarial treatments substantially reduce treatment failure, recrudescence, and gametocyte carriage.
High interferon production by plasmacytoid dendritic cells (PDC) was unexpectedly noted after their coculture with CD4+ cells from a healthy donor whose cells subsequently showed human herpesvirus type 6 and 7 infections. This release of interferon
was not observed with uninfected normal CD4+ cells. Induction of PDC interferon production could help screen for covert virus infections.
Human herpesvirus 6 (HHV-6) is a betaherpesvirus that is closely related to human cytomegalovirus. It was discovered in 1986, and HHV-6 literature has expanded considerably in the past 10 years. We here present an up-to-date and complete overview of the recent developments concerning HHV-6 biological features, clinical associations, and therapeutic approaches. HHV-6 gene expression regulation and gene products have been systematically characterized, and the multiple interactions between HHV-6 and the host immune system have been explored. Moreover, the discovery of the cellular receptor for HHV-6, CD46, has shed a new light on HHV-6 cell tropism. Furthermore, the in vitro interactions between HHV-6 and other viruses, particularly human immunodeficiency virus, and their relevance for the in vivo situation are discussed, as well as the transactivating capacities of several HHV-6 proteins. The insight into the clinical spectrum of HHV-6 is still evolving and, apart from being recognized as a major pathogen in transplant recipients (as exemplified by the rising number of prospective clinical studies), its role in central nervous system disease has become increasingly apparent. Finally, we present an overview of therapeutic options for HHV-6 therapy (including modes of action and resistance mechanisms).
We describe 4 patients with encephalitis due to possible reactivation of human herpesvirus 6 (HHV-6) infection who were enrolled
in the California Encephalitis Project. All were immunocompetent and had HHV-6 loads determined in cerebrospinal fluid specimens.
Tests for detection of HHV-6 should be considered for individuals with encephalitis.
Human herpesvirus 6 (HHV-6), the causative agent of exanthema subitum in childhood, can also induce meningoencephalitis in
immunocompromised individuals. In contrast, HHV-6 encephalitis in immunocompetent patients is rare, and the clinical syndrome
not well defined. We report a case of meningoencephalitis caused by HHV-6 type B in an otherwise healthy woman.
There is no safe, practical, and effective treatment for pregnant women infected with multidrug-resistant Plasmodium falciparum.
We recruited pregnant Karen women in the second or third trimesters of pregnancy who had uncomplicated falciparum malaria for a randomized, open-label trial with a restricted sequential trial design of 7 days of supervised quinine (SQ7) versus 3 days of artesunate-atovaquone-proguanil (AAP).
Eight-one pregnant women entered the study between December 2001 and July 2003; 42 were treated with SQ7 and 39 were treated with AAP. Fever, parasite clearance, and duration of anemia were significantly better with AAP; the treatment failure rate was 7 times lower (5% [2/39] vs. 37% [15/41]; relative risk, 7.1 [95% confidence interval, 1.7-29.2]; P = .001). There were no significant differences in birth weight, duration of gestation, or congenital abnormality rates in newborns or in growth and developmental parameters of infants monitored for 1 year.
AAP is a well-tolerated, effective, practical, but expensive treatment for multidrug-resistant falciparum malaria during the second or third trimesters of pregnancy. Despite the small number of subjects, our results add to the growing body of evidence that AAP is safe for the mother and the fetus.
Human herpesvirus 6 (HHV-6) was detected in specimens from patients hospitalized with symptoms of encephalitis or meningitis. A real-time PCR assay was developed which has a linear dynamic range of 5 to 5 x 10(6) copies of HHV-6 and a sensitivity of five gene copies per reaction. While the assay detects both subtypes, HHV-6A and HHV-6B, it is specific and does not cross-react with a selected specificity panel. A total of 1,482 patient specimens, which were collected between 2003 and 2007, were tested; 26 specimens from 24 patients were found to be positive for HHV-6 by real-time PCR. The HHV-6 detection rate in this population was therefore 1.75%. The majority of the specimens tested (>95%) were cerebrospinal fluid (CSF) specimens. We were able to type 20 of the 26 positive specimens by conventional PCR and sequence analysis; all were HHV-6B. Forty-two percent of the patients were 3 years of age or younger, which may indicate a primary infection in these patients. Given the ages of the remaining patients (from 4 to 81 years), their infections were most probably due to virus reactivations. Where information was available, symptoms of patients included fever (71%), altered mental status (67%), and abnormal CSF profile (75%). Fifty percent of patients of 3 years of age or younger suffered from seizures. The detection of HHV-6 in specimens from patients diagnosed with encephalitis or meningitis, in the absence of a positive PCR result for other agents, strongly suggests a role for HHV-6 in the pathogenesis of these central nervous system diseases.
Rectal administration of artemisinin derivatives has potential for early treatment for severe malaria in remote settings where injectable antimalarial therapy may not be feasible. Preparations available include artesunate, artemisinin, artemether and dihydroartemisinin. However each may have different pharmacokinetic properties and more information is needed to determine optimal dose and comparative efficacy with each another and with conventional parenteral treatments for severe malaria.
Individual patient data from 1167 patients in 15 clinical trials of rectal artemisinin derivative therapy (artesunate, artemisinin and artemether) were pooled in order to compare the rapidity of clearance of Plasmodium falciparum parasitaemia and the incidence of reported adverse events with each treatment. Data from patients who received comparator treatment (parenteral artemisinin derivative or quinine) were also included. Primary endpoints included percentage reductions in parasitaemia at 12 and 24 hours. A parasite reduction of >90% at 24 hours was defined as parasitological success.
Artemisinin and artesunate treatment cleared parasites more rapidly than parenteral quinine during the first 24 hours of treatment. A single higher dose of rectal artesunate treatment was five times more likely to achieve >90% parasite reductions at 24 hours than were multiple lower doses of rectal artesunate, or a single lower dose administration of rectal artemether.
Artemisinin and artesunate suppositories rapidly eliminate parasites and appear to be safe. There are less data on artemether and dihydroartemisinin suppositories. The more rapid parasite clearance of single high-dose regimens suggests that achieving immediate high drug concentrations may be the optimal strategy.
In order to study the pathogenesis of HHV-6 infection in central nervous system disorders, U251 cell line was infected with freshly isolated variant B HHV-6. Although IEA/ex 3 antigen (immediate early protein) was detected in infected cell nuclei, neither the presence of OHV-3 antigen (late antigen) nor production of infectious virus was demonstrated. These results indicate that abortive infection was established in the cells. After viral infection, the viral genome copy in the infected cells gradually decreased and became stable after 6 cell passages. At that point, HHV-6 gene expression was restricted to only 2 immediate early genes (U90 and U94). However, 12-O-tetra-decanoyl (TPA) treatment induced transcription of other genes (U31 and U39) by the 10th cell passage, indicating HHV-6 reactivation. Moreover, production of two proinflamatory cytokines (IL-6 and IL-1β) was up-regulated by the presence of the HHV-6 genome and TPA-induced activation of the viral transcripts. J. Med. Virol. 66:497–505, 2002. © 2002 Wiley-Liss, Inc.
A fatal case is reported of encephalitis in an 85-year-old man caused by the human herpesvirus 6 variant A. The virological diagnosis was based on the findings of the virus variant genomic sequences both in the cerebrospinal fluid and serum of the patient. Moreover, virus replication in nervous tissue was suggested by a viral load higher in the cerebrospinal fluid than in the peripheral blood. The association of a central nervous system infection with the A variant of human herpesvirus 6 is interesting because of the difficulty in establishing a pathological role for this virus strain. Epstein-Barr virus DNA was detected in the patient's cerebrospinal fluid in association with human herpesvirus 6 DNA. The presence of the Epstein-Barr virus genomic sequences in the cerebro-spinal fluid was considered to be unimportant clinically. J. Med. Virol. 65:133–137, 2001. © 2001 Wiley-Liss, Inc.
Sesquiterpene lactones (SLs) are the active compounds of a variety of traditionally used medicinal plants from the Asteraceae family. They are known to possess a considerable antiinflammatory activity in different inflammation models. They inhibit the transcription factor NF-kappaB probably by alkylating cysteine38 in the DNA binding domain of the p65 subunit. Here we investigate a set of 103 different sesquiterpene lactones representing 6 structural groups (44 germacranolides, 16 heliangolides, 22 guaianolides, 9 pseudoguaianolides, 2 hypocretenolides, 10 eudesmanolides) for their NF-kappaB inhibiting properties and the resulting IC(100)-values were submitted to a QSAR study. Properties important for the inhibition potency are discussed for the whole data set and for subsets of the different structural classes.
Traditional Chinese medicine commands a unique position among all traditional medicines because of its 5000 years of history.
Our own interest in natural products from traditional Chinese medicine was triggered in the 1990s, by artemisinin-type sesquiterpene
lactones from Artemisia annua L. As demonstrated in recent years, this class of compounds has activity against malaria, cancer cells, and schistosomiasis.
Interestingly, the bioactivity of artemisinin and its semisynthetic derivative artesunate is even broader and includes the
inhibition of certain viruses, such as human cytomegalovirus and other members of the Herpesviridae family (e.g., herpes simplex virus type 1 and Epstein-Barr virus), hepatitis B virus, hepatitis C virus, and bovine viral
diarrhea virus. Analysis of the complete profile of the pharmacological activities and molecular modes of action of artemisinin
and artesunate and their performance in clinical trials will further elucidate the full antimicrobial potential of these versatile
pharmacological tools from nature.
Monoclonal antibodies (MAbs) were developed against immunodominant HHV-6 (GS isolate) late and early proteins. The major late protein was identified as a probable glycoprotein with a molecular weight of approximately 110 kDa (gp 110). Immunoblotting of the early antigen yielded proteins of 41 and 38 kDa (p41/38). The MAb to the early protein reacted with cells infected with 14 different HHV-6 isolates. In contrast, the MAb against the late protein reacted with only 10 of these isolates, indicating that there was strain variation in this glycoprotein. The percentage of antibody-positive sera reactive with gp110 in the ELISA ranged from 56% to 96% among the different serum donor categories. In contrast, only 10-30% of the sera were positive for antibodies to p41/38 with the exception of sera from patients with African Burkitt's lymphoma (ABL) and Hodgkin's disease (HD). These antibody patterns denote the presence of active HHV-6 replication in patients with ABL and HD.
The potential inhibitory effect of 54 Mexican Indian medicinal plants on the activation of transcription factor NF-kappaB was studied. Band-shift experiments identified the ethanolic leaf extracts of Artemisia ludoviciana ssp. mexicana, Calea zacatechichi, and Polymnia maculata (all rich in sesquiterpene lactones) as inhibitors of NF-kappaB down to a concentration of 25 microg/ml. The sesquiterpene lactones isohelenin and parthenolide prevented NF-kappaB activation completely as low as 5 microM. Treatment of HeLa cells with leaf extract of A. ludoviciana ssp. mexicana, isohelenin and parthenolide prevented the induction of transcription on the IL-6 promoter. These experiments identify the eudesmanolide and germacranolide type of sesquiterpene lactones as potent non-antioxidant inhibitors of NF-kappaB. All plants active in the NF-kappaB assay also showed a delay in the onset of capillary reactions of the allantois membrane in a physiological model for anti-inflammatory activity - the HET-CAM assay.
The preliminary results of a clinical safety review that partly used the Cochrane methodology are presented. Despite methodological limitations including incomplete databases, this review collated evidence corroborating the benign safety profile of the artemisinin type of compounds. No difference was apparent amongst the various derivatives. At the time the workshop was held, 188 studies had been identified of which 108 (enrolling 9,241 patients) fulfilled criteria for analyses. These included both uncomplicated and severe malaria patients enrolled in either controlled and non-controlled studies as well as healthy volunteers. Safety was assessed by analysing adverse events, as well as clinical laboratory (haematology assessed in 4,062, blood chemistry in 3,893 patients), electrocardiographic (2638 patients) and neurological assessments as reported in the papers. No serious adverse event or severe significant toxicity was reported. Overall, the most commonly reported adverse experiences were gastro-intestinal. Occasional neutropenia (1.3%), reticulocytopenia (0.6%), elevated liver enzymes (0.9%) were reported. Transient bradycardia and prolonged QT interval were reported in circa 1.1% of patients monitored. A neurological assessment was performed primarily in the severe malaria patients. No difference was apparent with respect to quinine. In addition, four cases of neuropsychiatric adverse events were reported in patients receiving concomitant mefloquine.
The development of techniques for the culture of lymphoid cells and the isolation of viruses that infect these cells led to
the discovery of human herpesvirus (HHV) 6 in 1986. At the time, HHV-6 was the first new human herpesvirus to be discovered
in roughly a quarter of a century, and its isolation marked the beginning of an era of discovery in herpesvirology, with the
identification of HHV-7 and HHV-8 (Kaposi's sarcoma—associated herpesvirus) during the following decade. Like most human herpesviruses,
HHV-6 is ubiquitous and capable of establishing a lifelong, latent infection of its host. HHV-6 is particularly efficient
at infecting infants and young children, and primary infection with the virus is associated with roseola infantum (exanthem
subitum) and, most commonly, an undifferentiated febrile illness. Viral reactivation in the immunocompromised host has been
linked to a variety of diseases, including encephalitis, and HHV-6 has been tentatively associated with multiple sclerosis.
This article discusses the major properties of HHV-6, its association with human disease, and the pathobiological significance
of viral reactivation.
In order to study the pathogenesis of HHV-6 infection in central nervous system disorders, U251 cell line was infected with freshly isolated variant B HHV-6. Although IEA/ex 3 antigen (immediate early protein) was detected in infected cell nuclei, neither the presence of OHV-3 antigen (late antigen) nor production of infectious virus was demonstrated. These results indicate that abortive infection was established in the cells. After viral infection, the viral genome copy in the infected cells gradually decreased and became stable after 6 cell passages. At that point, HHV-6 gene expression was restricted to only 2 immediate early genes (U90 and U94). However, 12-O-tetra-decanoyl (TPA) treatment induced transcription of other genes (U31 and U39) by the 10th cell passage, indicating HHV-6 reactivation. Moreover, production of two proinflamatory cytokines (IL-6 and IL-1beta) was up-regulated by the presence of the HHV-6 genome and TPA-induced activation of the viral transcripts.
Antiviral therapy of primary and recurrent infections with human cytomegalovirus is reserved for severe manifestations and faces several limitations. Presently candidates for novel drugs with lower adverse side effects and a minimized frequency of resistance formation are under investigation. Here we demonstrate that artesunate, an antimalaria drug with highly valuable pharmacological properties, possesses antiviral activity. A concentration-dependent inhibition of the replication of human cytomegaloviruses with wild-type phenotype was demonstrated in several cell lines. Inhibition was quantified using recombinant green fluorescent protein expressing virus variants. The IC50 values were in the same range for ganciclovir-sensitive and ganciclovir-resistant human cytomegalovirus, as calculated with 5.8+/-0.4 microM and 6.9+/-0.2 microM, respectively. This indicated a strong antiviral potential and a lack of cross-resistance. The optimal antiviral concentrations of artesunate were separable from those inducing cytotoxicity. In addition, the replication of viruses from three genera was seen to be artesunate-sensitive to varying degrees. This suggests a mechanism linked to cellular activation pathways. Both the protein levels and the DNA binding activity of the two virus-induced cellular transcription factors Sp1 and NF-kappaB were found to be markedly reduced in the presence of artesunate. We also analyzed the cellular signaling kinase phosphoinositide 3-kinase, required for the activation of factors such as Sp1 and NF-kappaB in infected fibroblasts. The phosphorylation of two downstream effectors of phosphoinositide 3-kinase, Akt and p70S6K, was markedly inhibited in the presence of artesunate. Thus, artesunate possesses attractive antiviral characteristics which are suggestively based on the interference with essential steps in the host cell kinase cascades.
Human herpesviruses may cause infections of the central nervous system (CNS). The early diagnosis of herpesvirus-associated neurological diseases is of high importance.
The objective of this paper is to summarize the experience gained with the diagnosis of herpesvirus infections of the CNS at our institute by polymerase chain reaction (PCR)-based assays within the past few years.
A retrospective analysis of herpesvirus desoxy ribonucleic acid (DNA)-positive cerebrospinal fluid (CSF) samples was performed, with particular emphasis on data obtained by quantification of virus DNA in CSF by newly established real-time quantitative PCR assays.
Herpesviruses were found in 26.6% of all virus-positive CSF samples detected at our institute between 1995 and 2001. The overall broad testing for different herpesviruses from CSF has led to an increase in the detection rate, especially in relation to varicella zoster virus (VZV)-associated CNS disease. The herpesvirus DNA load in CSF was investigated by TaqMan real-time PCR assays that were established for the individual herpesviruses. The amount of virus varied among the individual diseases, associated with herpes simplex virus type 1, herpes simplex virus type 2, VZV and cytomegalovirus, while for Epstein-Barr virus and human herpesvirus type 6 only low levels of virus were detectable in CSF.
A generally broad testing for different herpesviruses in CSF samples is highly recommended. In addition, determination of the virus DNA level in CSF by quantitative assays seems to be of high importance for elucidating aspects concerning the prognosis of disease, the prediction of distinct CNS manifestations, and possibly the differentiation between specific virus-associated disease and unspecific presence of virus in CSF, especially in immunocompromised patients.
The frequency of human herpesvirus 6 (HHV-6) DNA was assessed in autopsy material from multiple sclerosis (MS) plaques and
normal-appearing white matter (NAWM) from brains of persons with MS, healthy brains, and brains of persons with other neurologic
diseases. Specific areas from formalin-fixed, paraffin-embedded brain tissue samples were isolated by laser microscope. DNA
was extracted from laser microdissected brain material, and HHV-6 genomic sequences were amplified by nested polymerase chain
reaction. We analyzed 44 NAWM samples and 64 MS plaques from 13 patients with MS, 46 samples from 13 patients with non-MS
neurologic disorders, and 41 samples from 12 healthy control brains. Of the 44 NAWM samples, 7 (15.9%) were positive for HHV-6
DNA sequences, versus 37 (57.8%) of 64 MS plaques (P<.0005). HHV-6 DNA was detected in 10 (21.7%) of 46 samples from patients
with non-MS neurologic disorders and in 11 (26.8%) of 41 samples from patients without known neurologic disease. Although
the frequency of HHV-6 DNA did not differ significantly by sample type, HHV-6 DNA was significantly more common in MS plaques,
suggesting that HHV-6 may play a role in MS pathogenesis
A discrepancy seems to prevail with regard to the toxicity and safety of the artemisinin family of antimalarials. While these compounds have been found to be virtually void of any serious side effects in humans, their neurotoxicity in animal models has raised concerns about their use. In this paper, we present selected examples of both pre-clinical and clinical studies dealing with adverse effects of artemisinin drugs. We suggest that the prolonged presence of artemisinins upon slow release from oil-based intramuscular formulations is the main cause of the observed toxicity in laboratory animals. In contrast, oral intake of these compounds, which is by far the most common formulation used for treatment of malaria patients, results in rapid clearance of these drugs and is thus unlikely to cause any toxicity in human subjects. Another plausible factor may be the relatively high doses of artemisinin compounds used in animal studies. In conclusion, the observation of the toxicity of artemisinin compounds in animals, but not in humans, is most likely due to different pharmacokinetic profiles after different routes of administrations.
The International Herpes Management Forum (IHMF) has produced guidelines to promote improved diagnosis of herpesvirus infections of the central nervous system (CNS). Recommendations include using polymerase chain reaction (PCR) analysis of cerebrospinal fluid (CSF) to help diagnose herpes simplex virus (HSV), varicella zoster virus (VZV) and cytomegalovirus (CMV) infections of the CNS. Laboratories routinely using such tests should participate in a proficiency testing programme. For retrospective diagnosis of herpesvirus infections of the CNS, intrathecal antibody detection can be used as an adjunct to PCR, assuming all appropriate controls are utilized. For suspected cases of herpes simplex encephalitis (HSE), a sensitive HSV PCR test of the CSF should be used in preference to other methods. Cultures are not recommended for HSE except as an adjunctive test in suspected neonatal HSV infections. While research continues into the role of PCR with VZV infections of the CNS, studies demonstrate that the technique is useful for diagnosing varicella-associated CNS syndromes but further research is required for its role in zoster-associated syndromes. For CMV CNS infections, PCR represents the most sensitive diagnostic method and can be used in conjunction with virus culture to determine suspected cases of CMV myelitis. For CNS infections with lymphotropic herpesviruses, a positive PCR test is suggestive, but not definitive, evidence of virus encephalitis. PCR analysis of CSF for Epstein-Barr virus can be useful for diagnosing AIDS-associated primary CNS lymphoma. This article presents the current evidence for these and other guidelines for the diagnosis of herpesvirus infections of the CNS.
Iron(II) heme-mediated activation of the peroxide bond of artemisinins is thought to generate the radical oxygen species responsible for their antimalarial activity. We analyzed the role of ferrous iron in the cytotoxicity of artemisinins toward tumor cells. Iron(II)-glycine sulfate (Ferrosanol) and transferrin increased the cytotoxicity of free artesunate, artesunate microencapsulated in maltosyl-beta-cyclodextrin, and artemisinin toward CCRF-CEM leukemia and U373 astrocytoma cells 1.5- to 10.3-fold compared with that of artemisinins applied without iron. Growth inhibition by artesunate and ferrous iron correlated with induction of apoptosis. Cell cycle perturbations by artesunate and ferrous iron were not observed. Treatment of p53 wild-type TK6 and p53 mutated WTK1 lymphoblastic cells showed that mutational status of the tumor suppressor p53 did not influence sensitivity to artesunate. The effect of ferrous iron and transferrin was reversed by monoclonal antibody RVS10 against the transferrin receptor (TfR), which competes with transferrin for binding to TfR. CCRF-CEM and U373 cells expressed TfR in 95 and 48% of the cell population, respectively, whereas TfR expression in peripheral mononuclear blood cells of four healthy donors was confined to 0.4-1.3%. This indicates that artemisinins plus ferrous iron may affect tumor cells more than normal cells. The IC(50) values for a series of eight different artemisinin derivatives in 60 cell lines of the U.S. National Cancer Institute were correlated with the microarray mRNA expression of 12 genes involved in iron uptake and metabolism by Kendall's tau test to identify iron-responsive cellular factors enhancing the activity of artemisinins. This pointed to mitochondrial aconitase and ceruloplasmin (ferroxidase).
In addition to cytomegalovirus (CMV), activation of other betaherpesviruses, especially human herpesvirus 6 (HHV-6), has been reported in liver transplant patients. The purpose of this study was to investigate the posttransplant HHV-6-DNAemia in relation to CMV-DNAemia in liver transplant patients. Thirty-one adult liver allograft recipients were regularly monitored for CMV and HHV-6 during the first 3 months after transplantation. For the diagnosis of CMV infections, pp65-antigenemia assay and quantitative DNA-PCR were used. HHV-6 was demonstrated by using quantitative DNA-PCR and HHV-6 antigenemia test. Altogether 253 blood specimens of 31 recipients were analyzed. In addition, CMV and HHV-6 specific antigens were demonstrated by immunohistochemistry in liver biopsy specimens in the case of graft dysfunction. Thirteen patients (40%) developed a clinically significant CMV infection, at a mean of 33 days (range 5 to 62 days) after transplantation and were treated with intravenous ganciclovir. The peak viral loads of these symptomatic CMV infections were high (CMV-DNA 34210 +/- 37557 copies/mL plasma). Six additional asymptomatic patients demonstrated significantly lower CMV-DNAemia levels (1020 +/- 1008 copies/mL, P < .05), and were not treated. Concurrently with CMV, HHV-6 DNAemia and antigenemia were detected in 17 of 19 patients, mean 11 days (range 6 to 24 days) after transplantation. HHV-6 appeared prior to CMV in most cases (12 of 17). However, the peak viral loads were low (HHV-6-DNA <1500 copies/mL blood), even in the five patients who demonstrated HHV-6 antigens on liver biopsy. All CMV infections were successfully treated with ganciclovir and the CMV DNAemia/antigenemia subsided. HHV-6 also responded to the antiviral treatment, but more slowly and less clearly. In conclusion, HHV-6 activations were common and usually associated with CMV infection in liver transplant patients. Further investigation of the clinical significance of HHV-6 DNAemia/antigenemia is necessary.
Treatment of human cytomegalovirus (HCMV) infections with any of the currently available antiviral agents is frequently associated with the occurrence of severe complications, seriously threatening the successful outcome of treatment. Therefore, the development of novel antiviral strategies is a challenging goal of current investigations. Previously, we reported that artesunate (ART) is an effective, non-cytotoxic inhibitor of HCMV in vitro. Here, we demonstrate that the efficacy of the antiviral effect of ART is augmented by co-treatment of HCMV-infected fibroblasts with ferrous iron, i.e. Ferrosanol, and/or the iron transfer-mediating molecule holo-transferrin. This could alleviate the HCMV-induced modulation of cell surface expression of adhesion molecule Thy-1, suggesting that ART might be able to prevent pro-inflammatory effects of infection. The iron-enhanced, antiviral effect of ART could also be demonstrated in cultured cells infected with rat cytomegalovirus. Experiments using the RCMV/rat model showed that both the viral DNA load and virus titers in the salivary glands from infected rats were significantly reduced upon treatment with ART. Furthermore, an additive antiviral effect for ART together with each one of conventional anti-HCMV drugs, i.e. ganciclovir, cidofovir or foscarnet, was detected in HCMV-infected fibroblasts. These findings might open new perspectives regarding the use of ART in clinical trials.
A variety of sesquiterpene lactones (SLs) possess considerable anti-inflammatory activity. Several studies have shown that they exert this effect in part by inhibiting the activation of the transcription factor NF-kappaB. In the present study we elaborated on the investigation of a data set of 103 structurally diverse SLs for which we had previously developed several different QSAR equations dependent on the skeletal type. Use of 3D structure descriptors resulted in a single model for the entire data set. In particular, local radial distribution functions (L-RDF) were used that centered on the methylene-carbonyl substructure believed to be the site of attack of cysteine-38 of the p65/NF-kappaB subunit. The model was developed by using a counterpropagation neural network (CPGNN), attesting to the power of this method for establishing structure-activity-relationships. The investigations shed more light onto the influence of the chemical structure on NF-kappaB inhibitory activity.
Human herpesvirus 6 (HHV-6) is a member of the Roseolovirus genus of the b-herpesvirus subfamily of human herpesviruses. HHV-6 infects virtually all children during the early years of life and, like other herpesviruses, establishes latency after primary infection. In immunocompromised hosts, especially transplant recipients, HHV-6 is able to reactivate and cause disease. There are two subtypes of HHV-6: type A and type B. The two subtypes share certain biological properties and a high level of sequence homology, but differ dramatically in their epidemiology. We have learned much about the epidemiology and clinical impact of HHV-6 in the decades since it was first identified, but many questions still remain. This update focuses on new findings regarding the epidemiology and clinical syndromes of HHV-6, especially as they pertain to primary infection, neurological disease, and the transplant setting. In addition, diagnostics and antiviral treatment are reviewed.
Human cytomegalovirus-encoded pUL50 and pUL53 belong to a group of conserved herpesviral nuclear proteins. This study describes: (i) the co-localization of pUL50 with components of the nuclear lamina such as lamins A/C and lamin B receptor by double immunofluorescent staining, (ii) a strong pUL50-mediated relocalization of pUL53 from a diffuse nuclear pattern towards a nuclear rim localization, (iii) a direct interaction between pUL50 and pUL53, as well as between pUL50 and protein kinase C (PKC), shown by yeast two-hybrid and co-immunoprecipitation analyses, (iv) in vitro phosphorylation of pUL50, which is highly suggestive of PKC activity, and finally (v) partial relocalization of PKC by pUL50/pUL53 from its main cytoplasmic localization to a marked nuclear lamina accumulation. These data suggest a role for pUL50 and pUL53 in the recruitment of PKC, an event that is considered to be important for cytomegalovirus-induced distortion of the nuclear lamina.
This is the first report of treatment of cytomegalovirus infection with artesunate, for a stem cell transplant recipient with
a newly identified foscarnet-resistant and ganciclovir-resistant DNA polymerase L776M mutation. Artesunate treatment resulted
in a 1.7–2.1-log reduction in viral load by treatment day 7, with a viral half-life of 0.9–1.9 days, indicating a highly effective
block in viral replication.
Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections Severe meningoencephalitis caused by human herpesvirus 6 type B in an immunocompetent woman treated with ganciclovir
- D Donati
- N Akhyani
- Fogdell
- A Hahn
- C Cermelli
- R Cassiani-Ingoni
- A Vortmeyer
Donati D, Akhyani N, Fogdell-Hahn A, Cermelli C, Cassiani-Ingoni R, Vortmeyer A, et al. Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections. Neurology 2003;61:1405–11. 10. Birnbaum T, Padovan CS, Sporer B, Rupprecht TA, Ausserer H, Jaeger G, et al. Severe meningoencephalitis caused by human herpesvirus 6 type B in an immunocompetent woman treated with ganciclovir. Clin Infect Dis 2005;40:887–9.
CytomegaloviralproteinspUL50andpUL53 areassociatedwiththenuclearlaminaandinteractwithcellularproteinkinase C
- Milbradtj
- Auerochss
- Marschallm
MilbradtJ,AuerochsS,MarschallM.CytomegaloviralproteinspUL50andpUL53 areassociatedwiththenuclearlaminaandinteractwithcellularproteinkinase C. J Gen Virol 2007;88:2642–50
- C S Crumpacker
- Ganciclovir
Crumpacker CS. Ganciclovir. N Engl J Med 1996;335:721-9.
Case of fatal encephalitis by HHV-6 variant A
- M Portolani
- M Pecorari
- M G Tamassia
- W Gennai
- F Beretti
- G Guaraldi
Portolani M, Pecorari M, Tamassia MG, Gennai W, Beretti F, Guaraldi G. Case of
fatal encephalitis by HHV-6 variant A. J Med Virol 2001;65:133-7.