The HIV Protease Inhibitor Nelfinavir Inhibits Kaposi's Sarcoma-Associated Herpesvirus Replication In Vitro

Department of Pediatrics, University of Washington, Seattle, Washington, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 03/2011; 55(6):2696-703. DOI: 10.1128/AAC.01295-10
Source: PubMed


Kaposi's sarcoma (KS) is the most common HIV-associated cancer worldwide and is associated with high levels of morbidity and
mortality in some regions. Antiretroviral (ARV) combination regimens have had mixed results for KS progression and resolution.
Anecdotal case reports suggest that protease inhibitors (PIs) may have effects against KS that are independent of their effect
on HIV infection. As such, we evaluated whether PIs or other ARVs directly inhibit replication of Kaposi's sarcoma-associated
herpesvirus (KSHV), the gammaherpesvirus that causes KS. Among a broad panel of ARVs tested, only the PI nelfinavir consistently
displayed potent inhibitory activity against KSHV in vitro as demonstrated by an efficient quantitative assay for infectious KSHV using a recombinant virus, rKSHV.294, which expresses
the secreted alkaline phosphatase. This inhibitory activity of nelfinavir against KSHV replication was confirmed using virus
derived from a second primary effusion lymphoma cell line. Nelfinavir was similarly found to inhibit in vitro replication of an alphaherpesvirus (herpes simplex virus) and a betaherpesvirus (human cytomegalovirus). No activity was
observed with nelfinavir against vaccinia virus or adenovirus. Nelfinavir may provide unique benefits for the prevention or
treatment of HIV-associated KS and potentially other human herpesviruses by direct inhibition of replication.

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Available from: Adam Geballe, Sep 30, 2015
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    • "Development of novel antivirals has been proposed to target HSV proteins that inhibit autophagy [76], and early studies suggest that agents that induce autophagy can inhibit HSV replication [77, 78]. "
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    ABSTRACT: Herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) infect a large proportion of the world's population. Infection is life-long and can cause periodic mucocutaneous symptoms, but it only rarely causes life-threatening disease among immunocompetent children and adults. However, when HSV infection occurs during the neonatal period, viral replication is poorly controlled and a large proportion of infants die or develop disability even with optimal antiviral therapy. Increasingly, specific differences are being elucidated between the immune system of newborns and those of older children and adults, which predispose to severe infections and reflect the transition from fetal to postnatal life. Studies in healthy individuals of different ages, individuals with primary or acquired immunodeficiencies, and animal models have contributed to our understanding of the mechanisms that control HSV infection and how these may be impaired during the neonatal period. This paper outlines our current understanding of innate and adaptive immunity to HSV infection, immunologic differences in early infancy that may account for the manifestations of neonatal HSV infection, and the potential of interventions to augment neonatal immune protection against HSV disease.
    Clinical and Developmental Immunology 03/2013; 2013(12):369172. DOI:10.1155/2013/369172 · 2.93 Impact Factor
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    • "Interestingly, HIV-1 PI atazanavir can inhibit PI3K cellular signaling pathway activated in human primary monocytes infected by canarypox and, as a consequence, the expression of heterologous antigens (as GFP or HIV-1 Gag) by ALVAC recombinant was significantly reduced (Hu et al., 2009). Moreover, it is remarkable that some HIV-1 PIs, as nelfinavir, could inhibit the in vitro replication of some DNA viruses, as Kaposi's sarcoma-associated herpesvirus, herpes simplex virus, and human cytomegalovirus (Gantt et al., 2011). Therefore, PIs could affect the biology of poxviruses acting on multiple enzymes and factors encoded or activated by poxviruses, as PI3K signaling pathway, which may result in an inhibition of poxvirus replication and expression of foreign antigens. "
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    ABSTRACT: MVA-B is an attenuated poxvirus vector expressing human immunodeficiency virus type 1 Env, Gag, Pol, and Nef antigens from clade B, and is considered a promising HIV/AIDS vaccine candidate. Recently, a phase I clinical trial in human healthy volunteers has shown that MVA-B is safe and highly immunogenic, inducing broad, polyfunctional, and long-lasting CD4(+) and CD8(+) T cell responses to HIV-1 antigens, with preference for effector memory T cells; and it also triggers the induction of specific antibodies to Env in most of the vaccines. While MVA recombinants expressing HIV-1 antigens are being used or plan to use in therapeutic clinical trials, little is known on the effect of HIV-1 highly active antiretroviral therapy in MVA life cycle. To define this role, here we have evaluated in established cell cultures and human dendritic cells to what extent different HIV-1 protease inhibitors affect virus replication and expression of HIV-1 antigens during MVA-B infection. The results obtained revealed that the most commonly used HIV-1 protease inhibitors (atazanavir, ritonavir, and lopinavir) had no effect on MVA-B virus growth kinetics, even at higher concentrations than those normally used on HAART. Furthermore, expression of gp120 and the fused Gag-Pol-Nef polyprotein in permissive and non-permissive cells infected with MVA-B were also not affected. These findings are relevant information for the therapeutic use of MVA-B as an HIV-1/AIDS vaccine.
    Virus Research 05/2012; 167(2):391-6. DOI:10.1016/j.virusres.2012.05.020 · 2.32 Impact Factor
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    • "The mechanisms by which HAART may exert an anti-HHV-8 effect remain unclear. The sample size or heterogeneity in HAART regimens was insufficient to evaluate whether specific components of HAART are associated with an inhibition of HHV-8 replication, as has recently been described[Gantt et al., 2011], but the mechanisms by which HAART may indirectly inhibit HHV-8 infection through immune reconstitution, suppression of HIV replication, etc. have been reviewed elsewhere[Casper and Wald, 2007]. Further studies using prospective cohorts to assess the effect of specific HAART components and other antiretroviral drugs on HHV-8 are needed. "
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    ABSTRACT: Human herpesvirus-8 (HHV-8) replication is a key factor in Kaposi sarcoma, primary effusion lymphoma, and Castleman disease pathogenesis. In vitro data suggest that antivirals inhibit HHV-8 replication, but little data exist in humans. Daily oropharyngeal swabs were analyzed from HIV/HHV-8 dually infected men enrolled in three previous clinical trials of valacyclovir and famciclovir for HIV-1 and/or HSV-2 suppression. Fifty-eight participants contributed 6,036 swabs. HHV-8 was detected in 1,128 (19%) of 6,036 swabs, including 618 (21%) of 2,992 on placebo, 323 (15%) of 2,221 on valacyclovir, and 187 (23%) of 823 on famciclovir. After adjusting for baseline HIV viral load and highly active antiretroviral therapy (HAART) use, an 18% reduction in HHV-8 shedding frequency (IRR 0.822; P = 0.011) was found in participants on valacyclovir and a 30% reduction (IRR 0.700; P < 0.001) on famciclovir. HAART was associated with an 89% (IRR 0.129; P = 0.048) reduction in HHV-8-shedding. Neither antiviral nor antiretroviral therapy was associated with decreased HHV-8 quantity. Valacyclovir and famciclovir were associated with modest but significant reductions in HHV-8 oropharyngeal shedding frequency. In contrast, HAART was a potent inhibitor of HHV-8 replication. Studies of whether antiviral therapy in combination with ART will prevent HHV-8-associated disease appear warranted.
    Journal of Medical Virology 10/2011; 83(10):1696-703. DOI:10.1002/jmv.22194 · 2.35 Impact Factor
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