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Tripterygium wilfordii Hook F extract in cART-treated HIV patients with poor immune response: a pilot study to assess its immunomodulatory effects and safety
Abstract
Despite combination antiretroviral therapy (cART), 20% of HIV-infected patients are unable to achieve adequate immunologic recovery, in which immune activation plays a crucial role. We hypothesize that extract of Tripterygium wilfordii Hook F (TwHF), a Chinese medication used to treat autoimmune diseases, has immunomodulatory effects that may help CD4 cell recovery.
Eighteen cART-treated HIV-infected patients virally suppressed for over 12 months with suboptimal CD4 cell recovery were enrolled. TwHF extract was administered at a dosage of 10 mg three times daily for 12 months. T-cell subsets and activation markers were evaluated at baseline and during follow-up. The trial was registered at Clinicaltrials.gov (NCT02002286).
TwHF extract was associated with a mean increase in CD4 cell count of 88 cells/μl (95% confidential interval [CI], 72-105 cells/μl) after one year of treatment. A significant increase in the mean rate of CD4 cell recovery (26 before vs 75 cells/μl/year after TwHF use, P < 0.001) was observed. Analysis of 13 patients with activation profiles suggested that TwHF extract was associated with a decrease in T-cell immune activation which was temporally correlated with CD4 cell recovery. No discontinuation of TwHF extract was reported.
Use of TwHF extract in HIV-infected patients was associated with a reduction in T-cell activation and improved CD4 recovery with an excellent safety profile.
... Our previous studies have proven that combined use of ART and TwHF can improve immunological recovery. [15] Here, we purposely tested whether such a combination could prolong the ART-free remission, and found that the patient peripheral HIV RNA and DNA levels remained suppressed for at least 12 months. consent was obtained from the participant. ...
... Our previous study showed that the use of immune-modulator TwHF was associated with reduced T cell activation and improved CD4 recovery in treated immunological non-responders. [15] Herein, we report a man with primary HIV-1 infection, who was treated by ART combined with TwHF and achieved delayed viral rebound despite ART discontinuation. This particular case has extended the frontier of TwHF's antiinflammation effect, by showing its potency in prolonging ARTfree remission. ...
... TGs are extracted from TwHF, and can be used to regulate immunity, reduce blood sugar, or as anti-inflammatories. 10,11 TGs have also been used to treat proteinuria in patients with DN. 12,13 Angiotensinconverting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are common treatments for DN. 14 In recent years, TGs have been used widely in China. However, randomized controlled trials (RCTs) are lacking, particularly those comparing treatment using ACE inhibitors or ARBs plus TGs with treatment using ACE inhibitors or ARBs alone. ...
... The pathogenesis of DN is multifactorial, and is often linked to hemodynamics, oxidative stress, inflammation, and, especially, the immune inflammatory response. 10,11,31,32 TGs are extracted from the traditional Chinese medicine, TwHF, which has been used to dispel wind and dampness, relieve swelling and pain, and promoting blood circulation to dredge collaterals. The active ingredients in TGs are diterpenoid alkaloids, as well as three terpenes. ...
Introduction
Tripterygium glycosides (TGs) have been widely used in China to treat diabetic nephropathy (DN); however, proof of their use is scarce. The present study aimed to evaluate the effectiveness and safety of adding TGs to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).
Methods
By searching Embase, MEDLINE, Cochrane Library, SINOMED, China National Knowledge Infrastructure, VIP Information/Chinese Scientific Journals, and WANFANG databases, we identified previous studies that met the specific selection criteria and included them in the meta-analysis. Analyses were performed using Review Manager (version 5.3).
Results
Nine randomized controlled trials were included in the final meta-analysis. Patients were compared before and after treatment with ACE inhibitors or ARBs plus TGs, or ACE inhibitors or ARBs alone. The results revealed that treatment with ACE inhibitors or ARBs plus TGs resulted in significantly greater reductions in 24-h urinary total protein (UTP) levels (trial duration <2 months, mean difference [MD]: −0.25; 95% confidence interval [CI]: −0.32, −0.18; trial duration between 2 and 6 months, MD: −0.39; 95% CI: −0.44, −0.33; trial duration >6 months, MD: −2.09; 95% CI: −2.89, −1.29) compared with treatment using ACE inhibitors or ARBs alone. Additionally, ACE inhibitors or ARBs plus TGs showed better results after long-term administration. Treatment with ACE inhibitors or ARBs plus TGs resulted in significantly greater reductions in serum creatinine (SCr) compared with ACE inhibitors or ARBs alone (MD: −9.87; 95% CI: −13.76, −5.97).
Conclusion
In patients with DN, adding TGs to ACE inhibitors or ARBs significantly lowered both the 24-h UTP and SCr levels. Therefore, ACE inhibitors or ARBs plus TGs might improve the treatment of DN in patients.
... A total of 62.3% of patients were male. The median age was 33 years (IQR, [27][28][29][30][31][32][33][34][35][36][37][38][39]. Among them, 21 patients were infected with the HIV-1 AE subtype and 19 patients with either the B, C, or BC subtype. ...
... Our study suggests that in the management of HIV-1-infected patients, the recovery of CD4/CD8 ratio should be given more attention. At the same time, combined use of immune modulators that can improve CD4 + T-cell recovery and decrease immune activation [39] may help achieve lower HIV-1 DNA levels. ...
Background
The HIV-1 DNA reservoir is an important marker that reflects viro-immunological status and can be affected by multiple viral or cellular factors. Determining the potential factors associated with the size of the HIV-1 DNA reservoir benefits the surveillance of disease progression and antiretroviral treatments. Methods
We conducted a case control study to explore the factors that may affect the level of HIV-1 DNA. The level of HIV-1 total DNA in peripheral blood at 5 time points was quantified by quantitative PCR. Chronically HIV-1-infected patients whose cell-associated HIV-1 DNA levels were below the detection limit after receiving antiretroviral therapy (ART) for 96 weeks were identified (group 1), and patients who still had detectable levels of cell-associated HIV-1 DNA after ATR treatment were used as the control (group 2). ResultsTwenty-one patients with ultralow levels of cell-associated HIV-1 DNA [<20 copies/106 peripheral blood mononuclear cells (PBMCs)] presented with a lower CD8+ T-cell count (average: 511 ± 191 versus 715 ± 256 cells/μL, p = 0.013) and a higher CD4/CD8 ratio (average: 1.04 ± 0.37 versus 0.72 ± 0.32, respectively, p = 0.002) at week 96. In the multivariate analysis, patients with a higher CD4/CD8 ratio at week 96 were more likely to have levels of HIV-1 DNA below the detection limit (per 0.1 increase, OR = 1.29, 95% CI, 1.05–1.59, p = 0.017). Conclusion
After matching baseline HIV-1 DNA levels, a higher CD4/CD8 ratio at week 96 was the only factor associated with an ultralow level of HIV-1 DNA. The CD4/CD8 ratio can be used as an easy biomarker to help monitor patients on ART who will be selected to participate in eradication studies.
... The poor recovery of the CD4 + T cell (CD4 cell) population after highly active antiretroviral therapy (HAART) is associated with a significant increase in the mortality and morbidity of acquired immunodeficiency syndrome (AIDS), 30 and receiving HAART timely may have a beneficial effect on immune reconstitution. 31 It has been reported that specific therapies targeting T cell immune activation, such as the extract of Tripterygium wilfordii Hook F (TwHF) and Vitamin, 32,33 are correlated with CD4 cell recovery. And the therapies spotting pro/anti-inflammatory cytokines, like interleukin-7 (IL-7) and interleukin-2 (IL-2), have also been reported to be beneficial for reconstituting T cell counts. ...
Objective:
Numerous studies have reported on the pathogenesis of poor immune reconstitution (PIR) after antiretroviral treatment in human immunodeficiency virus (HIV) patients. However, fewer studies focused on both immune-related genes (IRGs) and immune cells, and the correlation between IRGs and immune cells was evaluated via bioinformatics analyses.
Methods:
Gene expression profiling of GSE143742 from the Gene Expression Omnibus (GEO) database was analyzed to get differentially expressed immune-related genes (DEIRGs). The enrichment analysis and protein-protein interaction (PPI) networks of DEIRGs were established. The relative fractions of 22 immune cell types were detected using the "CIBERSORT". The correlation analysis between DEIRGs and immune cells was constructed to discover the potential IRGs associated with immune cells. A logistic regression diagnostic model was built, and a receiver operating characteristic (ROC) curve was performed to evaluate the model's diagnostic efficacy. The CMap database was used to find molecules with therapeutic potential. RT-qPCR was used to verify the expression of the hub DEIRGs.
Results:
We identified eight types of significantly changed immune cells and five hub IRGs in INRs. The DEIRGs were mainly enriched in lymphocyte activation, receptor-ligand activity, and T cell receptor signaling pathway. The correlation analysis showed that the expression of TNF, CXCR4 and TFRC correlate with CD8 cells, resting mast cells, activated NK cells, and naïve CD4 cells in INRs. Meanwhile, TFRC and IL7R relate to activated NK cells and resting memory CD4 cells respectively in IRs. A diagnostic model was constructed using multiple logistic regression and nine small molecules were identified as possible drugs.
Conclusion:
In this study, we suggested that the process of PIR might be related to TNF, CXCR4, TFRC, CD48, and IL7R. And these IRGs play roles in regulating immune-competent cells. And our constructed diagnostic model has excellent effectiveness. Moreover, some small-molecule drugs are screened to alleviate PIR.
... TCM can improve CD4+ T cell counts, naive CD4+ T cell counts, memory CD4+ T cell counts, and CD45RA and/or CD45RO cell counts while simultaneously decreasing T-cell immune activation. [5][6][7][8][9] A prior study showed that Mianyi granules (免疫Ⅱ颗粒) were effective in increasing CD4+ T cell counts in patients with HIV undergoing HAART.10 This trial was designed to evaluate the therapeutic effects of Mianyi granules on CD4+ T cells in HIV-positive patients with incomplete immune reconstitution following ART. ...
Objective:
To investigate whether Mianyi granules (+mianyi+) are effective and safe in reversing immune nonresponse following antiretroviral therapy (ART) in individuals with human immunodeficiency virus (HIV) infection.
Methods:
Randomized, double-blind, multi-center, placebo-controlled trial (factorial design) of daily oral Mianyi granules versus placebo for 72 weeks. A total of 361 HIV-positive individuals receiving ART at five Class III Grade I hospitals in China between September 2013 and January 2016 completed the study. The primary endpoints were frequencies of CD3+, CD4+, CD8+, and CD45RA+ cells at seven timepoints over the 72 weeks. Secondary endpoints included viral loads, clinical symptoms, and quality of life at 72 weeks.
Results:
A total of 400 participants were enrolled in the study and randomized, of whom 361 completed the study: 189 individuals (140 men and 49 women) in the Mianyi granule group and 172 individuals (135 men and 37 women) in the placebo group. In the intent-to-treat population, CD4+ T cell counts increased from (193 ± 71) cells/mm at baseline to (288 ± 131) cells/mm post-treatment in the Mianyi granule group and from (200 ± 75) cells/mm at baseline to (264 ± 124) cells/mm post-treatment in the placebo group. Patients treated with Mianyi granule had higher increases in CD4+ T cell counts than those treated with placebo ( = 0.045). Reversal of immune nonresponse was defined as a CD4+ T cell increase of more than 100 cells/mm3. After treatment for 72 weeks, Mianyi granule was effective in reversing immune nonresponse in a higher proportion of individuals (20.2%) compared with placebo (9.7%). CD45RA+ cell counts increased from (34 ± 32) cell/mm at baseline to (51 ± 61) cells/mm post-treatment in the Mianyi granule group and from (37 ± 33) cells/mm at baseline to (48 ± 37) cells/mm post-treatment in the placebo group. Mianyi granules were more effective than placebo in increasing CD45RA+ cell counts.
Conclusions:
In ART-treated HIV-positive adults with immune nonresponse, treatment with Mianyi granules for 72 weeks was safe and significantly increased CD4+ and CD45RA+ cell counts, thereby promoting immune reconstitution.
... Among the significant bioactive component extracted from TwHF, triptolide has been demonstrated to reduce LPS-induced inflammation [100][101][102][103]. Li et al. creatively combined TwHF (10 mg, three times/d) with ART in 18 immune nonresponder HIV patients. After one year of treatment by TwHF extract, CD4 + T cell count markedly increased, and the percentage of CD38 + HLA-DR + expressed on CD8 + T and CD4 + T cells decreased significantly during the 12-month treatment period [104]. Given these promising results, randomized placebo-controlled studies that enrolled more patients are warranted to evaluate the effects of TwHF extract on HIV patients. ...
Although antiretroviral therapy effectively controls human immunodeficiency virus (HIV) replication, a residual chronic immune activation/inflammation persists throughout the disease. This aberrant immune activation and inflammation are considered an accelerator of non-AIDS-related events and one of the driving forces of CD4+ T cell depletion. Unfortunately, HIV-associated immune activation is driven by various factors, while the mechanism of excessive inflammation has not been formally clarified. To date, several clinical interventions or treatment candidates undergoing clinical trials have been proposed to combat this systemic immune activation/inflammation. However, these strategies revealed limited results, or their nonspecific anti-inflammatory properties are similar to previous interventions. Here, we reviewed recent learnings of immune activation and persisting inflammation associated with HIV infection, as well as the current directions to overcome it. Of note, a more profound understanding of the specific mechanisms for aberrant inflammation is still imperative for identifying an effective clinical intervention strategy.
... By reviewing published articles, we found that studies on traditional Chinese medicine to improve immune reconstitution usually from three aspects to assess immunomodulatory effects: 1) in T-cell immune activation [23]. Regulating immune activation with TCM remains an important novel field of research. ...
Ethnopharmacological relevance
The bidirectional property of traditional Chinese medicines (TCMs) was recorded in the classic work Medicine Origin (Yi Xue Qi Yuan) as early as the Jin and Yuan dynasties of ancient China. Since then, this imperative theory has been applied to guide the clinical application of TCMs. Studies have been performed to investigate this phenomenon only over the last three decades. A limited number of reviews on the bidirectional role of TCMs have been published, and almost all current studies are published in the Chinese language.
Aim of the review: The aim of this review is to provide the first comprehensive evidence regarding the bidirectional effects and the underlying mechanisms of TCMs and their active compounds.
Materials and methods
Information relevant to opposing pharmacological activities or opposing properties exerted by TCM prescriptions, herbal medicines, and their active compound, as well as their mechanisms was summarized by searching Chinese and English databases, including the Chinese National Knowledge Infrastructure (CNKI), Wan Fang Data, Chinese Scientific Journal Database (VIP), Google Scholar, PubMed, Web of Science, Science Direct, and Wiley Online Library.
Results
Although the bidirectional regulation of TCMs has been applied in the clinic since ancient times in China, only limited reviews have been published in Chinese. The existing data showed that bidirectional effects can be found in TCM prescriptions, herbal medicines, and pure active compounds. Additionally, the bidirectional role of TCMs was primarily reported in the modulation of immune function, blood circulation and hemostasis, gastrointestinal motility, the central nervous system and blood pressure. This may because the therapeutic outcomes of these disorders are more obvious than those of other complicated diseases. Intriguingly, some herbal medicines have multiple bidirectional activities; for instance, Panax ginseng C. A. Meyer showed bidirectional regulation of immune function and the central nervous system; Astragalus membranaceus can bidirectionally regulate blood pressure and immune function; and Rheum officinale Baill exerts bidirectional effects on blood circulation and hemostasis, gastrointestinal motility and immune function. The mechanisms underlying the bidirectional effects of TCMs are largely attributed to the complexity of herbal constituents, dosage differences, the processing of herbal medicine, and compatibility of medicines, the physiological conditions of patients and adaptogenic effects.
Conclusion
Uncovering the bidirectional effects and mechanisms of TCMs is of great importance for both scientific research and clinical applications. This review may help to facilitate the recognition of the bidirectional role of TCMs, to explain some seemingly-opposite phenomena in the pharmacological study of herbal medicines and to provide guidance for TCM practitioners.
Backgrounds:
Human immunodeficiency virus (HIV) infections induce robust, generalized inflammatory responses and lead to pathological systemic immune activation. This abnormal immune status persists despite successful antiretroviral therapy (ART). Immune modulating strategies in conjunction with ART were tried to reduce abnormal immune activation. Previously, we demonstrated that Tripterygium Wilfordii Hook F has been shown immunosuppressive activity in HIV patients. (5R)-5-hydroxytriptolide (LLDT-8), a new analog of triptolide, and the most active ingredient of Tripterygium Wilfordii Hook F, has been shown to have lower cytotoxicity. However, the role of LLDT-8 in HIV or simian immunodeficiency virus (SIV) needs to be explored.
Methods:
Six male adult Chinese rhesus monkeys were enrolled in our study. All of them were healthy and negative for SIV, and chronically SIVmac239 infected macaques were treated with LLDT-8 combined with ART (n = 4) or ART only (n = 2) after 14 weeks of infection. ART was determined at week 33, and LLDT-8 was continued until week 48. T cell immune activation and inflammation were compared during the period, and viral rebound time and reservoir were supervised after stopping ART.
Results:
The RNA level of the two groups continued to decline after initiating ART, RNA of 4 rhesus monkeys declined to the lower limit of detection at week 20. LLDT-8 administration combined with ART did not affect T cell activation and plasma levels of IL-6 and CRP. The viral load of all the macaques in both groups was rebounded 2 weeks after ART discontinuation. Furthermore, no significant decrease of SIV DNA was observed in the LLDT-8 treatment group.
Conclusions:
LLDT-8 administration during chronic SIV infection had no effect on T cell activation and plasma levels; Furthermore, LLDT-8 may not contribute to suppression of viral rebound and reservoir. These results suggest that LLDT-8 is unlikely to reduce immune activation and viral persistence without additional interventions.
Background
: The HIV-1 infected Immunological non-responders (INRs) are characterized by poor immune reconstitution after long-term treatment. Tripterygium Wilfordii Hook F (TwHF) pill is a traditional Chinese patent drug with extensive immunosuppressive effects and has been clinically proven efficacy in treating INRs.
Purpose
: The therapeutic mechanism of TwHF pills in the treatment of INRs was investigated by the combined multi-omics analysis on clinical samples and network pharmacology approach.
Methods
: Clinically, the peripheral blood mononuclear cells (PBMC) samples of TwHF-treated INRs from different time points were collected to conduct the transcriptomic and proteomic profiling. Key effector pathways of TwHF were enriched and analyzed by the ingenuity pathway analysis (IPA). Computationally, the TwHF-related compounds were obtained from traditional Chinese medicine databases, and literature search and structural prediction were performed to identify TwHF-related targets. Integrated with the INR-related targets, the 'TwHF-compounds-targets-INR' network was constructed to analyze core effector targets by centrality measurement. Experimentally, the effects of TwHF compounds on the T cells activation and expression of identified targets were evaluated with in vitro cell culture.
Results
: 33 INRs were included and treated with TwHF pills for 17 (IQR, 12-24) months. These patients experienced rapid growth in the CD4⁺ T cell counts and decreased T cell activation. The multi-omics analysis showed that the interferon (IFN)-signaling pathway was significantly inhibited after taking TwHF pills. The network pharmacology predicted the central role of the signal transducer and activator of transcription 1 (STAT1) in the 'TwHF-compounds-targets-INR' network. Further bioinformatic analysis predicted STAT1 would regulate over 58.8% of identified down-regulated genes. Cell experiments validated that triptolide (TPL) would serve as the major bioactivity compound of TwHF pills to inhibit the immune cell activation, the production of IFN-γ, the expression of downstream IFN-stimulated genes, and the phosphorylation of STAT1.
Conclusion
: Our research is the first to systemic verify the mechanisms of TwHF in treating INRs. The IFN signaling pathway and the STAT1 would be the major effector targets of TwHF pills in treating INRs. The TPL would be the major bioactive compound to inhibit the IFN response and the phosphorylation of STAT1. Our observations suggest the basis for further application of TPL analogous in treating INRs.
Objective
To investigate the immunomodulatory effects of artesunate in the immunologic non-responders (INRs) in people living with HIV (PLWH), and suggest new adjuvant strategies for HIV treatment in INRs.
Methods
A total of 197 INRs receiving antiretroviral therapy (ART) for at least 24 months from eight medical centers in China were enrolled. Artesunate tablets at different dosages were administered based on the conventional antiviral treatment regimen for 48 weeks. We evaluated immunological parameters at the baseline and during the follow-up period.
Results
There were significant increases in CD4⁺ T cell counts and CD45RA⁺ T cell counts in the ART + high-dose artesunate group after 24 and 48 weeks of treatment. The recovery level of CD8⁺CD38⁺ T cell counts after 24 and 48 weeks was significantly lower in ART + low-dose artesunate group than ART + high-dose artesunate group. The level of CD4⁺Ki67⁺/CD4⁺, early apoptosis cell counts/CD4⁺ and early apoptosis cell counts/CD8⁺ in ART + high-dose artesunate group were significantly recovered during duration. There were no significant differences in the level of CD4⁺CD25⁺T cell counts and CD4⁺CD38⁺T cell counts among the three groups after 24 and 48 weeks of treatment.
Conclusions
High-dose artesunate could benefit INRs in terms of CD4⁺T cell counts by enhancing the functional recovery of the thymus and decreasing the level of immune activation and apoptosis. This study was registered at the Chinese Clinical Trial Registry with DOL number as CHiCTR1800015289.
Over a millennia, traditional Chinese medicine (TCM) has been used to treat various diseases in China. In recent years, more and more Chinese materia medica (CMM) have been studied in scientific research projects, applied in clinical practice, and their extracts have even appeared in some health products. However, the toxicity of some CMM is often overlooked, including hepatotoxicity, nephrotoxicity, neurotoxicity, cardiotoxicity, etc. In this review, the toxic components and their toxicological mechanisms of some toxic CMM were listed according to the chemical structure classification of toxic components. Afterwards, the traditional methods (processing and compatibility) and modern methods (structural modification, biotransformation, etc.) of attenuation of CMM were discussed. Since ancient times, it has been said that “fight fire with fire, fight poison with poison,” and toxic CMM are of great significance in the treatment of difficult and severe diseases. The rational application of toxic CMM and their components in clinical practice was also exemplified in this review. While the pharmacological effects of TCMs have been emphasized, the scientific attenuation and rational application of toxic components should be concerned. We hope this review can provide a reference for future related research.
Background:
The guidelines for pilot and feasibility studies were published in 2016. Little is known about the guideline adherence of TCM (traditional Chinese medicine) pilot trials or whether the guidelines can significantly enhance the quality of implementation and reporting of TCM pilot trials. We aimed to investigate the guideline adherence, assess the impact of guidelines on TCM pilot trials, and discuss potential challenges specific to TCM pilot trials, by conducting a literature review.
Methods:
We systematically searched MEDLINE, EMBASE, and CNKI to retrieve TCM pilot trials. We randomly chose 50 pilot trials from the eligible studies for analyses. The CONSORT extension to pilot and feasibility studies was used as a framework to assess the methodology and reporting quality of the studies.
Results:
The included studies had a guideline adherence level ranging from 4 to 96%, where the lowest adherence was found in the item 6c (prespecified criteria used to judge progression to future definitive trial). The guidance published in 2016 seemed to exert minimal effect on guideline adherence in TCM pilot trials. The unidentified issues related to TCM pilot trials from the guidelines included blinding, lack of standard formula of interventions, difficulty in comparison for effect assessment of interventions, and difficulty in bias control.
Conclusions:
The current practice in TCM pilot trials required substantial improvement in the literature. Further endeavors are needed for training and dissemination of guideline adherence, and development of more detailed methodology in the field of TCM pilot trials.
Purpose of Review
The introduction of the National Free Antiretroviral Therapy Program (NFATP) in 2003 by the China National Center for AIDS/STD Control and Prevention has led to dramatic increases in antiretroviral therapy (ART) coverage among HIV-infected Chinese patients. Despite limitations in the number of available free antiretroviral drugs, the overall mortality associated with HIV/AIDS has dropped from 39.3 per 100 person-years in 2002 to 3.1 in 2014. In this review, we summarize the challenges, responses, and achievements of antiretroviral therapy (ART) in China over the past 20 years.
Recent Findings
Continuous optimization of the Chinese National Guidelines for HIV/AIDS Diagnosis and Treatment has been guided by data from serial domestic multi-center studies aimed at evaluating efficacy and toxicity of available ART regimens among Chinese patients with HIV, with the goal of maximizing adherence, access, and efficacy. In addition, increasing attention has been focused on the importance of continuity in the HIV care cascade to promote linkage to care, and address the multidisciplinary chronic care needs HIV/AIDS patients on lifelong ART.
Summary
Great progress has been achieved in the past 20 years in terms of access to and optimization of antiretroviral treatment in China. As the number of patients receiving long-term ART continues to grow, the focus of HIV/AIDS treatment has gradually transitioned from urgent care to the management of non-AIDS-related chronic complications and control of chronic inflammation.
Background:
Terms and criteria to classify people living with HIV on antiretroviral therapy (ART) who fail to achieve satisfactory CD4 T cell counts are heterogeneous, and need revision and summarization.
Methods:
We performed a systematic review of PubMed original research articles containing a set of predefined terms, published in English between January 2009 and September 2018. The search retrieved initially 1360 studies, of which 103 were eligible. The representative terminology and criteria were extracted and analysed.
Results:
Twenty-two terms and 73 criteria to define the condition were identified. The most frequent term was "immunological non-responders" and the most frequent criterion was "CD4 T-cell count < 350 cells/µL after ≥ 24 months of virologic suppression". Most criteria use CD4 T cell counts as a surrogate, either as an absolute value before ART initiation or as a change after a defined period of time. Distinct values and time points were used. Only 9 of the 73 criteria were used by more than one independent research team. Herein we propose two criteria that could help to reach a consensus.
Conclusions:
The high disparity in terms and criteria here reported precludes data aggregation and progression of the knowledge on this condition because it renders impossible to compare data from different studies. This review will foster the discussion of terms and criteria to achieve a consensual definition.
Tripterygium wilfordii Hook F (TwHF) and its extracts have long been used for the treatment of rheumatoid arthritis, autoimmune diseases, and kidney disease due to their anti-inflammatory, immunoregulatory, and other pharmacological effects. However, the clinical immunoregulatory effects of TwHF and its extracts remain unclear, so we reviewed their effects for use in clinical practice. This review provides a comprehensive summary of the recent literature on the immunoregulatory effects of TwHF and its extracts in clinical studies. TwHF and its extracts affect the proliferation and activation of Tand B cells; ratio of Tcell subsets; inflammatory response of monocytes, macrophages, and immunoglobulins; and secretion of many cytokines. Together, these effects dictate immune function in a variety of diseases. TwHF and its extracts can be used alone or in combination with existing therapies against many immune disorders through immunomodulation.
Except for an essential step for the pathology of multiple diseases including atherosclerosis and rheumatoid arthritis, inflammation is an imperative therapeutic target for developing novel approaches for pharmacological interventions. Thus, molecular understanding of inflammation not only revealed the mechanisms of drug action and their biological targets but also has spawned innovative maneuvers to influence multifaceted biological systems, providing new prospects for drug designing and suggesting important new implications for existing clinical medicine. Meanwhile, modulation of inflammation with the use of medicinal plants proposed an alternate to conventional therapeutic strategies for numerous ailments, particularly when suppression of inflammation is expected. In modern literature, several species of medicinal plants have been shown substantial antiinflammatory and immunomodulatory actions including inhibitory effects on suppression of cellular and humoral immunity, lymphocyte activation, and propagation of apoptosis. Herein, we reviewed the molecular pharmacology of inflammation, chemical components and biological activities of medicinal plants such as, curcumin from Curcuma longa, and epigallocatechin-3-gallate from Camellia sinensis as well as their mechanism of action during inflammation at molecular level. An extensive review of the literature and electronic databases was conducted, encompassing PubMed, GoogleScholar, ScienceDirect, medlineplus, www.clinicaltrial.gov, www.fda.gov, www.ema.europa.eu, www.drugbank.ca, TrialBulletin.com, www.theplantlist.org, and www.pharmacodia.com for assembling the information. Additionally, data was attained from books, ethnopharmacological literature, and relevant publications for essential elements of molecular mechanisms, signal transduction networks, transcription factors, complement system, reactive species, and clinical trials are selected for substantial understanding of biochemistry, pathophysiology as well as clinical importance of medicinal plants during inflammatory diseases.
Objectives:
MicroRNA-155 (miR-155) regulates T-cell differentiation and activation. It has also been associated with HIV infection. However, it remains unclear whether miR-155 is related to the T-cell response in HIV-infected individuals (e.g. T-cell activation and exhaustion).
Methods:
We performed a cross-sectional study involving 121 HIV-1-infected patients on highly active antiretroviral therapy (HAART) and 43 HAART-naïve patients. MiR-155 levels in the peripheral blood were determined by quantitative reverse transcription-polymerase chain reaction (PCR). T-cell immune activation, exhaustion, and homeostasis were measured by determining the expression of CD38, programmed death 1 (PD-1) and CD127 via flow cytometry.
Results:
The levels of miR-155 in total peripheral blood mononuclear cells, CD4 T cells and CD8 T cells from HIV-1-infected patients were increased (P < 0.01). Nonresponders and HAART-naïve patients also exhibited a higher percentage of CD8(+) CD38(+) T cells and a lower percentage of CD4(+) CD127(+) and CD8(+) CD127(+) T cells (P < 0.05). We also found higher levels of PD-1 expression on the CD4(+) and CD8(+) T cells of HIV-1-infected patients (P < 0.05).
Conclusions:
Our findings suggest that miR-155 levels in the peripheral blood of HIV-1-infected patients are increased and associated with T-cell activation. Therefore, miR-155 is a potential biomarker of the immune response following HIV-1 infection.
Tripterygium wilfordii (Hook. f.) is a woody vine of the Celastraceae family, and native to China (south of the Yangtze River), Korea, and Japan, is used in the clinic for the treatment of inflammatory and autoimmune diseases, especially rheumatoid arthritis. In this study, we developed a urine metabolomic method by gas chromatographymass spectrometry (GC-MS) to evaluate the effect of Tripterygium wilfordii poisoning on rats. The Tripterygium wilfordii group rats were given 0.5 and 1.0 g/kg (Low, High) of Tripterygium wilfordii by continous intragastric administration each day for 7 days. Partial least squares-discriminate analysis (PLS-DA) revealed that Tripterygium wilfordii induced metabolic perturbations. Compared to the control group, increased L-glutamine, arabinitol, L-ornithine, arabinofuranose, xylonic acid, benzoic acid, pentitol, cinnamic acid, galactonic acid of Low group; while increased D-gluconic acid, arabinofuranose, glucaric acid, benzoic acid, galactonic acid of High group. The results indicate that metabolomic method by GC-MS may be useful to elucidate Tripterygium wilfordii poisoning.
BACKGROUND: Few studies consider the incidence of individual AIDS-defining illnesses (ADIs) at higher CD4 counts, relevant on a population level for monitoring and resource allocation.
METHODS: Individuals from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) aged ≥14 years with ≥1 CD4 count of ≥200 µL between 1998 and 2010 were included. Incidence rates (per 1000 person-years of follow-up [PYFU]) were calculated for each ADI within different CD4 strata; Poisson regression, using generalized estimating equations and robust standard errors, was used to model rates of ADIs with current CD4 ≥500/µL.
RESULTS: A total of 12 135 ADIs occurred at a CD4 count of ≥200 cells/µL among 207 539 persons with 1 154 803 PYFU. Incidence rates declined from 20.5 per 1000 PYFU (95% confidence interval [CI], 20.0-21.1 per 1000 PYFU) with current CD4 200-349 cells/µL to 4.1 per 1000 PYFU (95% CI, 3.6-4.6 per 1000 PYFU) with current CD4 ≥ 1000 cells/µL. Persons with a current CD4 of 500-749 cells/µL had a significantly higher rate of ADIs (adjusted incidence rate ratio [aIRR], 1.20; 95% CI, 1.10-1.32), whereas those with a current CD4 of ≥1000 cells/µL had a similar rate (aIRR, 0.92; 95% CI, .79-1.07), compared to a current CD4 of 750-999 cells/µL. Results were consistent in persons with high or low viral load. Findings were stronger for malignant ADIs (aIRR, 1.52; 95% CI, 1.25-1.86) than for nonmalignant ADIs (aIRR, 1.12; 95% CI, 1.01-1.25), comparing persons with a current CD4 of 500-749 cells/µL to 750-999 cells/µL.
DISCUSSION: The incidence of ADIs was higher in individuals with a current CD4 count of 500-749 cells/µL compared to those with a CD4 count of 750-999 cells/µL, but did not decrease further at higher CD4 counts. Results were similar in patients virologically suppressed on combination antiretroviral therapy, suggesting that immune reconstitution is not complete until the CD4 increases to >750 cells/µL.
BACKGROUND AND METHODS:
The SMART study compared 2 strategies for using antiretroviral therapy-drug conservation (DC) and viral suppression (VS)-in 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL. Rates and predictors of opportunistic disease or death (OD/death) and the relative risk (RR) in DC versus VS groups according to the latest CD4+ cell count and HIV RNA level are reported.
RESULTS:
During a mean of 16 months of follow-up, DC patients spent more time with a latest CD4+ cell count <350 cells/microL (for DC vs. VS, 31% vs. 8%) and with a latest HIV RNA level >400 copies/mL (71% vs. 28%) and had a higher rate of OD/death (3.4 vs. 1.3/100 person-years) than VS patients. For periods of follow- up with a CD4+ cell count <350 cells/microL, rates of OD/death were increased but similar in the 2 groups (5.7 vs. 4.6/100 person-years), whereas the rates were higher in DC versus VS patients (2.3 vs. 1.0/100 person-years; RR, 2.3 [95% confidence interval, 1.5-3.4]) for periods with the latest CD4+ cell count >or= 350 cells/microL-an increase explained by the higher HIV RNA levels in the DC group.
CONCLUSIONS:
The higher risk of OD/death in DC patients was associated with (1) spending more follow-up time with relative immunodeficiency and (2) living longer with uncontrolled HIV replication even at higher CD4+ cell counts. Ongoing HIV replication at a given CD4+ cell count places patients at an excess risk of OD/death.
To compare the efficacy and safety of Tripterygium wilfordii Hook F (TwHF) with methotrexate (MTX) in the treatment of active rheumatoid arthritis (RA).
Design: a multicentre, open-label, randomised controlled trial. All patients were assessed by trained investigators who were unaware of the therapeutic regimen. Intervention: 207 patients with active RA were randomly allocated (1:1:1) to treatment with MTX 12.5 mg once a week, or TwHF 20 mg three times a day, or the two in combination. At week 12, if reduction of the 28-joint count Disease Activity Score (DAS28) was <30% in the monotherapy groups, the patient was switched to MTX+TwHF. The primary efficacy point was the proportion of patients achieving an American College of Rheumatology (ACR) 50 response at week 24.
174/207 (84.1%) patients completed 24 weeks of the trial. In an intention-to-treat analysis, the proportion of patients reaching the ACR50 response criteria was 46.4% (32/69), 55.1% (38/69) and 76.8% (53/69), respectively, in the MTX, TwHF and MTX+TwHF groups (TwHF vs MTX monotherapy, p=0.014; MTX+TwHF vs MTX monotherapy, p<0.001). Similar statistically significant patterns at week 24 were found for ACR20, ACR70, clinical Disease Activity Index good responses, EULAR good response, remission rate and low disease activity rate. Significant improvement in the Health Assessment Questionnaire and 36-item Short-Form Health Survey questionnaire scores from baseline to week 24 was seen in each treatment arm (p<0.05), though no significant difference was found among the treatment arms (p>0.05). The result of per-protocol analysis agreed with that seen in the intention-to-treat analysis. Seven, three and five women in the TwHF, MTX and combination groups, respectively, developed irregular menstruation (TwHF vs MTX monotherapy, p=0.216).
TwHF monotherapy was not inferior to, and MTX+TwHF was better than, MTX monotherapy in controlling disease activity in patients with active RA.
NCT01613079.
The ability to reconstitute a normal immune system with antiretroviral therapy in the setting of HIV infection remains uncertain. This study aimed to characterize quantitative and qualitative aspects of various T cell subpopulations that do not improve despite effective ART. CD4∶CD8 ratio was evaluated in HIV-infected subjects with viral loads >10,000 copies/µl ("non-controllers", n = 42), those with undetectable viral loads on ART ("ART-suppressed", n = 53), and HIV-uninfected subjects (n = 22). In addition, T cell phenotype and function were examined in 25 non-controllers, 18 ART-suppressed, and 7 HIV-uninfected subjects. CD4∶CD8 ratio in non-controllers, ART-suppressed, and HIV-uninfected subjects was 0.25, 0.48, and 1.95 respectively (P<0.0001 for all comparisons). The increased ratio in ART-suppressed compared to non-controllers was driven by an increase of CD4+ T cells, with no change in the expanded CD8+ T cell population. Expansion of differentiated (CD28-CD27-CD45RA+/-CCR7-) T cell subpopulations persisted despite ART and minimal changes were noted in naïve T cell frequencies over time. Increased number of CD8+CD28- T cells and increased CD8+ CMV-specific T cell responses were associated with a decreased CD4∶CD8 ratio. Measures of T cell function demonstrated persistence of high frequencies of CD8+ T cells producing IFN-γ. Lastly, though all CD8+ subpopulations demonstrated significantly lower Ki67 expression in ART-suppressed subjects, CD4+ T cell subpopulations did not consistently show this decrease, thus demonstrating different proliferative responses in the setting of T cell depletion. In summary, this study demonstrated that CD4∶CD8 ratios remained significantly decreased and naïve T cell numbers were slow to increase despite long-term viral suppression on ART. In addition, there is a evidence of differential regulation of the CD4+ and CD8+ T cell subpopulations, suggesting independent homeostatic regulation of the two compartments.
Background
The pathogenesis of immunodeficiency due to human immunodeficiency virus (HIV)-1 is incompletely understood, but immune activation is believed to play a central role. Immunomodulatory agents that decrease immune activation may be useful in the treatment of HIV-1 infection.MethodologyA randomized, double blind, placebo-controlled pilot study of leflunomide for 28 days was performed in participants with HIV-1 infection who were not receiving antiretroviral therapy. Participants randomized to leflunomide were subsequently treated with cholestyramine until leflunomide levels were below detection limit.FindingsTreatment with leflunomide was well tolerated with mostly low-grade adverse events. Leflunomide administration reduced cycling of CD4 T cells (by ex vivo bromodeoxyuridine uptake and Ki67 expression) and decreased expression of activation markers (HLA-DR/CD38 co-expression) on CD8 T cells in peripheral blood. In addition, decreased expression of HIV-1 co-receptors was observed in both CD4 and CD8 T cells in the leflunomide group. There were no significant changes in naïve and memory T cell subsets, apoptosis of T cells or markers of microbial translocation.Conclusions
Leflunomide was effective in reducing immune activation in the setting of chronic HIV-1 infection suggesting that targeting immune activation with immunomodulatory agents may be a feasible strategy.Trial RegistrationClinicalTrials.gov NCT00101374
Persistent immune activation (IA) is a hallmark of chronic HIV infection. IA has been associated with poor CD4 T-cell recovery, non-AIDS defining illnesses and mortality during combination antiretroviral therapy (cART). Measures of chronic immune activation, namely T-cell activation and more recently monocyte activation and plasma inflammatory and thrombotic biomarkers, have all been shown to remain elevated despite years of suppressive cART. Here we review recent clinical trials and therapeutic approaches targeted to reduce persistent IA in HIV patients and discuss the impact of each of these approaches on clinically relevant end-points.
Treatment of HIV-infected patients with highly active antiretroviral therapy (HAART) usually results in diminished viral replication, increasing CD4⁺ cell counts, a reversal of most immunological disturbances, and a reduction in risk of morbidity and mortality. However, approximately 20% of all HIV-infected patients do not achieve optimal immune reconstitution despite suppression of viral replication. These patients are referred to as immunological nonresponders (INRs). INRs present with severely altered immunological functions, including malfunction and diminished production of cells within lymphopoetic tissue, perturbed frequencies of immune regulators such as regulatory T cells and Th17 cells, and increased immune activation, immunosenescence, and apoptosis. Importantly, INRs have an increased risk of morbidity and mortality compared to HIV-infected patients with an optimal immune reconstitution. Additional treatment to HAART that may improve immune reconstitution has been investigated, but results thus far have proved disappointing. The reason for immunological nonresponse is incompletely understood. This paper summarizes the known and unknown factors regarding the incomplete immune reconstitution in HIV infection, including mechanisms, relevance for clinical care, and possible solutions.
The recent introduction of new antiretroviral drugs, characterized by high efficiency and improved safety profiles, has not reduced the incidence of long-term adverse effects, in some cases manifested as selective organ damage. The presence of organ damage in patients receiving antiretroviral treatment is not only the expression of treatment toxicity, but also a complex interaction between individual risk factors, HIV-correlated effects, and antiretroviral drug toxicity. Kidney damage belongs to these adverse events. Renal function abnormalities are present in a large percentage of patients with HIV infection. Moreover, HIV-associated renal disease seems to be associated with progression to AIDS and death. In this review we address the various aspects of the epidemiology of renal damage, the interaction and the convergent effect of HIV and antiretroviral drugs in the onset of kidney injury, the interplay between kidney function and other organ systems, early clinical management, the monitoring of renal function, and a proposal of clinical approach to kidney disease in daily practice. Finally, we discuss future perspectives of renal damage in HIV patients and evaluate the patient's perspective.
Failure to normalize CD4(+) T-cell numbers despite effective antiretroviral therapy is an important problem in human immunodeficiency virus (HIV) infection.
To evaluate potential determinants of immune failure in this setting, we performed a comprehensive immunophenotypic characterization of patients with immune failure despite HIV suppression, persons who experienced CD4(+) T-cell restoration with therapy, and healthy controls.
Profound depletion of all CD4(+) T-cell maturation subsets and depletion of naive CD8(+) T cells was found in immune failure, implying failure of T-cell production/expansion. In immune failure, both CD4(+) and CD8(+) cells were activated but only memory CD4(+) cells were cycling at increased frequency. This may be the consequence of inflammation induced by in vivo exposure to microbial products, as soluble levels of the endotoxin receptor CD14(+) and interleukin 6 were elevated in immune failure. In multivariate analyses, naive T-cell depletion, phenotypic activation (CD38(+) and HLA-DR expression), cycling of memory CD4(+) T cells, and levels of soluble CD14 (sCD14) distinguished immune failure from immune success, even when adjusted for CD4(+) T-cell nadir, age at treatment initiation, and other clinical indices.
Immune activation that appears related to exposure to microbial elements distinguishes immune failure from immune success in treated HIV infection.
Chronic HIV infection is characterized by chronic immune activation and dysfunctional T cells with elevated intracellular
cyclic AMP (cAMP), which inhibits the T cell activation capability. cAMP may be induced by prostaglandin E2 following lipopolysaccharide (LPS)-induced upregulation of cyclooxygenase type 2 (COX-2) in monocytes due to the elevated
LPS levels in patients with chronic HIV infection. This hypothesis was tested using celecoxib, a COX-2 inhibitor, for 12 weeks
in HIV-infected patients without antiretroviral treatment in a prospective, open, randomized exploratory trial. Thirty-one
patients were randomized in the trial; 27 completed the study, including 13 patients on celecoxib. Celecoxib reduced chronic
immune activation in terms of CD38 density on CD8+ T cells (−24%; P = 0.04), IgA levels (P = 0.04), and a combined score for inflammatory markers (P < 0.05). Celecoxib further reduced the inhibitory surface receptor programmed death 1 (PD-1) on CD8+ T cells (P = 0.01), including PD-1 on the HIV Gag-specific subset (P = 0.02), enhanced the number of CD3+ CD4+ CD25+ CD127lo/− Treg or activated cells (P = 0.02), and improved humoral memory recall responses to a T cell-dependent vaccine (P = 0.04). HIV RNA (P = 0.06) and D dimers (P = 0.07) tended to increase in the controls, whereas interleukin-6 (IL-6) possibly decreased in the treatment arm (P = 0.10). In conclusion, celecoxib downmodulated the immune activation related to clinical progression of chronic HIV infection
and improved T cell-dependent functions in vivo.
Antiretroviral therapy (ART) partially corrects immune dysfunction associated with HIV infection. The levels of T-cell immune activation and exhaustion after long-term, suppressive ART and their correlation with CD4 T-cell count reconstitution among ART-treated patients in African cohorts have not been extensively evaluated.
T-cell activation (CD38+HLA-DR+) and immune exhaustion (PD-1+) were measured in a prospective cohort of patients initiated on ART; 128 patient samples were evaluated and subcategorized by CD4 reconstitution after long-term suppressive treatment: Suboptimal [median CD4 count increase 129 (-43-199) cells/μl], N = 34 ], optimal [282 (200-415) cells/μl, N = 64] and super-optimal [528 (416-878) cells/μl, N = 30].
Both CD4+ and CD8 T-cell activation was significantly higher among suboptimal CD4 T-cell responders compared to super-optimal responders. In a multivariate model, CD4+CD38+HLADR+ T-cells were associated with suboptimal CD4 reconstitution [AOR, 5.7 (95% CI, 1.4-23, P = 0.014)]. T-cell exhaustion (CD4+PD1+ and CD8+PD1+) was higher among suboptimal relative to optimal (P < 0.001) and super-optimal responders (P < 0.001). T-cell exhaustion was significantly associated with suboptimal responders [AOR, 1.5 (95%CI, 1.1-2.1), P = 0.022].
T-cell activation and exhaustion persist among HIV-infected patients despite long-term, sustained HIV-RNA viral suppression. These immune abnormalities were associated with suboptimal CD4 reconstitution and their regulation may modify immune recovery among suboptimal responders to ART.
Increased levels of activated T cells are a hallmark of the chronic stage of human immunodeficiency virus (HIV) infection
and are highly correlated with HIV disease progression. We evaluated chloroquine (CQ) as a potential therapy to reduce immune
activation during HIV infection. We found that the frequency of CD38+ HLA-DR+ CD8 T cells, as well as Ki-67 expression in CD8 and CD4 T cells, was significantly reduced during CQ treatment. Our data
indicate that treatment with CQ reduces systemic T-cell immune activation and, thus, that its use may be beneficial for certain
groups of HIV-infected individuals.
Triptolide is a diterpene triepoxide from the Chinese medicinal plant Tripterygium wilfordii Hook F., with known anti-inflammatory, immunosuppressive and anti-cancer properties.
Here we report the expression profile of immune signaling genes modulated by triptolide in LPS induced mouse macrophages. In an array study triptolide treatment modulated expression of 22.5% of one hundred and ninety five immune signaling genes that included Toll-like receptors (TLRs). TLRs elicit immune responses through their coupling with intracellular adaptor molecules, MyD88 and TRIF. Although it is known that triptolide inhibits NFkappaB activation and other signaling pathways downstream of TLRs, involvement of TLR cascade in triptolide activity was not reported. In this study, we show that triptolide suppresses expression of proinflammatory downstream effectors induced specifically by different TLR agonists. Also, the suppressive effect of triptolide on TLR-induced NFkappaB activation was observed when either MyD88 or TRIF was knocked out, confirming that both MyD88 and TRIF mediated NFkappaB activation may be inhibited by triptolide. Within the TLR cascade triptolide downregulates TLR4 and TRIF proteins.
This study reveals involvement of TLR signaling in triptolide activity and further increases understanding of how triptolide activity may downregulate NFkappaB activation during inflammatory conditions.
Tripterygium wilfordii Hook F. has been used for centuries in traditional Chinese medicine to treat rheumatoid arthritis, an autoimmune disease associated with increased production of the pro-inflammatory cytokine, tumor necrosis factor (TNF)-alpha. Triptolide is a compound originally purified from T. wilfordii Hook F. and has potent anti-inflammatory and immunosuppressant activities. In this study, we investigated the effect of triptolide on the global gene expression patterns of macrophages treated with lipopolysaccharide (LPS). We found that LPS stimulation resulted in >5-fold increase in expression of 117 genes, and triptolide caused a >50% inhibition in 47 of the LPS-inducible 117 genes. A large portion of the genes that were strongly induced by LPS and significantly inhibited by triptolide were pro-inflammatory cytokine and chemokine genes, including TNF-alpha, IL-1beta, and IL-6. Interestingly, LPS also induced the expression of micro-RNA-155 (miR-155) precursor, BIC, which was inhibited by triptolide. Confirming the cDNA array results, we demonstrated that triptolide blocked the induction of these pro-inflammatory cytokines as well as miR-155 in a dose-dependent manner. Profound inhibition of pro-inflammatory cytokine expression was observed at concentrations as low as 10-50 nM. However, triptolide neither inhibited the phosphorylation or degradation of IkappaBalpha after LPS stimulation, nor affected the DNA-binding activity of NF-kappaB. Surprisingly, we found that triptolide not only inhibited NF-kappaB-regulated reporter transcription, but also dramatically blocked the activity of other transcription factors. Our study offers a plausible explanation of the therapeutic mechanism of T. wilfordii Hook F.
CD38 expression on CD8+ T cells was longitudinally assessed in 31 human immunodeficiency virus (HIV)–infected persons with undetectable plasma viremia
who had undergone highly active antiretroviral therapy (HAART) for 12 months and were followed for a mean of 30 months thereafter.
Overall, CD4+T cell counts increased during follow-up, whereas CD38 expression remained stable. However, a subset of patients showed declines
in CD38 expression, and, conversely, another subset showed increases in CD38 expression. No association could be found between
long-term gains in CD4+ T cells and evolution of CD38 expression. Thus, activation of CD8+ T cells does not seem to be associated with the extent of CD4+ T cell recovery beyond the first year of successful HAART
Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here we show that circulating microbial products, probably derived from the gastrointestinal tract, are a cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, which we used as an indicator of microbial translocation, was significantly increased in chronically HIV-infected individuals and in simian immunodeficiency virus (SIV)-infected rhesus macaques (P <or= 0.002). We show that increased lipopolysaccharide is bioactive in vivo and correlates with measures of innate and adaptive immune activation. Effective antiretroviral therapy seemed to reduce microbial translocation partially. Furthermore, in nonpathogenic SIV infection of sooty mangabeys, microbial translocation did not seem to occur. These data establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide new directions for therapeutic interventions that modify the consequences of acute HIV infection.
Although untreated human immunodeficiency virus (HIV)-infected patients maintaining undetectable plasma HIV RNA levels (elite controllers) have high HIV-specific immune responses, it is unclear whether they experience abnormal levels of T cell activation, potentially contributing to immunodeficiency.
We compared percentages of activated (CD38(+)HLA-DR(+)) T cells between 30 elite controllers, 47 HIV-uninfected individuals, 187 HIV-infected individuals with undetectable viremia receiving antiretroviral therapy (antiretroviral therapy suppressed), and 66 untreated HIV-infected individuals with detectable viremia. Because mucosal translocation of bacterial products may contribute to T cell activation in HIV infection, we also measured plasma lipopolysaccharide (LPS) levels.
Although the median CD4(+) cell count in controllers was 727 cells/mm(3), 3 (10%) had CD4(+) cell counts <350 cells/mm(3) and 2 (7%) had acquired immunodeficiency syndrome. Controllers had higher CD4(+) and CD8(+) cell activation levels (P < .001 for both) than HIV-negative subjects and higher CD8(+) cell activation levels than the antiretroviral therapy suppressed (P = .048). In controllers, higher CD4(+) and CD8(+) T cell activation was associated with lower CD4(+) cell counts (P = .009 and P = .047). Controllers had higher LPS levels than HIV-negative subjects (P < .001), and in controllers higher LPS level was associated with higher CD8(+) T cell activation (P = .039).
HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4(+) T cell loss even without measurable viremia.
The SMART study compared 2 strategies for using antiretroviral therapy-drug conservation (DC) and viral suppression (VS)-in 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL. Rates and predictors of opportunistic disease or death (OD/death) and the relative risk (RR) in DC versus VS groups according to the latest CD4+ cell count and HIV RNA level are reported.
During a mean of 16 months of follow-up, DC patients spent more time with a latest CD4+ cell count <350 cells/microL (for DC vs. VS, 31% vs. 8%) and with a latest HIV RNA level >400 copies/mL (71% vs. 28%) and had a higher rate of OD/death (3.4 vs. 1.3/100 person-years) than VS patients. For periods of follow- up with a CD4+ cell count <350 cells/microL, rates of OD/death were increased but similar in the 2 groups (5.7 vs. 4.6/100 person-years), whereas the rates were higher in DC versus VS patients (2.3 vs. 1.0/100 person-years; RR, 2.3 [95% confidence interval, 1.5-3.4]) for periods with the latest CD4+ cell count >or= 350 cells/microL-an increase explained by the higher HIV RNA levels in the DC group.
The higher risk of OD/death in DC patients was associated with (1) spending more follow-up time with relative immunodeficiency and (2) living longer with uncontrolled HIV replication even at higher CD4+ cell counts. Ongoing HIV replication at a given CD4+ cell count places patients at an excess risk of OD/death.
Transient low-level viremia of 50-400 HIV RNA copies/mL (TLLV) is common during antiretroviral therapy, but its pathogenesis, consequences and optimal management are unclear. Heightened immune activation is associated with detrimental outcomes, including impaired CD4+ T-cell reconstitution. Using CD38/HLA-DR expression on CD8+ T-cells measured in two large studies, we determined associations between TLLV and immune activation levels before, during, and after TLLV. We found that TLLV does not significantly change CD8+ T-cell activation, and that higher CD8+ T-cell activation during viral suppression <50 copies/mL is associated with a modest increase in the risk of a subsequent TLLV.
Systemic immune activation is increased in HIV-infected individuals, even in the setting of virus suppression with antiretroviral therapy. Although numerous factors may contribute, microbial products have recently emerged as potential drivers of this immune activation. In this Review, we describe the intestinal damage that occurs in HIV infection, the evidence for translocation of microbial products into the systemic circulation and the pathways by which these products activate the immune system. We also discuss novel therapies that disrupt the translocation of microbial products and the downstream effects of microbial translocation.
Therapies to decrease immune activation might be of benefit in slowing HIV disease progression.
To determine whether hydroxychloroquine decreases immune activation and slows CD4 cell decline.
Randomized, double-blind, placebo-controlled trial performed at 10 HIV outpatient clinics in the United Kingdom between June 2008 and February 2011. The 83 patients enrolled had asymptomatic HIV infection, were not taking antiretroviral therapy, and had CD4 cell counts greater than 400 cells/μL.
Hydroxychloroquine, 400 mg, or matching placebo once daily for 48 weeks.
The primary outcome measure was change in the proportion of activated CD8 cells (measured by the expression of CD38 and HLA-DR surface markers), with CD4 cell count and HIV viral load as secondary outcomes. Analysis was by intention to treat using mixed linear models.
There was no significant difference in CD8 cell activation between the 2 groups (-4.8% and -4.2% in the hydroxychloroquine and placebo groups, respectively, at week 48; difference, -0.6%; 95% CI, -4.8% to 3.6%; P = .80). Decline in CD4 cell count was greater in the hydroxychloroquine than placebo group (-85 cells/μL vs -23 cells/μL at week 48; difference, -62 cells/μL; 95% CI, -115 to -8; P = .03). Viral load increased in the hydroxychloroquine group compared with placebo (0.61 log10 copies/mL vs 0.23 log10 copies/mL at week 48; difference, 0.38 log10 copies/mL; 95% CI, 0.13 to 0.63; P = .003). Antiretroviral therapy was started in 9 patients in the hydroxychloroquine group and 1 in the placebo group. Trial medication was well tolerated, but more patients reported influenza-like illness in the hydroxychloroquine group compared with the placebo group (29% vs 10%; P = .03).
Among HIV-infected patients not taking antiretroviral therapy, the use of hydroxychloroquine compared with placebo did not reduce CD8 cell activation but did result in a greater decline in CD4 cell count and increased viral replication.
isrctn.org Identifier: ISRCTN30019040.
Objective:
To evaluate the influence of hepatitis B virus (HBV) coinfection on immunological, virological and clinical responses to lamivudine (3TC)-based combined antiretroviral therapy (cART) in Chinese patients.
Design and methods:
This prospective, multicenter cohort study recruited 529 antiretroviral-naive participants (aged 18–65 years, both sexes) between 2008 and 2010.They were grouped by HBV serostatus. Virological and immunological responses were monitored at baseline and week 4, 8, 12, 24, 36 and 48. cART for all patients was nevirapine, 3TC with either zidovudine or stavudine.
Results:
First, HIV/HBV coinfection rate in our cohort was 14.6%. Second, among 508 patients with complete baseline information, median CD4 level was significantly lower in the chronic HBV-infected (CHB) group and isolated core group. In the CHB group,hepatitis B e antigen positivity rather than HBV DNA level was associated with lower CD4 cell count. Third, in the isolated core group, occult infection rate was 9.5%.Fourth, at week 48, rate of HIV suppression below 40 copies/ml was 74.2%. Median increase in the CD4 cell count at week 48 was 127 cells/ml. Of note, HBV serostatus did not influence virological and immunological response to cART at each follow-up time point. Although HBV serostatus was associated with different alanine aminotransferase levels during follow-up, hepatitis and hyperbilirubinemia rates were not significantly different. Fifth, the 3TC-based regimen was efficacious against HBV replication, with median decrease in HBV DNA of 2.87 log copies/ml. However, hepatitis B e antigen positivity was associated with poorer HBV DNA suppression.
Conclusion:
In our cohort, CHB infection and isolated hepatitis B core antibody positivity were related to faster HIV progression. Despite of this, virological and immunological responses were not affected by HBV serostatus.
Apart from cancer chronic (auto)immune-mediated diseases are a major threat for patients and a challenge for physicians. These conditions include classic autoimmune diseases like systemic lupus erythematosus, systemic sclerosis and dermatomyositis and also immune-mediated inflammatory diseases such as rheumatoid arthritis and psoriasis. Traditional therapies for these conditions include unspecific immunosuppressants including steroids and cyclophosphamide, more specific compounds such as ciclosporin or other drugs which are thought to act as immunomodulators (fumarates and intravenous immunoglobulins). With increasing knowledge about the underlying pathomechanisms of the diseases, targeted biologic therapies mainly consisting of anti-cytokine or anti-cytokine receptor agents have been developed. The latter have led to a substantial improvement of the induction of long term remission but drug costs are high and are not affordable in all countries. In China an extract of the herb Tripterygium wilfordii Hook F. (TwHF) is frequently used to treat autoimmune and/or inflammatory diseases due to its favourable cost-benefit ratio. Triptolide has turned out to be the active substance of TwHF extracts and has been shown to exert potent anti-inflammatory and immunosuppressive effects in vitro and in vivo. There is increasing evidence for an immunomodulatory and partly immunosuppressive mechanism of action of triptolide. Thus, compounds such as triptolide or triptolide derivatives may have the potential to be developed as a new class of drugs for these diseases. In this review we summarize the published knowledge regarding clinical use, pharmacokinetics and the possible mode of action of triptolide in the treatment of inflammatory diseases with a particular focus on psoriasis.
The aim is to review the recent confirmation of the continued high prevalence of HIV-associated neurocognitive disorders (HAND) despite highly active antiretroviral therapy (HAART) in a large cohort study and to review the recent studies that have begun to address the potential reasons for such persistence.
HAND remains prevalent, despite effective viral suppression in cerebrospinal fluid and plasma. Several studies have shown the benefit of a central nervous system (CNS) penetrating HAART regimen (neuro-HAART) in improving neurocognitive outcomes. New evidence supports the early initiation of HAART. There are recent data to suggest that HAART may be CNS toxic, but evidence is still limited. Ageing does not currently explain the persistence of HAND. A recent study has also shown a correlation between cardiovascular risk factors and HAND.
The prevalence of HAND remains high in the HAART era. Most studies point towards the benefit of neuro-HAART in the prevention and treatment of HAND. The possible neurotoxicity of HAART needs to be further evaluated. It may be too early to detect a combined ageing and HIV effect and long-term studies are required. The link between cardiovascular disease and neurocognitive decline in HIV needs further exploration. Effective screening in clinical practice is paramount in prevention of the morbidity and mortality associated with HAND.
Triptolide, a diterpene triepoxide, is one of the major components of most functional extracts of Tripterygium wilfordii Hook f, which is known to have various biological effects, including immunosuppressive, anti-inflammatory and anti-tumor functions. We studied the inhibitory effect of triptolide on endotoxemia (ETM)-induced oxidative stress, which was induced in C57BL/6 mice by lipopolysaccharide (LPS) and D-galactosamine (D-GalN). Pretreatment with triptolide decreased the reactive oxygen species (ROS) levels, mortality rate and liver injury after LPS/D-GalN injection. We utilized comprehensive proteomics to identify alterations in liver protein expression during pretreatment with triptolide or N-acetylcysteine (NAC) after LPS/D-GalN injection, 44 proteins were found to be related to oxidative stress, mitochondria, metabolism and signal transduction, and 23 proteins of them seemed to be significantly up- or down-regulated. Furthermore, both triptolide and NAC inhibited activation of c-jun NH2-terminal kinases (JNK) and mitogen-activated protein kinase p38 (p38), phosphorylation of inhibitor of nuclear factor-kappa B (IκB) and activation of nuclear factor-κB (NF-κB). These results demonstrated that triptolide inhibited the activation of JNK and p38 by decreasing ROS levels, which in turn inhibited the hepatic injury. In addition, we set and validated the phosphorylation model of extracellular signal-regulated kinase (ERK) and proposed that triptolide probably induced ERK phosphorylation through inhibiting its dephosphorylation rates. These results showed that triptolide can effectively reduce the oxidative stress and partially rescue the damage in the liver induced by LPS/D-GalN.
Approximately 20% of human immunodeficiency virus type 1 (HIV-1)--infected adults do not normalize their CD4(+) T lymphocytes after long-term effective highly active antiretroviral therapy (HAART). The mechanistic basis for this failure is unclear.
Seventy-four patients were followed up regularly for 3-7 years. Patients with undetectable plasma viral load (<50 copies/mL) for over 12 months were further classified into 2 groups: (1) immunological nonresponders, whose CD4(+) T-cell count was < 200/μL or <20% compared with baseline; and (2) immunological responders, whose CD4(+) T-cell count was > 300/μL or >30% compared with baseline.
Compared with 17 immunological responders, 13 immunological nonresponders had a lower magnitude of naive CD4(+) T-cell increase, a lower percentage of recent thymic immigrants (CD31(+)%), and a higher percentage of activated CD8(+) T cells. Furthermore, unlike CD4(+) T cells, which increased along with the decrease of viral load, the percentage of recent thymic immigrants (CD31(+)%) had little change in the majority of patients. These data were fit into a mathematical model, , from which we deduced that the initial rate of CD4(+) T-cell restoration is associated significantly with the percentage of recent thymic immigrants (CD31(+)%).
Our data indicate that the failure to restore CD4(+) T-cell count following HAART was associated primarily with a defect in recent thymic immigrants, which suggests the existence of thymus exhaustion.
The extract of Tripterygium wilfordii Hook F. (TwHF), which showed anti-inflammatory and immunosuppressive activities in human clinical trials for rheumatoid arthritis, was subjected to the activity-guided fractionation and spectroscopic characterization of bioactives. A tetrahydrofuran lignan, tripterygiol (1), and eight known compounds, all capable of suppressing pro-inflammatory gene expression were identified. Most of the pharmacological activity of the extract can be attributed to triptolide, its most abundant and active component, with some contribution from tripdiolide.
Despite optimal suppression of HIV replication, restoration of CD4(+) T cells is not always achieved in antiretroviral therapy-treated individuals. Defective CD4 recovery in immunologic nonresponders is possibly associated with TLR-mediated immune activation driven by alterations of gut permeability. Hydroxychloroquine (HCQ) reduces endosomal TLR signaling; thus, we verified whether HCQ could dampen immune activation and be associated with an increase in CD4(+) T cells. To this end, we enrolled in a prospective study 20 HIV-infected immunologic nonresponders (CD4 count < 200 cells/mL or CD4 increase < 5% in the last 12 months) who received 400 mg/day HCQ for 6 months. HCQ had a notable impact on immune activation as shown by significant modifications of the following parameters: (1) reduced plasma lipopolysaccharide; (2) decreased TLR4-expressing CD14(+) cells, TLR4-mediated signal transduction, and mRNA synthesis; (3) reduced percentages of activated CD4(+) (CD4(+)/Ki67(+)) and CD14(+) (CD14(+)/CD69(+)) cells; (4) increased T-regulatory cells (Tregs), naive Tregs, and TLR4-expressing Tregs; (5) augmented plasmacytoid dendritic cells and reduced IFNα-secreting plasmacytoid dendritic cells; and (6) reduced IL-6 and TNFα production. HCQ-induced immune modulation was associated with increased percentages of circulating CD4(+) T cells and was mostly retained 2 months after therapy interruption. HCQ reduces lipopolysaccharide/TLR-mediated immune activation; this compound could be a useful immunomodulant in HIV-infected patients. This study is registered at EutraCT as 2009-012499-28 with study number HLS01/2009-1-16-03-2009.
The failure to increase CD4 T-cell counts in some HAART-treated HIV-infected patients with satisfactory virological responses has been related to low CD4 T-cell production, high turnover and death. However, the relative contribution of these factors is still unclear, strongly limiting the definition of appropriate therapeutic strategies for these patients.
A cross-sectional study was designed to evaluate the contribution of thymic activity, microbial translocation, cellular activation and death to CD4 T-cell recovery. We included 230 HIV-infected individuals on suppressive HAART (>2 years); 95 of them were considered 'discordant' (CD4 T-cell count <350 cells/mul) and 135 were considered 'concordant'. Comparative and logistic regression analyses were performed.
Discordant patients showed higher levels of activated [human leukocyte antigen (HLA)-DRCD95 and CD38CD45RA] cells in both the CD8 and CD4 T-cell compartments. Notably, the most significant differences were observed in CD4 T cells. Discordant patients showed lower naive CD4 T-cell production (CD45RACD31 cells), higher spontaneous ex-vivo CD4 T-cell death and higher plasma levels of soluble CD14. Multivariate analysis showed that activation and death of CD4 T cells, along with nadir CD4 T-cell counts, were the only predictive factors for poor immune recovery. Moreover, the low correlations found between CD4 T-cell activation or death with thymic output and bacterial translocation suggest that additional factors modulate cellular activation and death and, in turn, CD4 T-cell recovery.
CD4 T-cell repopulation during HAART is determined by CD4 T-cell activation and death. Therefore, strategies aimed to reduce these parameters should be envisaged to treat discordant patients.
To evaluate deaths from AIDS-defining malignancies (ADM) and non-AIDS-defining malignancies (nADM) in the D:A:D Study and to investigate the relationship between these deaths and immunodeficiency.
Observational cohort study.
Patients (23 437) were followed prospectively for 104 921 person-years. We used Poisson regression models to identify factors independently associated with deaths from ADM and nADM. Analyses of factors associated with mortality due to nADM were repeated after excluding nADM known to be associated with a specific risk factor.
Three hundred five patients died due to a malignancy, 298 prior to the cutoff for this analysis (ADM: n = 110; nADM: n = 188). The mortality rate due to ADM decreased from 20.1/1000 person-years of follow-up [95% confidence interval (CI) 14.4, 25.9] when the most recent CD4 cell count was <50 cells/microl to 0.1 (0.03, 0.3)/1000 person-years of follow-up when the CD4 cell count was more than 500 cells/microl; the mortality rate from nADM decreased from 6.0 (95% CI 3.3, 10.1) to 0.6 (0.4, 0.8) per 1000 person-years of follow-up between these two CD4 cell count strata. In multivariable regression analyses, a two-fold higher latest CD4 cell count was associated with a halving of the risk of ADM mortality. Other predictors of an increased risk of ADM mortality were homosexual risk group, older age, a previous (non-malignancy) AIDS diagnosis and earlier calendar years. Predictors of an increased risk of nADM mortality included lower CD4 cell count, older age, current/ex-smoking status, longer cumulative exposure to combination antiretroviral therapy, active hepatitis B infection and earlier calendar year.
The severity of immunosuppression is predictive of death from both ADM and nADM in HIV-infected populations.
Studies have found that CD8 T-cell activation, as measured by CD38 expression, in HIV-1-infected individuals on suppressive therapy for longer than 12 months is not predictive of CD4 T-cell recovery. Owing to the fact that reconstitution of memory and naive T-cell populations occurs differentially over time, this study evaluated whether distinct memory/naive CD4 T-cell subsets correlated with CD38 on CD8 T-cells.
Whole blood from 13 participants was used to evaluate activation phenotypic markers on CD8 lymphocytes and memory/naive phenotypes on CD4 lymphocytes. These HIV-1-infected individuals had stable CD4 cell counts for more than 1 year while on suppressive combination antiretroviral therapy.
The results demonstrate that CD4 central memory and naive cell populations contribute to the magnitude of CD4 T-cell reconstitution. CD4 central memory has a significant negative correlation with the percentage of CD38-activated CD8 T-cells.
This suggests that CD8 activation is important in CD4 recovery from a low CD4 T-cell nadir.
To assess the association of HIV infection, HIV disease parameters (including CD4+ T-cell counts, HIV viral load, and AIDS) and antiretroviral medication use with subclinical carotid artery atherosclerosis.
Cross-sectional study nested within a prospective cohort study.
Among participants in the Women's Interagency HIV Study (1331 HIV-infected women, 534 HIV-uninfected women) and Multicenter AIDS Cohort Study (600 HIV-infected men, 325 HIV-uninfected men), we measured subclinical carotid artery lesions and common carotid artery intima-media thickness using B-mode ultrasound. We estimated adjusted mean carotid artery intima-media thickness differences and prevalence ratios for carotid lesions associated with HIV-related disease and treatments, with multivariate adjustment to control for possible confounding variables.
Among HIV-infected individuals, a low CD4+ T-cell count was independently associated with an increased prevalence of carotid lesions. Compared with the reference group of HIV-uninfected individuals, the adjusted prevalence ratio for lesions among HIV-infected individuals with CD4+ T-cell count less than 200 cells/mul was 2.00 (95% confidence interval, 1.22-3.28) in women and 1.74 (95% confidence interval, 1.04-2.93) in men. No consistent association of antiretroviral medications with carotid atherosclerosis was observed, except for a borderline significant association between protease inhibitor use and carotid lesions in men (with no association among women). History of clinical AIDS and HIV viral load were not significantly associated with carotid atherosclerosis.
Beyond traditional cardiovascular disease risk factors, low CD4+ T-cell count is the most robust risk factor for increased subclinical carotid atherosclerosis in HIV-infected women and men.
Highly active antiretroviral therapy (HAART) increases CD4(+) cell numbers, but its ability to correct the human immunodeficiency virus (HIV)-induced immune deficiency remains unknown. A three-phase T cell reconstitution was demonstrated after HAART, with: (i) an early rise of memory CD4(+) cells, (ii) a reduction in T cell activation correlated to the decreasing retroviral activity together with an improved CD4(+) T cell reactivity to recall antigens, and (iii) a late rise of "naïve" CD4(+) lymphocytes while CD8(+) T cells declined, however, without complete normalization of these parameters. Thus, decreasing the HIV load can reverse HIV-driven activation and CD4(+) T cell defects in advanced HIV-infected patients.
Immune activation is an independent surrogate marker of CD4 T-cell depletion in HIV-infected patients. Highly active antiretroviral therapy (HAART) reduces disease progression as a direct consequence of suppressing HIV replication. Immune function does not normalize completely in most subjects on HAART, however, perhaps reflecting residual HIV replication. So far, it is unclear to what extent immune activation may influence the evolution of CD4 T-cell counts in patients on HAART.
The expression of CD38 on naive and memory subsets of CD4+ and CD8+ T cells was measured quantitatively by flow cytometry in 62 drug-naive HIV-positive and 30 HIV-uninfected controls. In addition, the evolution of this marker as well as that of some virologic parameters (plasma viremia and proviral load) and CD4 counts were assessed in 25 HIV-infected individuals who initiated HAART and were followed for 12 months.
The mean level of CD38 on memory CD4+ and CD8+ T cells as well as in naive CD8+ cells was significantly higher in drug-naive HIV-positive subjects than in HIV-negative controls. Moreover, it was highly correlated with viral load titers. In patients on successful HAART, immune activation declined in all T-cell subsets, particularly among memory CD8+ cells. It remained elevated with respect to HIV-negative controls, however, even after 12 months of HAART. There was a significant correlation between the CD8+ T-cell activation decay and the increase of CD4+ T cells on HAART. Patients with the highest decline in CD8 activation were those showing the highest CD4 T-cell gains after 12 months of therapy.
The level of CD38 expression on different T-cell subsets is differentially upregulated in drug-naive HIV-infected patients. After successful HAART, immune activation decreases in all T-cell subsets, although it still remains elevated in most cases after 12 months of HAART. The extent of immune deactivation under successful HAART correlates with the ability to reconstitute CD4 counts.
To determine HIV/sexually transmitted infection (STI) prevalence, trends, and risk behaviors of men who have sex with men (MSM) and compare these with those of non-MSM attending STI clinics in Pune, India over a 10-year period.
Cross-sectional.
From 1993 through 2002, men attending 3 STI clinics in Pune underwent HIV/STI screening. Demographic, risk behavior, clinical, and laboratory data were collected using standardized questionnaires and laboratory procedures.
Of 10,785 men screened, 708 (6.6%) were MSM. Among these 708 MSM, 189 (31.7%) had 10 or more lifetime partners, 253 (35.7%) were married, 163 (23.1%) had sex with a hijra (eunuch), and 87 (13.3%) had exchanged money for sex. A total of 134 (18.9%) were HIV-positive, 149 (21.5%) had genital ulcer disease (GUD), 37 (5.8%) had syphilis, and 29 (4.3%) had gonorrhea (GC). Over the decade, neither HIV nor GC prevalence changed among MSM (P = 0.7), but syphilis and GUD decreased significantly (P < 0.0001). Compared with non-MSM, MSM were more likely to initiate sexual activity at age <16 years, to have >10 lifetime partners, to have sex with a hijra, and to use condoms regularly, but they did not differ significantly in HIV prevalence and had a lower prevalence of GC, GUD, and syphilis. Independent factors associated with HIV among MSM were employment (adjusted odds ratio [AOR] = 3.08; P = 0.02), history of GUD (AOR = 1.86; P = 0.003), and syphilis (AOR = 2.09; P = 0.05).
Same-sex and high-risk sexual behaviors are prevalent among men attending STI clinics in India. Although syphilis and GUD rates decreased, HIV prevalence remained high during the decade, highlighting the importance of additional targeted efforts to reduce HIV risk among all men, including MSM, in India.
To date few therapies have been shown to reliably prevent the evolution of Crohn's disease (CD). The traditional Chinese medicine, Tripterygium wilfordii Hook F (TWHF), has both immunomodulatory and anti-inflammatory activities. Our aim was to investigate the potential efficacy of T2, the major constituent of extracts of TWHF, in inducing remission of active CD. Twenty adult patients with active CD were enrolled to be treated with T2 pills (60 mg daily) for 12 weeks. Plasma levels of C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta were measured at entry and every 2 weeks thereafter until week 12. At each visit the CD Activity Index (CDAI) was calculated. The CD Endoscopic Index of Severity was measured at entry and week 12. Sixteen patients completed the study. A significant decrease in serum levels of CRP, TNF-alpha, and IL-1beta occurred rapidly after commencement of treatment. CDAI scores showed a rapid decline during the first 8 weeks and reached their lowest at week 10. Endoscopic improvements were observed at week 12. In conclusion, T2 appears to be effective for the treatment of mildly or moderately active CD. Further controlled studies are warranted for this promising drug.
CD4+ T-cell depletion is the hallmark of AIDS pathogenesis. Multiple mechanisms may contribute to the death of productively infected
CD4+ T cells and innocent-bystander cells. In this study, we characterize a novel mechanism in which human immunodeficiency virus
type 1 (HIV-1) infection preferentially depletes peripheral memory CD4+ T cells before the completion of reverse transcription. Using a recombinant HIV-1 carrying the green fluorescent protein
reporter gene, we demonstrate that memory CD4+ T cells were susceptible to infection-induced cell death at a low multiplicity of infection. Infected memory CD4+ T cells underwent rapid necrotic cell death. Killing of host cells was dependent on X4 envelope-mediated viral fusion, but
not on virion-associated Vpr or Nef. In contrast to peripheral resting CD4+ T cells, CD4+ T cells stimulated by mitogen or certain cytokines were resistant to HIV-1-induced early cell death. These results demonstrate
that early steps in HIV-1 infection have a detrimental effect on certain subsets of CD4+ T cells. The early cell death may serve as a selective disadvantage for X4-tropic HIV-1 in acute infection but may play a
role in accelerated disease progression, which is associated with the emergence of X4-tropic HIV-1 in the late stage of AIDS.
Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antire-troviral therapy: a randomized controlled trial
- Paton Ni Rl Goodall
- Dunn
- Dt
17 Paton NI, Goodall RL, Dunn DT, et al. Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antire-troviral therapy: a randomized controlled trial. JAMA. 2012; 308:353–361.
Persistent immune activation in chronic HIV infection: do any interventions work? Comparison of Tripterygium wilfordii Hook F versus sulfasala-zine in the treatment of rheumatoid arthritis: a randomized trial
- Rajasuriar R G Khoury
- A Kamarulzaman
- Cameron Ma Pu French
- Wilson R M Lewin
- R Fleischmann
18 Rajasuriar R, Khoury G, Kamarulzaman A, French MA, Cameron PU, Lewin SR. Persistent immune activation in chronic HIV infection: do any interventions work? AIDS. 2013;27(8):1199. 19 Goldbach-Mansky R, Wilson M, Fleischmann R, et al. Comparison of Tripterygium wilfordii Hook F versus sulfasala-zine in the treatment of rheumatoid arthritis: a randomized trial. Ann Intern Med. 2009;151, 229–240, W249–251.
Increased HLA-DR expression on peripheral blood monocytes in subsets of subjects with primary HIV infection is associated with elevated CD4 T-cell apoptosis and CD4 T-cell depletion
- R L Gascon
- A B Narvaez
- R Zhang