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Background: Several studies have reported that combination antiretroviral therapy (cART) enhances the hepatitis B surface antigen (HBsAg) clearance rate in Human Immunodeficiency Virus-1/Hepatitis B Virus (HIV/HBV) coinfected patients, yet the associated immunological characteristics remain unclear., Methods: Global and specific immune phenotypic profiles were examined in 48 patients with HIV/HBV coinfection before cART and at 1-year, and 3-year after cART using flow cytometry. In addition, 61 patients with HBV monoinfection were included for comparison., Results: HBsAg response (sAg-R) was defined as > 0.5 log decrease within six months of cART initiation, and 16 patients achieved it. Patients with sAg-R (the sAg-R group) exhibited distinct immune phenotypes compared to those of HBsAg-retained patients (the sAg-NR group). Notably, patients with sAg-R had lower CD4 + T cell counts and a higher number of HBcAg-specific T cells. Further, the sAg-R group exhibited upregulation of HLA-DR, Ki67, and PD-1 in CD4 + T cells and heightened HLA-DR and T-bet in CD8 + T cells. However, the sAg-R group had fewer TEMRA cells but more TEM and Th17 cells than those in the sAg-NR group. Expression of various markers, including HLA-DR + CD4 + , Ki67 + CD4 + , PD-1 + CD4 + , CD38 + CD8 + , HLA-DR + CD8 + , TIM-3 + CD8 + , HBV-specific CD4 + T cell secreting IFN-γ and IL-2, and specific CD8 + T cell secreting IFN-γ and IL-2, correlated with HBsAg decrease., Conclusion: The decline in HBsAg levels during cART in HIV/HBV coinfection involves significant alterations in CD4 + and CD8 + T cells phenotypes, offering a novel perspective on a functional HBV cure., (© 2024. The Author(s).)

Background: Comorbidity of Myasthenia gravis (MG) and Graves' disease (GD) in treated HIV-infected individuals has rarely been described and little study has been done on the link between HIV-related immune reconstitution and autoimmune diseases occurring post antiretroviral therapy., Case Presentation: Here we report on a 33-year-old Chinese man with HIV infection who had been virologically suppressed since 2018. The patient was diagnosed with GD and was treated in 2020. Early in 2022, he developed fluctuating weakness and fatigue involving the bilateral extraocular muscles and limbs. With a positive neostigmine test, he was considered to have MG, but showed a poor response to oral medication. After multiple failed medication attempts, a thymectomy was finally performed to resolve his symptoms. The consecutive onset of immunological events may have partially resulted from immune reconstitution after viral control., Conclusions: This is a rare case of HIV-related immune reconstitution-associated autoimmune disease (IRAD) with comorbidity of MG and GD which was reported initially. Cooperation with multidisciplinary teams is essential to avoid misdiagnosis and to promote the overall health of HIV-infected patients., (© 2023 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Objective: This study aims to analyze the efficacy of anti-syphilis treatment and the impact of syphilis events on HIV virology and immunology in HIV/syphilis co-infected patients on long-term antiretroviral therapy (ART) and to investigate the incidence and factors of syphilis recurrence/re-infection/serofast state. The insights derived from this investigation can potentially guide strategies for preventing and managing syphilis and AIDS., Methods: A retrospective case-control study was conducted at the AIDS clinic of Peking Union Medical College Hospital from January 2003 to December 2022. The study involved 86 HIV/syphilis co-infected patients and 86 HIV mono-infected patients matched based on age, baseline CD4 + T cell counts, and viral load. We examined the clinical characteristics of HIV/syphilis co-infected patients, evaluated the efficacy of anti-syphilis treatment, and analyzed the dynamic changes in HIV virology and immunology. The Generalized Estimating Equations (GEE) model investigated the factors associated with HIV/syphilis co-infection and syphilis recurrence/reinfection/serofast state., Results: Syphilis serofast state was observed in 11.6% (10/86) of HIV/syphilis co-infected patients after treatment, and 33.7% (29/86) had syphilis recurrence or re-infection. The overall effectiveness of syphilis treatment stood at 76.8% (63/82). Notably, the effectiveness of syphilis treatment displayed a significant correlation with baseline syphilis titers exceeding 1:128 ( p  = 0.003). Over the 10-year follow-up period on ART, the HLA-DR + CD8+/CD8 + % levels in the HIV/syphilis co-infected group were markedly higher than those in the HIV mono-infected group ( p  < 0.05). However, no significant differences were observed between the two groups regarding HIV viral load, CD4+ T cell counts, CD8+ T cell counts, CD4/CD8 ratio, and CD38 + CD8+/CD8 + % ( p  > 0.05). GEE analysis model revealed that elevated HLA-DR + CD8+/CD8 + % levels were associated with HIV/syphilis co-infection (OR = 1.026, 95% CI = 1.007-1.046; p  = 0.007) and syphilis recurrence/reinfection/serofast state (OR = 1.036, 95% CI = 1.008-1.065; p  = 0.012)., Conclusion: While HIV/syphilis co-infected patients typically receive adequate treatment, the incidence of syphilis recurrence and reinfection remain notably elevated. A heightened HLA-DR + CD8+/CD8+ % is a notable risk factor for HIV/syphilis co-infection and syphilis recurrence/reinfection/serofast state. Therefore, it is advisable to reinforce health education efforts and ensure regular follow-ups for people living with HIV undergoing ART to monitor syphilis infection or increased risk of syphilis infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Lu, Song, Liu, Yang, Chen, Tang, Han, Lv, Cao and Li.)

Background: Chronic immune activation plays a significant role in the pathogenesis and disease progression of human immunodeficiency virus (HIV), and the existing interventions to address this issue are limited. In a phase II clinical trial, (5R)-5-hydroxytriptolide (LLDT-8) demonstrated promising potential in enhancing CD4 + T cell recovery. However, the therapeutical effects of LLDT-8 remained to be systemic explored., Methods: To assess the treatment effects of LLDT-8, we conducted flow cytometry and RNA-seq analyses on eight Chinese rhesus monkeys infected with simian immunodeficiency virus (SIV). Additionally, we performed comprehensive transcriptomic analyses, including cross-sectional and longitudinal differentially expressed gene (DEG) analysis, gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and deconvolution analysis using peripheral blood mononuclear cell (PBMC) samples from 14-time points. These findings were further validated with RNA-seq analysis on patients who received LLDT-8 treatment, along with in vitro cellular experiments using human PBMCs., Results: Flow cytometry analysis revealed that LLDT-8 treatment significantly reduced the percentage of HLA-DR + CD38 + CD8 + T cells in SIV-infected rhesus monkeys (P < 0.001). The cross-sectional and longitudinal analysis identified 2531 and 1809 DEGs, respectively. GSEA analysis indicated that LLDT-8 treatment led to significant downregulation of proliferation-related pathways, such as E2F targets, G2M checkpoint, and mitotic spindle pathways. WGCNA analysis identified two modules and 202 hub genes associated with CD8 activation levels. Deconvolution analysis showed a significant decrease in the proportion of CD8 + T cells and activated CD4 + T cells during LLDT-8 treatment. Gene ontology results demonstrated that the common DEGs between LLDT-8-treated patients and rhesus monkeys were primarily enriched in cell activation and cell cycle progression. Furthermore, in vitro cellular experiments validated the consistent impact of LLDT-8 in inhibiting proliferation, activation (HLA-DR and CD38 expression), exhaustion (PD-1 expression), and IFN-γ production in human CD4 + and CD8 + T cells., Conclusion: LLDT-8 exhibited notable efficacy in alleviating immune activation in both an in vivo animal model and in vitro human cell experiments. These findings suggest that LLDT-8 may hold potential as a drug for managing systemic immune activation associated with SIV/HIV infection, warranting further prospective clinical exploration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Chronic metabolic changes relevant to human immunodeficiency virus type 1 (HIV-1) infection and in response to antiretroviral therapy (ART) remain undetermined. Moreover, links between metabolic dysfunction caused by HIV and immunological inflammation in long-term treated individuals have been poorly studied., Methods: Untargeted metabolomics and inflammatory cytokine levels were assessed in 47 HIV-infected individuals including 22 immunological responders (IRs) and 25 non-responders (INRs) before and after ART. The IRs and INRs were matched by age, gender, baseline viral load, and baseline CD4+T cell counts. Another 25 age-matched uninfected healthy individuals were also included as controls., Results: Among the 770 plasma compounds detected in the current study, significant changes were identified in lipids, nucleotides, and biogenic amino acids between HIV-infected patients and healthy controls. Principal Component Analysis (PCA) and the Random Forest (RF) model suggested that levels of selected metabolites could differentiate HIV-infected patients clearly from healthy controls. However, the metabolite profiles identified in our patients were similar, and only three metabolites, maltotetraose, N, N-dimethyl-5-aminovalerate, and decadienedioic acid (C10:2-DC), were different between IRs and INRs following long-term ART. The pathway enrichment analysis results revealed that disturbances in pyrimidine metabolism, sphingolipid metabolism, and purine metabolism after HIV infection and these changes did not recover to normal levels in healthy controls even with suppressive ART. Correlation analysis of the metabolism-immune network indicated that interleukin (IL)-10, D-dimer, vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and TNF-RII were positively correlated with most of the significantly changed lipid and amino acid metabolites but negatively correlated with metabolites in nucleotide metabolism., Conclusions: Significant changes in many metabolites were observed in HIV-infected individuals before and after ART regardless of their immunological recovery status. The disturbed metabolic profiles of lipids and nucleotides in HIV infection did not recover to normal levels even after long-term ART. These changes are correlated with modified cytokines and biomarkers of chronic non-AIDS events, warranting tryout of interventions other than ART., Competing Interests: Authors ZY and ZK were employed by company DIAN Diagnostics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lu, Yang, Yang, Wu, Liu, Li, Chen, Han, Song, Kong, Cao and Li.)

Background: Antiretroviral therapy (ART) improved the prognosis of people living with human immunodeficiency virus (HIV) (PLWH). Life-long treatment is required in PLWH and is accompanied by various metabolic abnormalities in the disease course. Data about the epidemiology and the dynamic changes of dyslipidemia in PLWH receiving antiretroviral therapy were scarce in Asian countries. This study aimed to explore the risk factors of dyslipidemia and analyze the longitudinal changes of dyslipidemia among Chinese PLWH receiving HAART., Methods: We conducted a longitudinal analysis of PLWH enrolled in two large multicenter clinical trials across China, and outpatients followed at the clinic of Peking Union Medical College Hospital. Demographic data and clinical parameters were collected. The risk factors and longitudinal changes in lipid profiles associated with HIV-1 infection were analyzed. The definition of dyslipidemia was made based on the National Cholesterol Education Program, Adult Treatment Panel (NCEP-ATP) III guidelines., Results: A total of 1542 PLWH were included. The median follow-up was 6 years. At baseline, the concentrations of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were 4.1 ± 0.91 mmol/L, 1.2 (interquartile ranges [IQR] 0.85-1.75) mmol/L, 1.1 ± 0.37 and 2.4 ± 0.76 mmol/L, respectively. The rate of hypercholesterolemia, hyperglyceridemia, high LDL-C, and low HDL-C were 10.18%, 26.39%, 9.08%, and 44.94%, respectively. The overall prevalence of dyslipidemia was 69.3%, which raised to 84.3% after antiretroviral therapy, substantially higher. CD4/CD8 ratio < 0.3 and viral load > 10 5 copies/mL were risk factors associated with any subtype of dyslipidemia. A negative correlation between CD8 + CD38 + percentage and HDL-C concentration was found. The regimens including efavirenz (EFV) and tenofovir (TDF) showed better lipid profiles. Longitudinal analysis revealed that both the level and the percentage of abnormal TG and HDL-C occurred drastic change in the first 6 months after ART initiation (from 4.07 to 4.41, from 1.11 to 1.28mmol/L, from 26.39 to 31.1% and from 44.94 to 29.5%, respectively)., Conclusions: The prevalence of dyslipidemia is high in PLWH and increases after ART, mainly represented as high TG and low HDL-C and associated with advanced stage of HIV-1 infection. The greatest changes in lipids occurred in the early stage after initiating ART therapy. The results suggest that dyslipidemia should be monitored and managed when starting ART., (© 2023. BioMed Central Ltd., part of Springer Nature.)

We studied the relationship between HIV DNA and CD8 + T-cell activation in a retrospective cohort. We observed that the expression level of HLA-DR remained high in CD8 + T-cells and was positively correlated with total HIV DNA [odds ratio (OR)  =  1.86, P  = 0.028) during 8 years of suppressive antiretroviral therapy (ART). This study illustrated the long-term interplay between HIV DNA reservoir and host inflammatory state despite viral suppression., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Several studies have described the rapid decline and clearance of hepatitis B surface antigen (HBsAg) in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfection after initiating combined antiretroviral therapy (cART). Early decline of HBsAg levels is associated with HBsAg seroclearance in the treatment of chronic HBV infection. This study aims to evaluate the HBsAg kinetics and the determinants of early HBsAg decline in patients with HIV/HBV coinfection during cART., Methods: A total of 51 patients with HIV/HBV coinfection were enrolled from a previously established HIV/AIDS cohort and followed for a median of 59.5 months after cART initiation. Biochemical tests, virology and immunology assessments were measured longitudinally. The kinetics of HBsAg during cART were analyzed. Soluble programmed death-1 (sPD-1) levels and immune activation markers (CD38 and HLA-DR) were measured at baseline, 1-year and 3-year during treatment. HBsAg response was defined as a decline of more than 0.5 log 10 IU/ml at 6 months from the baseline after initiation of cART., Results: HBsAg declined faster (0.47 log 10 IU/mL) in the first six months and attained a decrease of 1.39 log 10 IU/mL after 5-year therapy. Seventeen (33.3%) participants achieved a decline of more than 0.5 log 10 IU/ml at the first 6 months of cART(HBsAg response) of which five patients achieved HBsAg clearance at a median of 11 months (range: 6-51 months). Multivariate logistic analysis showed the lower baseline CD4 + T cell levels (OR=6.633, P =0.012) and sPD-1 level (OR=5.389, P =0.038) were independently associated with HBsAg response after cART initiation. The alanine aminotransferase abnormality rate and HLA-DR expression were significantly higher in patients who achieved HBsAg response than in those who did not achieve HBsAg response after cART initiation., Conclusion: Lower CD4 + T cells, sPD-1, and immune activation were related to a rapid HBsAg decline in patients with HIV/HBV-coinfection after the initiation of cART. These findings imply that immune disorders induced by HIV infection may disrupt immune tolerance to HBV, leading to a faster decline in HBsAg levels during coinfection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Xu, Lu, Liu, Yang, Wu, Han, Li, Li, Song, Cao and Li.)

Background: Current antiretroviral regimens have, for the most part, achieved optimal antiretroviral efficacy and tolerability, transforming HIV infection from a deadly disease into a manageable chronic condition. However, adherence to daily oral drug intake remains an issue, as it is the most important determinant for sustained viral suppression and prevention of the emergence of drug-resistant viral strains. The long-acting injection antiretroviral cabotegravir and rilpivirine combination, a novel drug delivery approach, is about to revolutionise the therapy for people living with HIV. In this protocol, we aim to generate a clinically useful summary of the interventions based on their efficacy., Methods and Analysis: We searched the literature for eligible studies published from inception up to 16 August 2022 through PubMed, EMBASE, Cochrane Library, Scopus and ClinicalTrials.gov. Two methodologically trained researchers will select the qualified studies for data extraction independently. Cochrane Risk of Bias tool will be used to assess the risk of bias in included studies. Statistical heterogeneity will be computed by Cochrane X 2 and I 2 tests. Sensitivity analysis will be conducted to evaluate the stability of the results. Publication biases will be evaluated by Begg's and Egger's tests. The quality of evidence will be assessed by the Grading of Recommendations Assessment, Development and Evaluation system. The RevMan V.5.3 and Stata V.14.0 software will be applied for statistical analyses., Ethics and Dissemination: Ethical approval will not be required for this systematic review because the data used are not linked to the individual patient. The results of this review will be disseminated by being published in a peer-reviewed journal., Prospero Registration Number: CRD42022310414., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The extent of immune reconstitution in human immunodeficiency virus (HIV) infected persons receiving long-term antiretroviral therapy (ART) with controlled viral load has been controversial. We studied the extent and speed of T cell subsets retrieval after long-term antiretroviral treatment., Methods: 662 HIV-infected patients followed at least 2 years whose plasma HIV-1 RNA load <50 copies/mL were evaluated for longitudinal and functional phenotypic indices of immune restoration. Determinants of change in magnitude and importance of recovery have been evaluated using mixed linear regression models., Results: Almost all robust immune restorations achieved occurred after 2-3 years of ART. The median CD4 lymphocyte count increased 449 cells/μl (IQR 303-604) from 226 cells/μl (IQR 83-336) at baseline during the third year ( P < 0.001); CD4+T lymphocyte rises during the sixth and tenth years were not significant. Naive and memory CD4+T cells'reconstitution occurred in the sixth and eighth years of ART but no significant change thereafter. The change of CD45RA+Naïve and CD45RA-memory CD4+T cell reconstitution is different in baseline CD4+T cell counts <100 cells/μl group and in baseline CD4+T cell counts >100 cells/μl group. Activation antigen expression (CD38 or HLA-DR) on CD8 lymphocytes declined mostly during the first till second year, and after 4 years, activation antigen expression on patient lymphocytes showed no significant change. The proportion of CD4 cells expressing CD28 climbed during the first years and reached normal levels in the second year., Conclusions: Immune restoration was dependent on the capacity of immune system during the first 2-3 year of ART. But the significant change of CD4 and compartments of CD4+T cells could persist until 6-8 years. The pattern of CD38+CD8+, HLA-DR+CD8+, CD28+CD4+ T cells could quickly return to normal level and no significant change after sufficient time of ART. In general, the immune response compared to the baseline status may be the overall effect from the age and time of antiretroviral treatment.

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., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Data on hepatitis B virus (HBV) pregenomic (pgRNA) levels in HIV/HBV coinfected patients pre- and post-combined antiretroviral therapy (cART) are limited. This study aimed to evaluate the distribution of HBV pgRNA levels in treatment-naive coinfected patients and explore the changes that occur after the initiation of cART by examining patients from multicentre cohort studies performed in China. We included HIV/HBV coinfected subjects from the China AIDS Clinical Trial cohorts established from 2008 to 2014. Clinical and serological markers of HIV and HBV infection and biochemical data were acquired at baseline and after 96 and 240-480 weeks of cART. The correlations between HBV pgRNA and HBV DNA levels as well as HBsAg levels were calculated using Spearman's bivariate correlation analysis, and multivariate regression analysis was performed to determine factors associated with undetectable HBV pgRNA levels before cART and HBeAg loss after cART. A total of 132 HIV/HBV coinfected patients were enrolled, and 100 individuals were HBeAg-negative. A total of 34.4% (32/93) of patients were positive for HBV pgRNA, and the median HBV pgRNA level was 4.92 (IQR: 4.21-6.12) log 10 copies/mL before cART. The median HBV pgRNA level was significantly lower in HBeAg-negative individuals than in HBeAg-positive individuals (4.22 (IQR: 2.70-4.84) log 10 copies/mL vs. 5.77 (IQR: 4.63-6.55) log 10 copies/mL, p = 0.002). HBV pgRNA was moderately correlated with HBsAg (r = 0.594, p = 0.001), and positively associated with HBV DNA (r = 0.445, p = 0.011). The factors independently associated with undetectable HBV pgRNA level before cART were HBV DNA (OR: 5.61, 95% CI: 1.50-20.96, p = 0.01) and HBeAg status (OR: 5.95, 95% CI: 1.52-23.25, p = 0.01). A total of 87.5% (28/32) of patients were followed for a median duration of 138 (IQR: 54-240) weeks, and the HBV pgRNA levels became undetectable in seven patients. The 132 patients were observed for 695.5 person-years, and no HBsAg loss occurred. Thirteen individuals achieved HBeAg loss, four patients had undetectable levels of HBV pgRNA pre-cART, and the level of six individuals became undetectable during the 48-week (IQR: 48-264) follow-up period. HBeAg status was significantly associated with HBV pgRNA level in HIV/HBV coinfected patients pre- and post-cART. Additionally, undetectable HBV pgRNA level may be associated with HBeAg loss after cART., (© 2022 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

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., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Pre-exposure prophylaxis (PrEP) is a promising HIV prevention method. However, the rollout of PrEP among men who have sex with men (MSM) is facing challenges. This study sought to understand PrEP acceptability and service use challenges among MSM in China. The study was conducted in 2018 in Guangdong Province using a mixed-methods approach. Among 489 HIV-negative MSM who completed an online survey, 374 (76.5%) had heard of PrEP before. The most common PrEP information sources were internet/social media (32.1%) and community-based organizations (30.4%). Two-thirds ( n =328) of the MSM would accept PrEP even the protective efficacy is less than 100%, 60.1% ( n =294) expressed willingness to use PrEP once it is approved in China, and 59.3% ( n =290) were willing to pay out of pocket. Employment, disclosure of MSM status, and mental health issues were associated with PrEP acceptability. In-depth interviews with 30 MSM revealed that high cost, low accessibility, and stigma in clinic settings were barriers to PrEP using. Primary care-based PrEP services were acceptable, but patients' confidentiality was a concern. PrEP promotion efforts should address social and mental health challenges among MSM and mobilize primary care systems and community-based organizations to achieve the best result.

Purpose: The incomplete immune reconstitution is a complex phenomenon among human immunodeficiency virus (HIV)-infected patients despite the fact that they have achieved persistent viral suppression under the combined antiretroviral therapy. This study aims to screen and verify the immunological characteristics and underlying mechanisms of immunological non-responders (INRs)., Methods: The RNA-seq and the differentially expressed genes (DEGs) analysis were used to explore potential characteristics among INRs. Gene Ontology (GO) enrichment, ingenuity pathway analysis (IPA) analysis, Gene set enrichment analysis (GSEA) analysis, and the weighted gene co-expression network analysis (WGCNA) were used to explore the potential mechanism. The transcriptional meta-analysis was used to analyze the external efficiency., Results: The RNA-seq identified 316 DEGs among INRs. The interferon signaling pathway was enriched via GO and IPA analysis among DEGs. The combined GSEA and WGCNA analysis confirmed that the IFN response was more correlated with INR. Furthermore, IFI27 (IFN-α Inducible Protein 27, also known as ISG12) was chosen based on combined DEG analysis, WGCNA analysis, and the transcriptional meta-analysis conducted on other published datasets about INRs. The expression of IFI27 was significantly negatively correlated with the CD4+ T-cell counts of PLWH, and the predictive efficiency of IFI27 level in distinguishing PLWH with poor immune recovery was also with significant power (AUC = 0.848)., Conclusion: The enhanced expression of IFI27 and the IFN response pathway are among the important immunological characteristics of INRs and exhibited promising efficiency as biomarkers for CD4 + T-cell recovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Lin, Lu, Li, Han, Qiu, Li, Li, Song, Cao and Li.)

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., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Tingxia Lv et al.)

Hepatitis delta virus (HDV) is an obligate satellite of hepatitis B virus (HBV). HIV/HDV co-infection is associated with a high rate of hepatic decompensation events and death. We aimed to characterize the epidemiology of HDV infection in HIV/HBV co-infected individuals. We systematically searched PubMed, Embase, Cochrane Library, Web of Science, CINAHL and Scopus for studies published from 1 Jan 2002 to 7 May 2018 measuring prevalence of HDV among the HIV population. Pooled seroprevalence was calculated with the DerSimonian-Laird random-effects model. Our search returned 4624 records, 38 of which met the inclusion and exclusion criteria. These studies included data for 63 cohorts from 18 countries and regions. The overall HDV seroprevalence of HIV-infected individuals was 1.03% (95% CI 0.43-1.85) in 2002-2018 globally. Moreover, the estimated pooled HDV seroprevalence among the general population was 1.07% (95% CI 0.65-1.59) in 2002-2018, which was not significantly different from the HDV seroprevalence of individuals living with HIV (p = 0.951). The overall HDV seroprevalence of the HBsAg positive population was 12.15% (95% CI 10.22-14.20), p = 0.434 when compared with the corresponding data of HIV/HBV co-infected individuals. This meta-analysis suggested that there was no difference between the HDV seroprevalence in HIV-infected individuals and the general population., (© 2021 John Wiley & Sons Ltd.)

Background: Some long-term non-progressors (LTNPs) have decreasing CD4 + T cell counts and progress to AIDS. Exploring which subsets of CD4 + T cell decreasing and the determinants associated with the decay in these patients will improve disease progression surveillance and provide further understanding of HIV pathogenesis., Methods: Twenty-five LTNPs infected with HIV by blood products were classified as decreased (DG) if their CD4 + cell count dropped to < 400 cells/μL during follow-up or as non-decreased (non-DG) if their CD4 + cell count was ≥400 cells/μL. Laboratory and clinical assessments were conducted at 6 consecutive visits to identify DG characteristics., Results: The LTNPs were infected with HIV for 12 (IQR: 11.5-14) years, and 23 were classified as the B' subtype. Six individuals lost LTNP status 14.5 (IQR: 12.5-17.5) years after infection (DG), and the CD4 + T cell count decreased to 237 (IQR: 213-320) cells/μL at the latest visit. The naïve CD4 + T cell count decrease was greater than that of memory CD4 + T cells [- 128 (IQR: - 196, - 107) vs - 64 (IQR: - 182, - 25) cells/μL)]. Nineteen individuals retained LTNP status (non-DG). At enrolment, the viral load (VL) level (p = 0.03) and CD8 + CD38 + percentage (p = 0.03) were higher in DG than non-DG individuals. During follow-up, viral load and CD8 + CD38 + percentage were significantly increased and negatively associated with CD4 + cell count [(r = - 0.529, p = 0.008), (r = - 0.476, p = 0.019), respectively]. However, the CD8 + CD28 + percentage and B cell count dropped in DG and were positively correlated with CD4 + T cell count [(r = 0.448, p = 0.028), (r = 0.785, p < 0.001)]., Conclusion: Immunological progression was mainly characterized by the decrease of naïve CD4 + T cell in LTNPs infected with HIV by blood products and it may be associated with high HIV RNA levels.

This is the first 5-year analysis among persons with HIV (PWH) that reports both trabecular bone score (TBS), which is a novel index that estimates bone microarchitecture, and bone mineral density (BMD) over time to evaluate the long-term impact of antiretroviral therapy (ART) on bone health., Purpose: HIV infection and antiretroviral therapy (ART) have been associated with decreased bone mineral density (BMD). This study aims to evaluate long-term changes in trabecular bone score (TBS), a novel index that estimates bone microarchitecture, and BMD among Chinese persons with HIV (PWH) treated with ART., Methods: We conducted a retrospective chart review of adult PWH at a large tertiary care hospital in China. Patients who had a DXA scan prior to ART and at least one follow-up DXA after ART initiation were included. Subgroup analyses examined the TBS and BMD changes in patients who switch from a non-TDF-containing regimen to one containing TDF, as compared to those who did not switch., Results: Four hundred fifty-nine PWH were included. Among 68 patients ≥ 50 years, 13 patients (19.1%) had a normal BMD but partially degraded or degraded TBS. The mean percent decrease in lumbar spine (LS) BMD nadired at 48 weeks after ART initiation and then gradually improved. Percent decrease in femoral neck (FN) and total hip (TH) BMD nadired at 96 weeks and remained stably low thereafter. After switch to a TDF-containing regimen, only percent change in TH BMD was significant (-3.2%, p = 0.006). In the regression analyses, switch to a TDF-containing regimen was not associated with long-term change in TBS or BMD., Conclusion: This is the first study among PWH to evaluate the long-term impact of ART on TBS and BMD. At baseline, approximately 20% of patients had a normal BMD but impaired bone microstructure based upon TBS. For patients with 5 years of exposure to ART, there is a stabilization of TBS and BMD after initial nadir in the first 144 weeks. However, FN BMD, TH BMD, and TBS remained low at 5 years relative to baseline.

Background: The plasma concentration of patients treated with efavirenz (EFV) 600 mg was found to exceed the upper limit of the proposed therapeutic window in most Chinese HIV-infected individuals; thus, dosage reduction of EFV to 400 mg daily warranted consideration. This study aimed to assess the pharmacodynamics of EFV 400 mg for HIV-1-infected patients in China., Method: Twenty cART-naïve individuals were enrolled in this study. EFV 400 mg combined with tenofovir (TDF) and lamivudine (3TC) as an initial antiretroviral regimen was administered for 48 weeks. EFV concentration and T cell subsets as well as HIV RNA load were evaluated at baseline and at 4, 12, 24, and 48 weeks. Moreover, neuropsychiatric adverse effects were also assessed by the Hamilton depression (HAMD) scale and Pittsburgh sleep quality index (PSQI)., Results: Eighteen males and two females whose median age was 26 (interquartile range [IQR]: 23-32) years completed 48 weeks of follow-up. The median EFV concentrations were 1.88 (IQR: 1.54-2.42), 1.74 (IQR: 1.36-1.93), 1.93 (IQR: 1.66-2.22), and 1.85 (IQR: 1.54-2.14) mg/L at weeks 4, 12, 24, and 48, respectively. The viral load was 4.59 (IQR: 4.10-5.19) log 10 copies/mL at baseline, and it decreased by 4.6 (IQR: 3.98-5.18) log 10 copies/mL from baseline to week 48. Three of 20 (15%), 10 of 20 (50.0%), 17 of 20 (85%), and 18 of 19 (95%) participants had a plasma viral load less than 50 copies/mL at weeks 4, 12, 24, and 48, respectively. The median CD4 cell count was 330 (IQR: 237-410) cells/μL at baseline, and it increased to 473 (IQR: 344-574) cells/μL at 48 weeks. The HAMD score was 5 (IQR: 3-9.8) and 3 (IQR: 2.25-4) at baseline and 48 weeks, respectively. The PSQI score was 4 (IQR: 2-5.8) and 3 (IQR: 2-4) at baseline and 48 weeks, respectively. Dizziness was the most common event, occurring in 70% of patients within the first 2 weeks of treatment., Conclusion: Patients prescribed with EFV 400 mg-containing agents demonstrated favourable virological and immunological responses. And the plasma EFV concentration was within the recommended therapeutic range, with fewer adverse reactions than with EFV 600 mg. EFV 400 mg was effective and safe in Chinese HIV-infected patients., Trial Registration: NCT04596488 ; Registered 21 October, 2020; Retrospectively registered.

Background: A more time saving, convenient, reproducible, and scalable method is needed to assess total HIV-1 DNA levels., Methods: Frozen whole blood and peripheral blood mononuclear cell (PBMC) samples both 200 μl at the same point were used to detect total HIV-1 DNA. Automatic extraction of total HIV-1 DNA was used to ensure the consistency of sample extraction efficiency. The detection reagent was HIV-1 DNA quantitative detection kit and real-time quantitative PCR was utilized., Results: Of the 44 included patients, 42 were male and 2 were female, with a median age of 33 years. Thirty-three cases were collected after receiving antiviral treatment, with a median duration of treatment of 3 months, and the other 11 cases were collected before antiviral treatment. The median viral load was 1.83 log10 copies/mL, the median CD4 and CD8 count were 94 and 680 cells/μL, and the median CD4/CD8 ratio was 0.18. The results of the two samples were 3.02 ± 0.39 log10 copies/10 6 PBMCs in PBMC samples and 3.05 ± 0.40 log10 copies/10 6 PBMCs in whole blood samples. The detection results of the two methods were highly correlated and consistent by using paired t test (P = 0.370), pearson correlation (r = 0.887, P < 0.0001) and intra-group correlation coefficient (ICC = 0.887, P < 0.0001) and bland-altman [4.55% points were outside the 95% limits of agreement (- 0.340 ~ 0.390)]., Conclusions: The results of the whole blood sample test for total HIV-1 DNA are consistent with those of PBMC samples. In a clinical setting it is recommended to use whole blood samples directly for the evaluation of the HIV reservoir.

Stigma poses considerable challenges to the mental health of people living with HIV who use drugs (PLHWUD). In this study, we explored factors related to different types of stigma (perceived and internalized) attached to layered stigmatizing characters (HIV and drug use) and their mental health influences on PLHWUD. The study used baseline data of an ongoing randomized controlled trial among 241 PLHWUD recruited between March and December 2018 in Vietnam. A structural equation model was used to assess the relationships among different types and layers of stigma and mental health status. Both perceived and internalized drug-related stigma measures were significantly higher than their corresponding HIV-related stigma. HIV-related stigma was negatively associated with mental health status; however, we did not find a significant relationship between drug-related stigma and mental health. Tailored intervention strategies in consideration of types and layers of stigma are needed to address stigma-related challenges faced by PLHWUD.

Background: It is not completely clear whether a very high pre-therapy viral load (≥ 500 000 copies/ml) can impair the virological response. The aim of this study was to examine the influence of very high baseline HIV-RNA levels on long-term virological responses under one type of regimen., Methods: A retrospective study was performed based on data from two multicenter cohorts in China from January to November 2009, and from May 2013 to December 2015. Untreated HIV infected adults between 18 and 65 years old were recruited before receiving non-nucleoside reverse transcriptase inhibitor-based regimen. All patients had baseline HIV-RNA levels over 500 copies/ml, good adherence, and were followed for at least 24 weeks. Virological suppression was defined as the first HIV-RNA < 50 copies/ml. Virological failure was defined as any of incomplete viral suppression (HIV-RNA ≥ 200 copies/ml without virological suppression within 24 weeks of treatment) and viral rebound (confirmed HIV-RNA level ≥ 50 copies/ml after virological suppression). Chi-square test, Kaplan-Meier analysis, Cox proportional hazards model and Logistic regression were used to compare virological response between each pretreated viral load stratum., Results: A total of 758 treatment-naïve HIV patients in China were enlisted. Median follow-up time (IQR) was 144 (108-276) weeks. By week 48, rates of virological suppression in three groups (< 100 000, 100 000-500 000 and ≥ 500 000 copies/ml) were 94.1, 85.0, and 63.8%, respectively (P < 0.001). Very high baseline HIV viremia over 500 000 copies/ml were found to be associated with delayed virological suppression (≥ 500 000 vs <  100 000, adjusted relative hazard = 0.455, 95% CI: 0.32-0.65; P < 0.001) as well as incomplete viral suppression (≥ 500 000 vs < 100 000, adjusted odds ratio [aOR] = 6.084, 95% CI: 2.761-13.407; P < 0.001) and viral rebound (≥ 50 000 vs < 100 000, aOR = 3.671, 95% CI: 1.009-13.355, P = 0.048)., Conclusions: Very high levels of pre-treatment HIV-RNA were related with delayed efficacy of NNRTI-based ART and increased risk of treatment failure. More potent initial regimens should be considered for those with this clinical character.

Combination antiretroviral therapy (cART) is effective but not curative, and no successful vaccine is currently available for human immunodeficiency virus-1 (HIV-1). Broadly neutralizing antibodies (bNAbs) provide a new approach to HIV-1 prevention and treatment, and these promising candidates advancing into clinical trials have shown certain efficacies in infected individuals. In addition, bNAbs have the potential to kill HIV-1-infected cells and to affect the course of HIV-1 infection by directly engaging host immunity. Nonetheless, challenges accompany the use of bNAbs, including transient suppression of viraemia, frequent emergence of resistant viruses in rebound viraemia, suboptimal efficacy in virus cell-to-cell transmission, and unclear effects on the cell-associated HIV-1 reservoir. In this review, we discuss opportunities and potential strategies to address current challenges to promote the future use of immunotherapy regimens.

Background: The impact of HIV-1 subtype (CRF01&#95;AE and non-CRF01&#95;AE) on HIV-1 DNA levels in HIV-1 chronically infected patients with suppressive antiretroviral therapy (ART) remains poorly understood. To evaluate the correlation of HIV-1 subtype with DNA level, and identify baseline predictors of HIV-1 DNA decay., Methods: ART-naïve HIV-1-infected patients from two large multi-center studies in China were classified into CRF01&#95;AE and non-CRF01&#95;AE subtype groups. Peripheral blood samples were collected at baseline and week 12, 24, 48 and 96 after ART initiation and total HIV-1 DNA levels were quantified by real-time PCR. HIV-1 DNA levels at week 96 were categorized into high, moderate, and low levels, reflecting HIV-1 DNA ≥ 3, 2-3, ≤ 2 log 10 copies/10 6 PBMCs, respectively, and the corresponding proportion of CRF01&#95;AE and non-CRF01&#95;AE subtype were compared. The baseline predictors of low HIV-1 total DNA levels (≤ 2 log 10 copies/10 6 PBMCs) at week 96 were evaluated using a logistic regression model., Results: Compared to the non-CRF01&#95;AE subtypes (n = 185), patients with CRF01&#95;AE subtype (n = 188) harboured a higher level of HIV-1 DNA (median: 3.19 vs. 2.95 log 10 copies/10 6 PBMCs, P < 0.001) prior to treatment. After 96 weeks of ART, HIV-1 DNA levels remained higher in the CRF01&#95;AE subtype group (median: 2.63 vs. 2.39 log 10 copies/10 6 PBMCs, P = 0.002). There was no significant difference in the proportion of patients achieving high (22.3% vs. 14.6%, P = 0.054), moderate (59.6% vs. 60.5%, P = 0.849) and low levels (18.1% vs 24.9%, P = 0.111) between CRF01&#95;AE and non-CRF01&#95;AE groups. In the multivariable analysis, baseline HIV-1 DNA level and CD4 + T cell count but not the subtype were independent risk factors for achieving HIV-1 DNA level ≤ 2 log 10 copies/10 6 PBMCs., Conclusion: HIV-1 CRF01&#95;AE subtype is neither correlated with HIV-1 DNA reservoir decline nor a prognostic factor for achieving lower HIV-1 DNA levels (≤ 2 log 10 copies/10 6 PBMCs) after ART. However, higher HIV-1 DNA level in HIV-1 CRF01&#95;AE patients should be aroused much attention and strengthen surveillance during ART.

Background: Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and Treponema pallidum (TP) infections are considered classic transfusion-transmissible infections (TTIs). Few data are available about the prevalence of TTIs in patients before blood transfusion in China. This study aimed to investigate the seroprevalence of four TTIs among patients before blood transfusion in Xiangya Hospital Central South University, China., Methods: From 2011 to 2016, 442,121 hospitalized patients before possible blood transfusion were tested for hepatitis B surface antigen (HBsAg), anti-HCV, syphilis antibody (anti-TP) and anti-HIV., Results: Of the 442,121 patients, the overall positivity of the four TTI serum markers was 15.35%. The positive rates of HBsAg, anti-HCV, anti-HIV and anti-TP were 10.98, 1.43, 0.16 and 2.78%, respectively. TTI serum markers showed a significant difference by gender, with positive rates of 17.98% for males and 12.79% for females. The prevalence of TTI serum markers varied significantly by age. The overall co-infection rate was 0.63%, and the top three multiple infections were HBV-TP, HBV-HCV, and HCV-TP. The co-infection rates of HBV-TP and HBV-HCV showed a significant decrease from 2011 to 2016, while the rates of other co-infections remained stable., Conclusions: The prevalence of TTIs in patients before blood transfusion is much higher compared to that in blood donors in the region. The infection rates of HIV and TP increased, and the infection rate of HBsAg decreased in recent years.

Introduction: Guidelines regarding antiretroviral therapy (ART) initiation in HIV infection have varied over time, with the 2015 World Health Organization recommendation suggesting ART initiation at the time of diagnosis regardless of CD4 T-cell counts. Herein, we investigated the influence of socio-demographic and clinical factors in addition to time trends on early ART initiation among participants of the Montreal Primary HIV Infection Study., Methods: The Montreal Primary HIV Infection Study is a prospective cohort established in three community medical centres (CMCs) and two university medical centres (UMCs). Recently diagnosed HIV-infected adults were categorized as receiving early (vs. delayed) ART if ART was initiated within 180 days of the baseline visit. Associations between early ART initiation and socio-demographic, socio-economic and behavioural information were examined. Independent associations of factors linked with early ART initiation were determined using multivariable binary logistic regression analysis., Results: A total of 348 participants had a documented date of HIV acquisition of <180 days. The median interquartile range (IQR) age of participants was 35 (28; 42) years and the majority were male (96%), having paid employment (63%), men who have sex with men (MSM) (78%) and one to four sexual partners in the last three months (70%). Participants presented with a median IQR HIV plasma viral load of 4.6 (3.7; 5.3) log 10 copies/ml, CD4 count of 510 (387; 660) cells/μl and were recruited in CMCs (52%) or UMCs (48%). Early ART initiation was observed in 47% of the participants and the trend followed a V-shaped curve with peaks in 1996 to 1997 (89%) and 2013 to 2015 (88%) with a dip in 2007 to 2009 (22%). Multivariable analyses showed that having a paid employment adjusted odds ratio (aOR: 2.43; 95% CI: 1.19, 4.95), lower CD4 count (aOR per 50 cell increase: 0.93; 95% CI: 0.87, 0.99) and care at UMCs (aOR: 2.03; 95% CI: 1.06 to 3.90) were independently associated with early ART initiation., Conclusions: Early ART initiation during primary HIV infection was associated with diminished biological prognostic factors and calendar time mirroring evolution of treatment guidelines. In addition, socio-economic factors such as having a paid employment, contribute to early ART initiation in the context of universal access to care in Canada., (© 2018 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.)

Introduction: HIV infection leads to a disturbed T-cell homeostasis, featured by a depletion of CD4 T-cells and a persistent elevation of CD8 T-cells over disease progression. Most effort of managing HIV infection has been focused on CD4 T-cell recovery, while changes in the CD8 compartment were relatively underappreciated in the past., Methods: A comprehensive literature review of publications in English language was conducted using major electronic databases. Our search was focused on factors contributing to CD8 T-cell dynamics in HIV infection and following antiretroviral therapy (ART)., Discussion: Normalization of CD8 counts is seldom observed even with optimal CD4 recovery following long-term treatment. Initiation of ART in primary HIV infection leads to enhanced normalization of CD8 count compared with long-term ART initiated in chronic infection. Importantly, such CD8 elevation in treated HIV infection is associated with an increased risk of inflammatory non-AIDS-related clinical events independent of CD4 T-cell recovery. The mechanisms underlying CD8 persistence remain largely unknown, which may include bystander activation, exhaustion and immunosenescence of CD8 T-cells. The information provided herein will lead to a better understanding of factors associated with CD8 persistence and contribute to the development of strategies aiming at CD8 normalization., Conclusions: Persistence of CD8 T-cell elevation in treated HIV-infected patients is associated with an increased risk of non-AIDS-related events. Now that advances in ART have led to decreased AIDS-related opportunistic diseases, more attention has been focused on reducing non-AIDS events and normalizing persistent CD8 T-cell elevation.

Background: CD8 T-cell counts remain elevated in human immunodeficiency virus (HIV) infection even after long-term antiretroviral therapy (ART), which is associated with an increased risk of non-AIDS-related events. We assessed the impact of ART initiation in early versus chronic HIV infection on trajectories of CD8 cell counts over time., Methods: Of 280 individuals enrolled during primary HIV infection (PHI), 251 were followed up for 24 months; 84 started ART before 6 months of infection (eART), 49 started between 6 and 24 months, and 118 remained untreated. Plasma HIV viral load (VL), CD4 and CD8 cell counts were assessed at each study visit. CD8 counts were also examined in 182 age-matched HIV-infected individuals who started ART during chronic infection and maintained undetectable plasma VL for ≥5 years., Results: At PHI baseline, higher CD8 cell counts were associated with more recent infection (P = .02), higher CD4 cell counts (P < .001), and higher VL (P < .001). The CD8 count in the eART group decreased from 797 to 588 cells/µL over 24 months (P < .001), to a level lower than that in untreated PHI (834 cells/µL; P = .004) or in long-term-treated patients with chronic HIV infection (743 cells/µL; P = .047). More prominent CD4 T-cell recovery was observed in the eART group than in the delayed ART group., Conclusions: ART initiated in early HIV infection is associated with improved resolution of CD8 T-cell elevation compared with long-term ART initiated in chronic infection. Early ART may help reduce the risk of non-AIDS-related events by alleviating this elevation., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

The recent advances in the understanding of primary HIV-1 infection and the development of well-tolerated antiretroviral therapies have highlighted the potential impact of early treatment initiation on immune responses and gut mucosal barrier dysfunction. Immunological and virological assessments in the blood as well as in gut-associated lymphoid tissues during the early phase of infection indicate the crucial role of HIV-1-specific responses and non-specific immune activation in disease progression. The clinical benefit of early antiretroviral therapy has been somewhat disappointing, with the exception of a small group of patients exhibiting sustained control of HIV replication after transient antiretroviral therapy, designated as post-treatment controllers. This review focuses on the influences of antiretroviral therapy initiated early or very early in the course of infection on the clinical and immunological outcomes as well as its impact on the gut mucosal dysfunction. The evidence presented herein paves the way for the development of immunological interventions combined with early antiretroviral therapy to enhance HIV-1-specific responses and to modulate immune activation that will contribute to HIV remission and cure.

Introduction: Absolute CD4 T cell count and plasma viral load have been established as predictors of HIV disease progression, and CD4 T cell count is used as an indicator for initiation of antiretroviral therapy. Following long-term therapy, patients generally present with significant CD4 T cell recovery contrasting with persistently elevated CD8 T cell counts, which leads to a partial restoration of CD4:CD8 ratio. This review focuses on the relevance of the CD4:CD8 ratio on clinical outcomes, immune dysfunction and HIV reservoir size in long-term treated patients., Method: We conducted a comprehensive literature review of publications in English language using major electronic databases. Our search was focused on factors contributing to CD4:CD8 T cell ratio and clinical outcome in adult HIV-positive patients in the context of treated infection., Discussion: Low CD4:CD8 ratio has been linked to ageing and acts as a predictor of mortality in the general population. This ratio may represent the combined effects of inflammation and immunological changes called "inflammaging." Although the mechanisms underlying partial correction of the CD4:CD8 ratio and persistently elevated CD8 T cell count in long-term treated patients remain poorly understood, it has been recently indicated that patients with optimal CD4 T cell recovery and low CD4:CD8 ratio still harbour increased immune activation, an immune senescent phenotype and have a higher risk of non-AIDS morbidity and mortality. This review reconsiders CD4:CD8 ratio in the light of advances in the understanding of immune dysfunction and examines its pathophysiological features and implications on clinical outcome and HIV reservoir size in long-term treated HIV-positive adults., Conclusion: The CD4:CD8 ratio can contribute to the immunological evaluation of treated patients in a long-term follow-up and may be applied for monitoring both immune dysfunction and viral reservoir size in immune-based clinical trials.

Tryptophan degradation along the kynurenine pathway is associated with a wide variety of pathophysiological processes, of which tumor tolerance and immune dysfunction in several chronic viral infections including HIV are well known. The kynurenine pathway is at the crossroads of metabolism and immunity and plays an important role in inflammation while also playing an opposing role in the control of acute and chronic infections. In this review we have summarized findings from recent studies reporting modulation of tryptophan degrading the kynurenine pathway in the context of HIV infection. This immuno-metabolic pathway is modulated by three distinct inducible enzymes: indoleamine 2,3-dioxygenase 1 and 2 and tryptophan 2,3-dioxygenase. Increased expression of these enzymes by antigen-presenting cells leads to local or systemic tryptophan depletion, resulting in a mechanism of defense against certain microorganisms. Conversely, it can also lead to immunosuppression by antigen-specific T-cell exhaustion and recruitment of T regulatory cells. Recently, among these enzymes, indoleamine 2,3-dioxygenase 1 has been recognized to be an immune response checkpoint that plays an important role in HIV immune dysfunction, even in the context of antiretroviral therapy. In addition to the activation of the kynurenine pathway by HIV proteins Tat and Nef, the tryptophan-degrading bacteria present in the intestinal flora have been associated with dysfunction of gut mucosal CD4 Th17/Th22 cells, leading to microbial translocation and creating a systemic kynurenine pathway activation cycle. This self-sustaining feedback loop has deleterious effects on disease progression and on neurocognitive impairment in HIV-infected patients. Therapy designed to break the vicious cycle of induced tryptophan degradation is warranted to revert immune exhaustion in HIV-infected persons.

Objective: To determine the clinical characteristics of HIV infected patients in China in order to improve early recognition and diagnosis of AIDS., Methods: A total of 297 newly diagnosed HIV/AIDS patients were enrolled in Peking Union Medical College Hospital (PUMCH) from January 2001 to December 2012, including 19 patients of primary phase, 115 of asymptomatic phase and 163 of AIDS phase. Clinical characteristics of these patients were retrospectively analyzed., Results: Two hundred and nineteen out of 297 patients reported clinical symptoms with variety. The main systemic symptoms included fever (100 cases, 33.7%), weight loss (50 cases, 16.8%) and fatigue (38 cases, 12.8%). Organ involvement included mucocutaneous (67 cases, 22.6%), respiratory (62 cases, 20.9%), gastrointestinal (40 cases, 13.5%) systems. Patients in AIDS phase were more symptomatic. Seventy-three out of 173 (42.2%)patients have been referred by 2 healthcare providers at least before the diagnosis of HIV infection was confirmed. Initial diagnoses were made in Departments of Infectious Diseases (36.9%), Gastroenterology (16.4%), and Emergency (13.7%). Opportunistic infections accounted for most AIDS defining conditions (ADC), including pneumocystis jiroveci pneumonia (PCP) (36 cases, 22.1%), cytomegalovirus infection (25 cases, 15.3%) and tuberculosis (22 cases, 13.5%). Median peripheral CD(+)4 T lymphocyte count in patients with ADC were 36 cells/µl., Conclusions: Common clinical presentations of HIV/AIDS included fever, weight loss, diarrhea, short of breath and mucocutaneous lesions. Opportunistic infections mainly affected respiratory and gastrointestinal system, with PCP the most common one. The diagnosis of HIV infection was delayed in most cases, suggesting that more efforts are required especially in universal education of clinicians and accurate viral detection.

Background: HIV transmission between discordant couples has become an important source of new infections in China. To describe the seroconversion rate among serodiscordant couples and to identify salient behavioral and clinical risk factors including ART that affect heterosexual HIV transmission risk among couples in rural China., Methods: Longitudinal follow-up of an open cohort of HIV serodiscordant couples took place between 2007 and 2011 in Zhumadian, a city in southern Henan province in China, where blood plasma selling in 1990s led to a regional HIV epidemic. Annual follow-up included separate face-to-face interviews of husbands and wives, and HIV antibody testing for non-index partners. Cox proportional-hazard modeling was used to assess the relationship between HIV seroconversion and covariates of interest., Results: By the end of 2011, 4499 HIV serodiscordant couples had been enrolled in at least two follow-up interviews; 100 non-index partners seroconverted during the entire observation period for an incidence rate of 0.82 per 100 person-years (95% CI: 0.66-0.99). The incidence rates by the end of 2008, 2009, and 2010 were 2.14, 1.51, and 0.90 per 100 personyears respectively. Always using condoms in the past year of sex, gender of the index partner, frequency of sex, and ART exposure were all significant predictors of HIV seroconversion in the negative spouse. ART was highly protective against seroconversion whether the index partner was actively receiving treatment at the last follow-up (RR = 0.05, 95% CI, 0.01-0.16) or if the index partner had ever received ART (RR = 0.01, 95% CI, 0.00, 0.12). The risk of seroconversion in the nonindex spouse also decreased the longer the duration of the index partner's exposure to ART., Conclusions: ART exposure and always using condom were highly protective against HIV seroconversion in the negative spouse. HIV incidence in serodiscordant couples has been decreasing over time, associated with ART treatment time within 7 years in the index partner. Gender of the index spouse and frequency of sex were also important predictors. Treatment as part of a combination prevention package may be a feasible method of HIV control in this population.

Objective: To perform cost-effectiveness analysis of interventions in female sex workers in Dehong prefecture in China, with an aim of providing evidence for rational resource allocation in female sex worker interventions in the future., Methods: The data of expenses for female sex worker interventions in Dehong from 2005 - 2007 were obtained through questionnaire survey. Meanwhile, the data from baseline survey in 2004, from surveillance of female sex workers from 2005 through 2007 as well as from the special survey on sexual transmission in 2007 were collected. Intervention effectiveness was estimated by using SEX 2.0 Tool recommended by UNAIDS. The cost-effectiveness ratio is calculated as the total cost divided by the number of estimated non-HIV patients due to these interventions., Results: The total cost for female sex worker interventions is 916 400 RMB from 2005 through 2007, and a total of 3297 female sex workers were effectively intervened in these three years. Thus, the actual intervention cost for each female sex worker (unit cost) is 277.9 RMB. If all the intervention work is performed as required, the predicted unit cost for female sex worker intervention would be 500.5 RMB. During the period of 2005 through 2007, 69 female sex workers had been successfully prevented from HIV infection; therefore, the cost-effectiveness ratio is 13 282 RMB., Conclusion: Intervention among female sex workers is highly cost-effective.

Objective: To explore the relationship between types of social support and roles of supporters, on people living with HIV/AIDS, in rural areas of Henan province., Methods: A rural area from Henan province where the main route of HIV transmission was through blood collection was selected as the research site. Survivors registered in that area were randomly selected as subjects. Questionnaire on social support related to social network analysis paradigm was designed and face-to-face interview was used to collect information. Correspondence analysis method was adopted to analyze the relationship between types of social support and roles of social supporters., Results: 204 questionnaires were sorted out with 2227 pairs of bind between types of social support and roles of social supporters analyzed. According to scatter plot of row and column points, our data showed that support from the spouses was mainly associated with caring for daily life and companionship for medical treatment on the patients. The research subjects stated that they would primarily discuss over the major issues or chat with their parents and children as they were the ones that they could trust the most. However, they would turn to their brothers, sisters or other relatives to borrow money or asking for other kinds of help. Non-relatives were the resources on social interaction, like going-out together or borrowing life necessities., Conclusion: Supporters with different social roles on HIV/AIDS issues, appeared to be corresponded to specific types of social support in rural areas of Henan province.

Sustained simian immunodeficiency virus (SIV) infection of the central nervous system (CNS) depends on macrophage-tropic (M-tropic) strains that are often easily neutralizable. The CNS is often thought of as an immunologically privileged site that fosters replication of M-tropic quasispecies. Yet, there are limited data addressing the intrathecal antibody response or the role of the humoral response, in general, to control M-tropic strains. We investigated the temporal course of the intrathecal fusion inhibitory activity against an M-tropic viral variant and found an inverse relationship between the magnitude of this neutralization and the prevalence of M-tropic populations. These studies suggest a role for the humoral response in the suppression of M-tropic viral species in the CNS in experimental SIV infection.

And it is more stable using Cystatin C and eGFR SB CysC sb levels for assessing glomerular filtration rate than merely serum creatinine and eGFR SB cr sb when evaluating renal function in DTG-treatment patients. Total of patients were prescribed dolutegravir, including 37 patients were treated-naïve DTG+TDF-containing (group 1),23 patients treated with DTG-containing but no TDF (group 2) and 31 patients were switched-to DTG (group 4). Keywords: HIV; antiretroviral therapy; dolutegravir; renal function; cystatin C; serum creatinine EN HIV antiretroviral therapy dolutegravir renal function cystatin C serum creatinine 1695 1706 12 05/11/22 20220401 NES 220401 Introduction With the advent of antiretroviral therapy (ART) has contributed to protracted survival in patients infected with human immunodeficiency virus 1 (HIV-1), comorbidities with aging and side effects of ART have emerged as new concerns. Bland-Altman diagram and Intra-class correlation coefficient of eGFR SB cr sb and eGFR SB CysC sb proved the less consistent results in DTG-treatment patients rather than TDF-treatment patients. [Extracted from the article]

As a response to the human immunodeficiency virus (HIV) epidemic and part of ­Canadian Institutes for Health Research’s mandate to support international health research capacity building, the Canadian Institutes for Health Research Canadian HIV Trial Network (CTN) developed an international postdoctoral fellowship award under the CTN’s Postdoctoral Fellowship Awards Program to support and train young HIV researchers in resource-limited settings. Since 2010, the fellowship has been awarded to eight fellows in Cameroon, China, Lesotho, South Africa, Uganda and Zambia. These fellows have conducted research on a wide variety of topics and have built a strong network of collaboration and scientific productivity, with 40 peer-reviewed publications produced by six fellows during their fellowships. They delivered two workshops at international conferences and have continued to secure funding for their research, using the fellowship as a stepping stone. The CTN has been successful in building local HIV research capacity and forming a strong network of like-minded junior low- and middle-income country researchers with high levels of research productivity. They have developed into mentors, supervisors and faculty members, who, in turn, build local capacity. The sustainability of this international fellowship award relies on the recognition of its strengths and the involvement of other stakeholders for additional resources. [ABSTRACT FROM AUTHOR]

Abstract: We previously described envelope glycoproteins of an HIV-1 isolate adapted in vitro for growth in microglia that acquired a highly fusogenic phenotype and lower CD4 dependence, as well as resistance to inhibition by anti-CD4 antibodies. Here, we investigated whether similar phenotypic changes are present in vivo. Envelope clones from the brain and spleen of an HIV-1-infected individual with neurological disease were amplified, cloned, and sequenced. Phylogenetic analysis demonstrated clustering of sequences according to the tissue of origin, as expected. Functional clones were then used in cell-to-cell fusion assays to test for CD4 and co-receptor utilization and for sensitivity to various antibodies and inhibitors. Both brain- and spleen-derived envelope clones mediated fusion in cells expressing both CD4 and CCR5 and brain envelopes also used CCR3 as co-receptor. We found that the brain envelopes had a lower CD4 dependence, since they efficiently mediated fusion in the presence of low levels of CD4 on the target cell membrane, and they were significantly more resistant to blocking by anti-CD4 antibodies than the spleen-derived envelopes. In contrast, we observed no difference in sensitivity to the CCR5 antagonist TAK-779. However, brain-derived envelopes were significantly more resistant than those from spleen to the fusion inhibitor T-1249 and concurrently showed slightly greater fusogenicity. Our results suggest an increased affinity for CD4 of brain-derived envelopes that may have originated from in vivo adaptation to replication in microglial cells. Interestingly, we note the presence of envelopes more resistant to a fusion inhibitor in the brain of an untreated, HIV-1-infected individual. [Copyright &y& Elsevier]