Prevalence and transmission of pretreatment drug resistance in people living with HIV-1 in Shanghai China, 2017-2021.

The implementation of pretreatment drug-resistance (PDR) surveillance among people living with HIV-1 (PLWH) is a top priority in countries using efavirenz (EFV)/nevirapine (NVP) for first-line ART. In this study, we assessed the prevalence of PDR among PLWH in Shanghai, China during 2017-2021, and to reveal PDR transmission between Shanghai and other regions of China. A total of 5050 PLWH not on ART during 2017-2021 were included. Partial HIV-1 pol sequences were amplified, sequenced, and analysed for drug-resistance mutations (DRMs). Besides, transmission network of PDR variants was inferred using HIV-TRACE. The overall prevalence of PDR was 4.8% (242/5050; 95% CI, 4.2-5.4). Prevalence of NNRTI-associated PDR was 3.9% (95% CI, 3.4-4.5), higher than those of NRTI-associated (0.8%; 95% CI, 0.5-1.1) and PI-associated PDR (0.9%; 95% CI, 0.6-1.2). High prevalence of PDR (especially high-level resistance) to EFV (132/5050, 2.6%) and NVP (137/5050, 2.7%) were found. CRF01_AE (46.0%) was the predominant HIV-1 genotype with any DRMs, followed by CRF55_01B (21.0%), and CRF07_BC (15.1%). Two NRTI-associated (S68G/N/R and T215A/N/S/Y), five NNRTI-associated (V179D/E/T/L, K103N/R/S/T, E138A/G/K, V106M/I/A and Y181C/I) and two PI-associated mutations (M46I/L/V and Q58E) were the most common observed DRMs in PDR patients in Shanghai. The vast majority of S68G occurred in CRF01_AE (45%). M46I/L/V and Q58E showed a relatively high prevalence in CRF01_AE (4.1%) and CRF07_BC (12.6%). Transmission network analyses demonstrated cross-regional transmission links of PDR variants between Shanghai and other regions of China, which was mainly driven by the potential low-level DRM V179D/E. These results provide crucial information for clinical decision making of first-line ART in PLWH with PDR.

Progress towards World Health Organization HIV Infection 95-95-95 measures in Newfoundland and Labrador, Canada.

The HIV program in Newfoundland and Labrador (NL) provides care for all persons living with HIV (PLWH) in NL, yet progress toward UNAIDS 95-95-95 goals for diagnosis, linkage to care and viral suppression has not previously been documented. This analysis describes engagement in HIV care and virologic outcomes for the NL cohort in 2016 and 2019 and compares this data to the Canadian HIV Observational Cohort (CANOC). A retrospective review of the NL clinic included adults aged >18 years and descriptive statistics for demographics, risk factors, and clinical variables were assessed and compared using χ2 test or Fisher's Exact test (categorical) or Wilcoxon Sum Rank test (continuous). Engagement in care and virologic outcomes for the NL cohort were consistently high over the 2016 to 2019 period with > 98% on antiretroviral therapy (ART), and > 96% having a suppressed virus load. Engagement in care and virologic outcomes among PLWH in NL is high and compares favorably to a national cohort.

Virological outcomes of third-line antiretroviral therapy in a global context: a systematic reviews and meta-analysis.

BACKGROUND: Despite remarkable progress, HIV's influence on global health remains firm, demanding continued attention. Understanding the effectiveness of third-line antiretroviral therapy in individuals who do not respond to second-line drugs is crucial for improving treatment strategies. The virological outcomes of third-line antiretroviral therapy vary from study to study, highlighting the need for robust global estimates. METHODS: A comprehensive search of databases including PubMed, MEDLINE, International Scientific Indexing, Web of Science, and Google Scholar, was conducted. STATA version 17 statistical software was used for analysis. A random-effects model was applied to compute the pooled estimates. Subgroup analysis, heterogeneity, publication bias, and sensitivity analysis were also performed. The prediction interval is computed to estimate the interval in which a future study will fall. The GRADE tool was also used to determine the quality of the evidence. RESULTS: In this systematic review and meta-analysis, 15 studies involving 1768 HIV patients receiving third-line antiretroviral therapy were included. The pooled viral suppression of third-line antiretroviral therapy was 76.6% (95% CI: 71.5- 81.7%). The viral suppression rates at 6 and 12 months were 75.5% and 78.6%, respectively. Furthermore, third-line therapy effectively suppressed viral RNA copy numbers to ≤ 50 copies/mL, ≤ 200 copies/mL, and ≤ 400 copies/mL with rates of 70.7%, 85.4%, and 85.7%, respectively. CONCLUSION: More than three-fourths of patients on third-line antiretroviral therapy achieve viral suppression. Consequently, improving access to and timely initiation of third-line therapy may positively impact the quality of life for those with second-line treatment failure.

Immunological and molecular assessment of HIV-1 mutations for antiretroviral drug resistance in Saudi Arabia.

Human Immunodeficiency Virus (HIV) is a significant threat to public health. HIV genotyping and antiretroviral resistance testing may have contributed to improved non-treated management. Immune markers might assist HIV-1 diagnosis and drug-resistant variant identification. HIV-1 immunogenicity and molecular characteristics of antiretroviral drug resistance are evaluated in 56 treatment-naive HIV patients. DNA sequencing and retroviral resistance testing identified HIV-1 genotypes. 55.4% of patients were susceptible to protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI) antiretroviral drugs, whereas 44.6% had drug-resistance mutations against at least one antiretroviral drug. 3.6% of cases had PI-resistant mutations, while 30.4% had NRTI-resistant mutations, and 30.4% had NNRTI-resistant mutations. In patients who are susceptible to PI, the mean value of human plasma sCD80 is 2.11 ± 0.65 ng/mL; in patients with mutations, it is 3.93 ± 2.91 ng/mL. Individuals who are susceptible to PI have plasma sCD27 levels of 78.7 ± 63.2 U/mL, whereas individuals who are mutant have levels of 56.5 ± 32.1 U/mL. IP-10's mean value was 363 ± 109.2 pg/mL for the susceptible patients and 429 ± 20.7 pg/mL for the mutated patients. In susceptible patients, the plasma sCD4 level is 0.163 ± 0.229 ng/mL; in mutant patients, it is 0.084 ± 0.012 ng/mL. The data showed a relative relation between immunological parameters such as sCD80, sCD27, sCD4, and IP-10 and mutation for drug resistance.

High viral suppression rates among PLHIV on dolutegravir who had an initial episode of viral non-suppression in Uganda September 2020-July 2021.

BACKGROUND: In 2019, WHO recommended dolutegravir (DTG) as a backbone for first- and second-line antiretroviral therapy (ART) regimens for people living with HIV (PLHIV). According to the 2018 Uganda's HIV treatment guidelines, patients with viral non-suppression (≥1,000 copies/mL) should receive intensive adherence counseling (IAC) with repeat viral load (VL) within 6 months. This analysis focused on the prevalence and factors associated with viral suppression following IAC among PLHIV on DTG-based regimens (DBRs) with an initial episode of viral non-suppression (VNS) in Uganda. METHODS: We conducted a retrospective analysis for PLHIV on DBRs with an initial episode of VNS (≥1,000 copies/mL) in Uganda during October 2019-September 2020 who had a follow up VL test result during September 2020-July 2021. Data were abstracted from the Central Public Health Laboratory (CPHL) database, including patient demographics and VL results. Viral non-suppression (VNS) was defined as a VL test result of ≥1,000 copies/mL. We characterized PLHIV on DBRs and used logistic regression models to determine factors associated with VL suppression after an initial episode of VNS. RESULTS: A total of 564 PLHIV on DBRs with an initial episode of VNS were followed up and 43 were excluded due to missing data. Of the 521, 220 (42.2%) were children (<15 years) and 231 (44.3%) were female. Median age was 28 years (interquartile range [IQR]: 12-43 years), and median duration on DBRs was 12 months (IQR: 6-15 months). Overall, 80.8% (421/521) PLHIV had a suppressed viral load at first follow up testing (children = 74.5% [164/220]; adults = 85.4% [257/301]). Children with initial VL results ≥5,000 copies/mL were less likely to achieve viral suppression at follow up testing compared to those with <5,000 copies/mL (AOR: 0.38; 95% CI: 0.20-0.71; p = 0.002). CONCLUSIONS: In a programmatic setting, most adults and children suppressed following an initial episode of VNS on DBRs. High rates of suppression after VNS suggest adherence challenges, rather than drug resistance. Continuation of DBRs should be considered before regimen switch.

Prevalence of occult hepatitis B infection among treatment-naive persons living with HIV in Ghana.

Hepatitis B virus (HBV) constitutes a significant global health challenge, with more than 2 billion people infected globally and almost 291 million chronic cases. In Africa, coinfection of HBV with Human Immunodeficiency Virus (HIV) is high, yet the condition remains overlooked in many countries. While antiretroviral therapy (ART) has improved HIV survival, viral hepatitis continues to contribute to morbidity and mortality. Occult Hepatitis B infection (OBI), characterized by a low-level of HBV DNA in individuals with negative hepatitis B surface antigen (HBsAg), is an emerging concern among HIV seropositive individuals due to the risk of HBV reactivation and associated complications, especially hepatocellular carcinoma (HCC). Ghana has an estimated HBV/HIV coinfection prevalence of 13.6% making it important to also determine potential cases of OBI. This study aims to assess OBI prevalence in persons living with HIV (PLHIV). A cross-sectional study was conducted in five health facilities in the Cape Coast Metropolis. HBV-related serological markers were determined among 116 PLHIV using the Enzyme-Linked Immunosorbent Assay (ELISA) method. HBV DNA was extracted from 30 participants found to be HBsAg negative but positive for hepatitis B core antibody (HBcAb+). Nested PCR was employed in detecting HBV DNA and HBV viral load was performed using qPCR. The median age of the participants was 37 years (IQR 22-65). Serologically, 7.8% (n = 9, 95% CI: 3.5-22.7), 12.1% (n = 14), and 25.9% (n = 30) tested positive for solely HBsAg, HBsAb, and HBcAb respectively. OBI prevalence among HBsAg-/HBcAb+ participants was 16.7% (n = 5, 95% CI: 6.5-23.7) with a median HBV DNA level of 139.2 IU/ml (IQR, 96.7-142.0). The prevalence of OBI among HIV-positive participants in the Cape Coast Metropolis highlights the need to consider screening for HBV among HIV patients using nucleic acid amplification tests. This can inform medical management and reduce the risk of liver complications, including HCC.

Premature Activation of the HIV-1 Protease Is Influenced by Polymorphisms in the Hinge Region.

HIV-1 protease inhibitors are an essential component of antiretroviral therapy. However, drug resistance is a pervasive issue motivating a persistent search for novel therapies. Recent reports found that when protease activates within the host cell's cytosol, it facilitates the pyroptotic killing of infected cells. This has led to speculation that promoting protease activation, rather than inhibiting it, could help to eradicate infected cells and potentially cure HIV-1 infection. Here, we used a nanoscale flow cytometry-based assay to characterize protease resistance mutations and polymorphisms. We quantified protease activity, viral concentration, and premature protease activation and confirmed previous findings that major resistance mutations generally destabilize the protease structure. Intriguingly, we found evidence that common polymorphisms in the hinge domain of protease can influence its susceptibility to premature activation. This suggests that viral heterogeneity could pose a considerable challenge for therapeutic strategies aimed at inducing premature protease activation in the future.

HCV Cascade of Care in HIV/HCV Co-Infected Individuals: Missed Opportunities for Micro-Elimination.

People living with HIV-HCV co-infection comprise a target group for HCV-micro-elimination. We conducted an HCV cascade of care (CoC) for HIV-HCV co-infected individuals living in Greece and investigated factors associated with different HCV-CoC stages. We analyzed data from 1213 participants from the Athens Multicenter AIDS Cohort Study. A seven-stage CoC, overall and by subgroup (people who inject drugs (PWID), men having sex with men (MSM), men having sex with women (MSW), and migrants], was constructed, spanning from HCV diagnosis to sustained virologic response (SVR). Logistic/Cox regression models were employed to identify factors associated with passing through each CoC step. Among 1213 anti-HCV-positive individuals, 9.2% died before direct-acting antiviral (DAA) availability. PWID exhibited higher mortality rates than MSM. Of 1101 survivors, 72.2% remained in care and underwent HCV-RNA testing. Migrants and PWID showed the lowest retention rates. HCV-RNA was available for 79.2% of those in care, with 77.8% diagnosed with chronic HCV. Subsequently, 71% initiated DAAs, with individuals with very low CD4 counts (<100 cells/µL) exhibiting lower odds of DAA initiation. SVR testing was available for 203 individuals, with 85.7% achieving SVR. The SVR rates did not differ across risk groups. In 2023, significant gaps and between-group differences persisted in HCV-CoC among HIV-HCV co-infected individuals in Greece.

HIV-1 Tat-Mediated Human Müller Glial Cell Senescence Involves Endoplasmic Reticulum Stress and Dysregulated Autophagy.

Antiretroviral treatments have notably extended the lives of individuals with HIV and reduced the occurrence of comorbidities, including ocular manifestations. The involvement of endoplasmic reticulum (ER) stress in HIV-1 pathogenesis raises questions about its correlation with cellular senescence or its role in initiating senescent traits. This study investigated how ER stress and dysregulated autophagy impact cellular senescence triggered by HIV-1 Tat in the MIO-M1 cell line (human Müller glial cells). Cells exposed to HIV-1 Tat exhibited increased vimentin expression combined with markers of ER stress (BiP, p-eIF2α), autophagy (LC3, Beclin-1, p62), and the senescence marker p21 compared to control cells. Western blotting and staining techniques like SA-ß-gal were employed to examine these markers. Additionally, treatments with ER stress inhibitor 4-PBA before HIV-1 Tat exposure led to a decreased expression of ER stress, senescence, and autophagy markers. Conversely, pre-treatment with the autophagy inhibitor 3-MA resulted in reduced autophagy and senescence markers but did not alter ER stress markers compared to control cells. The findings suggest a link between ER stress, dysregulated autophagy, and the initiation of a senescence phenotype in MIO-M1 cells induced by HIV-1 Tat exposure.

The Use of Broadly Neutralizing Antibodies (bNAbs) in HIV-1 Treatment and Prevention.

BACKGROUND: Although antiretroviral therapy (ART) effectively halts disease progression in HIV infection, the complete eradication of the virus remains elusive. Additionally, challenges such as long-term ART toxicity, drug resistance, and the demanding regimen of daily and lifelong adherence required by ART highlight the imperative need for alternative therapeutic and preventative approaches. In recent years, broadly neutralizing antibodies (bNAbs) have emerged as promising candidates, offering potential for therapeutic, preventative, and possibly curative interventions against HIV infection. OBJECTIVE: This review aims to provide a comprehensive overview of the current state of knowledge regarding the passive immunization of bNAbs in HIV-1-infected individuals. MAIN FINDINGS: Recent findings from clinical trials have highlighted the potential of bNAbs in the treatment, prevention, and quest for an HIV-1 cure. While monotherapy with a single bNAb is insufficient in maintaining viral suppression and preventing viral escape, ultimately leading to viral rebound, combination therapy with potent, non-overlapping epitope-targeting bNAbs have demonstrated prolonged viral suppression and delayed time to rebound by effectively restricting the emergence of escape mutations, albeit largely in individuals with bNAb-sensitive strains. Additionally, passive immunization with bNAb has provided a "proof of concept" for antibody-mediated prevention against HIV-1 acquisition, although complete prevention has not been obtained. Therefore, further research on the use of bNAbs in HIV-1 treatment and prevention remains imperative.

Applying Flow Virometry to Study the HIV Envelope Glycoprotein and Differences Across HIV Model Systems.

The HIV envelope glycoprotein (Env) is a trimeric protein that facilitates viral binding and fusion with target cells. As the sole viral protein on the HIV surface, Env is important both for immune responses to HIV and in vaccine designs. Targeting Env in clinical applications is challenging due to its heavy glycosylation, high genetic variability, conformational camouflage, and its low abundance on virions. Thus, there is a critical need to better understand this protein. Flow virometry (FV) is a useful methodology for phenotyping the virion surface in a high-throughput, single virion manner. To demonstrate the utility of FV to characterize Env, we stained HIV virions with a panel of 85 monoclonal antibodies targeting different regions of Env. A broad range of antibodies yielded robust staining of Env, with V3 antibodies showing the highest quantitative staining. A subset of antibodies tested in parallel on viruses produced in CD4+ T cell lines, HEK293T cells, and primary cells showed that the cellular model of virus production can impact Env detection. Finally, in addition to being able to highlight Env heterogeneity on virions, we show FV can sensitively detect differences in Env conformation when soluble CD4 is added to virions before staining.

Interferon-Regulated Expression of Cellular Splicing Factors Modulates Multiple Levels of HIV-1 Gene Expression and Replication.

Type I interferons (IFN-Is) are pivotal in innate immunity against human immunodeficiency virus I (HIV-1) by eliciting the expression of IFN-stimulated genes (ISGs), which encompass potent host restriction factors. While ISGs restrict the viral replication within the host cell by targeting various stages of the viral life cycle, the lesser-known IFN-repressed genes (IRepGs), including RNA-binding proteins (RBPs), affect the viral replication by altering the expression of the host dependency factors that are essential for efficient HIV-1 gene expression. Both the host restriction and dependency factors determine the viral replication efficiency; however, the understanding of the IRepGs implicated in HIV-1 infection remains greatly limited at present. This review provides a comprehensive overview of the current understanding regarding the impact of the RNA-binding protein families, specifically the two families of splicing-associated proteins SRSF and hnRNP, on HIV-1 gene expression and viral replication. Since the recent findings show specifically that SRSF1 and hnRNP A0 are regulated by IFN-I in various cell lines and primary cells, including intestinal lamina propria mononuclear cells (LPMCs) and peripheral blood mononuclear cells (PBMCs), we particularly discuss their role in the context of the innate immunity affecting HIV-1 replication.

Human Immunodeficiency Virus Type-1 Genetic Diversity and Drugs Resistance Mutations among People Living with HIV in Karachi, Pakistan.

The human immunodeficiency virus type-1 epidemic in Pakistan has significantly increased over the last two decades. In Karachi, Pakistan, there is a lack of updated information on the complexity of HIV-1 genetic diversity and the burden of drug resistance mutations (DRMs) that can contribute to ART failure and poor treatment outcomes. This study aimed to determine HIV-1 genetic diversity and identify drug-resistance mutations among people living with HIV in Karachi. A total of 364 HIV-positive individuals, with a median age of 36 years, were enrolled in the study. The HIV-1 partial pol gene was successfully sequenced from 268 individuals. The sequences were used to generate phylogenetic trees to determine clade diversity and also to assess the burden of DRMs. Based on the partial pol sequences, 13 distinct HIV-1 subtypes and recombinant forms were identified. Subtype A1 was the most common clade (40%), followed by CRF02_AG (33.2%). Acquired DRMs were found in 30.6% of the ART-experienced patients, of whom 70.7%, 20.7%, and 8.5% were associated with resistance to NNRTIs, NRTIs, and PIs, respectively. Transmitted DRMs were found in 5.6% of the ART-naïve patients, of whom 93% were associated with resistance against NNRTIs and 7% to PIs. The high prevalence of DRMs in ART-experienced patients poses significant challenges to the long-term benefits and sustainability of the ART program. This study emphasizes the importance of continuous HIV molecular epidemiology and drug resistance surveillance to support evidence-based HIV prevention, precise ART, and targeted AIDS care.

The Impact of Drugs and Substance Abuse on Viral Pathogenesis-A South African Perspective.

Illicit drug and alcohol abuse have significant negative consequences for individuals who inject drugs/use drugs (PWID/UDs), including decreased immune system function and increased viral pathogenesis. PWID/UDs are at high risk of contracting or transmitting viral illnesses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). In South Africa, a dangerous drug-taking method known as "Bluetoothing" has emerged among nyaope users, whereby the users of this drug, after injecting, withdraw blood from their veins and then reinject it into another user. Hence, the transmission of blood-borne viruses (BBVs) is exacerbated by this "Bluetooth" practice among nyaope users. Moreover, several substances of abuse promote HIV, HBV, and HCV replication. With a specific focus on the nyaope drug, viral replication, and transmission, we address the important influence of abused addictive substances and polysubstance use in this review.

Making a Monkey out of Human Immunodeficiency Virus/Simian Immunodeficiency Virus Pathogenesis: Immune Cell Depletion Experiments as a Tool to Understand the Immune Correlates of Protection and Pathogenicity in HIV Infection.

Understanding the underlying mechanisms of HIV pathogenesis is critical for designing successful HIV vaccines and cure strategies. However, achieving this goal is complicated by the virus's direct interactions with immune cells, the induction of persistent reservoirs in the immune system cells, and multiple strategies developed by the virus for immune evasion. Meanwhile, HIV and SIV infections induce a pandysfunction of the immune cell populations, making it difficult to untangle the various concurrent mechanisms of HIV pathogenesis. Over the years, one of the most successful approaches for dissecting the immune correlates of protection in HIV/SIV infection has been the in vivo depletion of various immune cell populations and assessment of the impact of these depletions on the outcome of infection in non-human primate models. Here, we present a detailed analysis of the strategies and results of manipulating SIV pathogenesis through in vivo depletions of key immune cells populations. Although each of these methods has its limitations, they have all contributed to our understanding of key pathogenic pathways in HIV/SIV infection.

Hepatitis C Virus as a Possible Helper Virus in Human Hepatitis Delta Virus Infection.

Previous studies reported that the hepatitis C virus (HCV) could help disseminate the hepatitis D virus (HDV) in vivo through the unrelated hepatitis B virus (HBV), but with essentially inconclusive results. To try to shed light on this still-debated topic, 146 anti-HCV-positive subjects (of whom 91 HCV/HIV co-infected, and 43 with prior HCV eradication) were screened for anti-HDV antibodies (anti-HD), after careful selection for negativity to any serologic or virologic marker of current or past HBV infection. One single HCV/HIV co-infected patient (0.7%) tested highly positive for anti-HD, but with no positive HDV-RNA. Her husband, in turn, was a HCV/HIV co-infected subject with a previous contact with HBV. While conducting a thorough review of the relevant literature, the authors attempted to exhaustively describe the medical history of both the anti-HD-positive patient and her partner, believing it to be the key to dissecting the possible complex mechanisms of HDV transmission from one subject to another, and speculating that in the present case, it may have been HCV itself that behaved as an HDV helper virus. In conclusion, this preliminary research, while needing further validation in large prospective studies, provided some further evidence of a role of HCV in HDV dissemination in humans.

Determinants of virologic failure among adult HIV patients on first line antiretroviral treatment in Oromia, Central Ethiopia: 2022 a case-control study.

BACKGROUND: Ethiopia's viral suppression rate was less than 90% by 2020, and more than 10% of adult clients on ART in Woliso Town were unsuppressed at the end of March 2022. This study aims to identify determinants of virologic failure among adult clients on ART at health facilities in Oromia region of Ethiopia. METHODS: A facility-based unmatched case-control study was conducted at health facilities in Oromia region from August 1 to September 1, 2022. The study cases were clients with virologic-confirmed first-line ART failure, while controls were clients on first-line ART with a suppressed viral load. A total of 135 cases and 268 control participants were selected using simple random sampling techniques, and data were collected by reviewing the client's document. Epi-Info7 was used for data entry and SPSS version 20 for data analysis. Variables having a P-value of less than 0.25 in the bi-variable analysis were included in multivariable logistic regression. Determinants of virologic failure were determined based on an adjusted odds ratio using 95% CI and a P-value of < 0.05. RESULT: In this study, clients with an age ≥ 35 years (AOR = 3.4, 95% CI: 1.6, 7.0), clients with a baseline regimen of AZT + 3TC + NVP (AOR = 3.5, 95% CI: 1.4, 8.8), clients with a base-line CD4 count < 350 mm3 (AOR = 2.3, 95% CI: 1.1, 4.5), being single marital status (AOR = 3.7, 95% CI: 1.4, 10.5), TB-HIV coinfection (AOR = 2.58, 95% CI: 1.3, 5.1), and having opportunistic infection other than TB in the last six months (AOR = 3.06, 95% CI: 1.5, 6.3) were factors significantly associated with virologic failure while clients within the appointment spacing model (AOR = 0.05, 95% CI: 0.03, 0.10) is inversely associated with virologic failure. CONCLUSION: This study showed that age ≥ 35 years, being single, baseline ART regimen with (AZT + 3TC + NVP), baseline CD4 cell count < 350 mm3, Tb-co infection, and opportunistic infection in the last 6 months were factors associated with virologic failure. Involvement in the appointment spacing model was found to be protective.

Measuring HBV pregenomic RNA may be a potential biomarker to determine HBV functional cure in HIV/HBV-co-infected patients with HBsAg loss.

Functional cure of hepatitis B virus (HBV) is an optimal treatment goal for chronic hepatitis B, with the loss of hepatitis B surface antigen (HBsAg) being a crucial indicator. However, the adequacy of HBsAg loss for evaluating functional cure of HBV in patients co-infected with HBV/human immunodeficiency virus (HIV) remains controversial. In this study, we measured HBV pregenomic RNA (pgRNA), a potential biomarker that correlates with covalently closed circular DNA, in the frozen plasma of 98 patients with HBsAg loss from a large HIV/HBV co-infection cohort in Guangzhou, China. HBV pgRNA was still detected in 43.9% (44/98) of the patients, suggesting active HBV replication in individuals with HBsAg loss. Our observations imply that HBsAg loss may not be a reliable predictor of HBV functional cure in cases of HIV/HBV co-infection.

Broad synergistic antiviral efficacy between a novel elite controller-derived dipeptide and antiretrovirals against drug-resistant HIV-1.

Introduction: The naturally occurring dipeptide Tryptophylglycine (WG) is enhanced in human immunodeficiency virus (HIV-1) infected Elite Controllers (EC). We have shown that this dipeptide has an anti-HIV-1 effect and evaluated now its synergistic antiretroviral activity, in combination with current antiretrovirals against multi-drug resistant HIV-1 isolates. Methods: Drug selectivity assay with WG-am and ARVs agains HIV-1 resistant isolates were carried out. Subsequently, two methods, Chou-Talalay's Combination Index (CI) and ZIP synergy score (SS), were used to quantify the synergism. Results: WG-am had a moderate/strong synergism with the four tested antiretrovirals: raltegravir, tenofovir, efavirenz, darunavir. WG-am:TDF had strong synergism at ED50, ED75, ED90 (CI: <0.2) in isolates resistant to protease inhibitors or integrase strand inhibitors (INSTI), and a slightly less synergism in isolates resistant to non-nucleoside or nucleotide reverse transcriptase inhibitors. WG-am combined with each of the four drugs inhibited all drug-resistant isolates with over 95% reduction at maximum concentration tested. The highest selectivity indexes (CC50/ED50) were in INSTI-resistant isolates. Conclusion: Our data suggest that WG, identified as occurring and enhanced in Elite Controllers has a potential to become a future treatment option in patients with HIV-1 strains resistant to any of the four major categories of anti-HIV-1 compounds.

Dysregulation of Gamma Delta T-Cells, CD8+ T Cells, CD4+ T Cells, and Natural Killer Cells in Brain Pathology: Understanding HIV-Induced Impairment and Exploring Targeted GSH Therapy.

This review comprehensively explores the dysregulation of Gamma Delta T-cells, CD8+ T Cells, and Natural Killer T Cells in the context of Human Immunodeficiency Virus (HIV) infection and its implications for brain pathology. It encompasses an overview of the HIV disease process, immune cell dysregulation, association with neurological diseases, and the critical role of Glutathione (GSH) in T-cell function. The alterations in Gamma Delta T-cells during chronic infection, the intricate dynamics of Vδ1 and Vδ2 subsets, and the potential of Vγ9Vδ2 T cells in inhibiting HIV replication are discussed. Additionally, the review addresses the exhaustion, impaired cytotoxicity, and premature senescence of CD8+ T cells, as well as the dysregulation of Natural Killer Cells (NKCs) and their impact on overall immune system activity. Furthermore, it examines the role of Gamma Delta (γδ) T-cells in brain injuries, infections, and tumors and highlights the therapeutic implications of elevated GSH levels in promoting a T helper 1 (Th1) immune response. However, HIV-infected patients with decreased GSH exhibit a T helper 2 (Th2) bias, compromising protection against intracellular pathogens. Finally, the review discusses studies in murine models demonstrating the impact of GSH levels on immune responses and underscores the therapeutic potential of targeting GSH to enhance immunity in HIV patients. Overall, this review provides valuable insights into the complex interplay between immune dysregulation, GSH levels, and HIV-associated brain pathology, offering insights into potential therapeutic avenues for mitigating immune compromise and neurological impairments in HIV patients.