AIDS research and human retroviruses最新文献

Yunnan Province, a critical southwestern Chinese border region and gateway to Southeast Asia, faces a complex human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infection epidemic. Molecular data on HCV Core domain I in persons living with HIV and HCV (PLWHH) remain scarce here. This study addresses this gap by analyzing prevalent HCV strains, identifying amino acid mutations, and predicting immune epitopes and structural motifs to inform clinical and vaccine strategies. The serum samples from 128 PLWHH, which were collected across 14 cities in Yunnan Province between January 2019 and September 2021, were analyzed. RNA was extracted from these samples, and complementary DNA was subsequently synthesized. PCR amplification of the HCV Core domain I was performed using genotype-specific primers, followed by sequencing. Bioinformatics tools were used for phylogenetic analysis, amino acid mutation analysis, and the prediction of B-cell and T-cell epitopes, as well as N-glycosylation sites. In addition, secondary and tertiary structure modeling was carried out. HCV genotypes included 1a (n = 3), 1b (n = 23), 3a (n = 29), 3b (n = 51), 6a (n = 4), 6n (n = 15), and 6xa (n = 3). Eleven mutations were identified in Core domain I, with R70Q (41.4%, n = 53) and R70P (14.06%, n = 18) linked to severe disease progression. B-cell epitope analysis revealed three antigenic sites in genotypes 1/3 and four in genotype 6. T-cell epitope prediction identified two antigenic sites across genotypes 1/3/6, but no cytotoxic T-cell epitopes or N-glycosylation sites were detected. Structural modeling showed Core domain I in genotypes 1/3/6 comprised helices, sheets, turns, and coils (coils predominant), with significant structural variations between genotypes. In the PLWHH in Yunnan, HCV exhibits diverse epidemiological characteristics. Multiple amino acid mutations in Core domain I, often linked to severe disease outcomes, are frequently observed. This region also contains several immune-related antigenic epitopes. In addition, variations in the secondary and tertiary structures of Core domain I differ across genotypes.

Retaining persons with HIV (PWH) in HIV care and ensuring access to antiretroviral therapy are crucial for reducing HIV transmission and enhancing health outcomes. HIV care engagement rates in the United States have plateaued over the last decade, indicating the need for innovative re-engagement strategies. We developed an automated electronic health record-based alert system to identify out-of-care (OOC) PWH presenting to any emergency department (ED) within the Duke University Health System. OOC was defined as no HIV care clinical visit in over 12 months. Automated alerts were processed by the HIV Rapid Response Re-engagement Team (H3RT), which connected with disengaged PWH by phone after an alert was triggered by an ED visit. Re-engagement was defined as a completed HIV clinic visit after H3RT outreach. The alert system identified 217 PWH, of whom 117 (54%) had transferred care to another health system. Among the 71 truly OOC PWH, 63% were male, 82% Black, and 34% uninsured. Median ED utilization while OOC was 1.30 ED visits/year [interquartile range (IQR): 0.66-2.37], compared with 1.05 ED visits/year [IQR: 0.33-1.85] when engaged in care. H3RT successfully re-engaged 46 (64.8%) of the 71 OOC PWH. The H3RT cohort had a higher proportion of persons assigned female sex at birth, uninsured, and Black compared with the overall engaged HIV clinic population. This low-cost, informatics-driven approach successfully re-engaged OOC PWH from priority populations within a large, multi-facility health system. Higher ED utilization rates among PWH while OOC support the integration of HIV care re-engagement efforts into these points of health care access. H3RT represents a scalable approach to HIV care re-engagement in Southern health care systems.

Adeno-associated virus (AAV)-vectored delivery of HIV-1 broadly neutralizing antibodies (bNAbs) holds promise for achieving durable HIV-1 immunity in a practical and scalable way, yet AAV-encoded bNAbs often elicit antidrug antibody (ADA) responses that limit transgene expression. Engagement of T cell-expressed CD28 with its ligands CD80/CD86 on professional antigen-presenting cells is crucial for initiating adaptive immunity. Because the immunoglobulin-fusion protein CTLA4Ig can outcompete CD28 for binding to CD80/CD86, CTLA4Ig can inhibit T cell activation and prevent immune responses. Hence, we hypothesized that co-delivering CTLA4Ig during AAV/bNAb administration would prevent ADAs in primates. Six rhesus macaques (RMs) were treated intramuscularly with AAV-1 vectors encoding "rhesusized" (rh) versions of the bNAbs 3BNC117 (IgG1) and 10-1074 (IgG2). The experimental monkeys (n = 3) were dosed intravenously with 20 mg/kg of rh-CTLA4Ig on days 0, 2, 7, and 14, while the control animals (n = 3) did not receive any additional intervention. The experimental monkeys mounted ADAs that inhibited bNAb expression, albeit at different rates for rh-3BNC117-IgG1 (66%) and rh-10-1074-IgG2 (33%). In the control group, the incidence of ADAs leading to loss of bNAb expression was 100% for rh-3BNC117-IgG1 and 0% for rh-10-1074-IgG2. There was no significant difference between the groups in their cumulative levels of ADAs or bNAb expression measured over 20 weeks. Despite the development of ADAs against rh-3BNC117-IgG1 in five out of six animals, and in one out of six against rh-10-1074-IgG2, macaques in both groups exhibited minimal T cell responses to both bNAbs. AAV-1 capsid-specific CD4⁺ T cells trended higher in the control animals. In conclusion, a short course rh-CTLA4Ig did not significantly reduce the immunogenicity of AAV-encoded bNAbs in RMs. Although our study was not powered to detect marginal effects, robust improvements in AAV-driven expression of hypermutated HIV-1 bNAbs may require combination approaches, such as multiple co-stimulation blockers, pharmacological immunosuppression, and/or muscle-specific promoters.

Little is known about the relationships between circulating short-chain fatty acids (SCFAs) and genital microbiota, inflammation, and the risk for HIV infection in women. As circulating SCFAs are potentially modifiable, for example, through dietary fiber or probiotics, we investigated association of circulating SCFA levels with these outcomes. We carried out a nested matched case-control study within a randomized trial of an antiretroviral microbicide to prevent HIV infection to study the association between circulating SCFAs and HIV acquisition (primary outcome for case definition), vaginal microbiota, and genital inflammation. Levels of the SCFAs butyrate, acetate, and propionate were quantified in plasma using mass spectrometry. Vaginal microbiota was assessed using metaproteomics and characterized as Lactobacillus dominant (LD) or low Lactobacillus (LL). Genital inflammation was measured using multiplex immunoassays. Logistic regression models were used to study the association of SCFAs with each outcome. Study population (N = 99) characteristics were similar between cases (33 who acquired HIV) and controls (66 who did not acquire HIV). We did not observe any associations between any of the circulating SCFAs with HIV acquisition or with LL vaginal microbiota status. However, there was an inverse association between circulating SCFAs and several pro-inflammatory genital cytokines, including interleukin-6 (IL-6), IL-1α, and IL-8. In our study of women with high risk of HIV infection, higher levels of circulating SCFAs were associated with lower levels of various genital inflammatory markers, but not with HIV acquisition or a LL microbiota profile. Future larger studies, including genital SCFA assessment, are needed to confirm these findings.

Pregnancy affects adiposity, which may be influenced by HIV infection or antiretroviral therapy (ART). The objective of this study was to examine adiposity measures in the perinatal period, by HIV status and ART class. A total of 214 women (113 women with HIV [WWH], 71 initiated ART postconception), enrolled between 24 and 28 weeks of gestation and followed until 6-12 months postpartum, were assessed for longitudinal weight and cross-sectional postpartum anthropometry. A subset of 65 (52 WWH, 42 initiated ART postconception) had cross-sectional adiposity (body composition and fat distribution) measured at 6-12 months postpartum using dual-energy X-ray absorption scan. Multivariable linear and modified Poisson regression, adjusted for maternal age, pre-pregnancy body mass index, socioeconomic status, and postpartum months, examined associations of HIV status and postconception ART (dolutegravir-based [DTG] vs. efavirenz-based [EFV]) with anthropometry and adiposity outcomes. At enrollment, the median age was 30 years (interquartile range, 26-34) and 82% were multiparous. Between pre-pregnancy and postpartum, women gained an average of 2.33 kg (0.90 kg WWH), 30% lost weight (35% WWH), and 48% gained weight (38% WWH). WWH gained weight slower during pregnancy (0.27 vs 0.38 kg/week, p = .03) and were less likely to gain weight postpartum (RR = 0.72 95% CI 0.55, 0.93; p = .01) compared with women without HIV. Postpartum, mean body mass index was 32 kg/m² (standard deviation = 7.33) and 58% (53% WWH) of women had obesity. HIV was not associated with cross-sectional measures of postpartum anthropometry and adiposity. Among WWH, compared with EFV-based ART, DTG-based ART was not associated with weight gain during pregnancy or anthropometry and adiposity postpartum. Despite high rates of postpartum weight gain and obesity, no significant differences were observed in anthropometry and adiposity measures by HIV status and postconception ART. Nonetheless, these findings underscore the need for interventions to support healthy weight gain in pregnancy and postpartum weight loss to minimize pregnancy-associated obesity.

Accumulating evidence indicates that HIV acquisition may be associated with premature aging. However, the causal relationship and the direction of the effect between HIV acquisition and aging remain controversial. In the present study, we aimed to investigate the causal associations between HIV acquisition and biological aging. Summary data for biological aging proxy and HIV acquisition were collected from the most updated and available genome-wide association studies. Biological aging proxied by telomere length (TL) and four epigenetic clocks, including intrinsic epigenetic age acceleration, GrimAge acceleration, HannumAge acceleration, and PhenoAge acceleration. Four Mendelian randomization (MR) methods, including inverse-variance weighted (IVW), weighted median, MR-Egger, and weighted mode, were used to assess causal associations. Multiple sensitivity analyses, including heterogeneity analysis, leave-one-out sensitivity analysis, and horizontal pleiotropy analysis, were further performed to verify the robustness of our findings. The IVW MR results indicated that genetically predicted HIV acquisition was not significantly associated with biological aging (all p > .05). Similarly, the reverse-direction MR also did not identify potentially causal effects of biological aging on HIV acquisition (all p > .05). This study found no obvious evidence of the causal relationship between HIV acquisition and biological aging. More studies are needed to future unravel the potential causal relationship and the exact mechanism.

Bictegravir/Emtricitabine/Tenofovir alafenamide (BIC/FTC/TAF) is a convenient, well-tolerated, once-daily, and single-tablet regimen. There are few data on its use during pregnancy. The primary objective was to evaluate the efficacy of BIC/FTC/TAF at delivery, defined as a plasma viral load <50 cp/mL. We conducted a retroprospective, single-center study including pregnant women living with HIV-1 who were on BIC/FTC/TAF. From January 2020 to January 2023, 12 women living with HIV-1 received BIC/FTC/TAF during pregnancy and at delivery. Two were receiving BIC/FTC/TAF at conception and remained on the same combination antiretroviral therapy (cART) throughout the pregnancy, and 10 received BIC/FTC/TAF at least during the third trimester and at delivery. Ten had a plasma viral load <50 cp/mL at delivery. The two who were not suppressed at delivery reported nonadherence to BIC/FTC/TAF, which was not related to treatment side effects. Reported tolerance was good. BIC/FTC/TAF might be a good option during pregnancy and particularly to simplify previous cART but it is necessary to counsel patients to ensure good adherence to this one.

HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) pathology has been associated with Tax protein secreted from HTLV-1 infected CD4⁺-T-lymphocytes, which interacts with soluble SEMA-4D (Semaphorin 4D) inducing growth cone collapse in neurons. We investigated HTLV-1-induced phenotypic and signaling changes during PC12 neuronal differentiation that may mediate growth cone collapse effects. We measured kinases and phosphatases associated with microtubule-associated proteins and molecular motor functions. Phosphorylation status of proteins that participate in the cytoskeleton and axonal transport such as Tau, microtubule-associated protein 1B (MAP1B), motor proteins (kinesin-1 and dynein) and collapsin response mediator protein (CRMP-2), all involved in neurite extension and branching, were measured. The phosphorylation/dephosphorylation of these proteins is catalyzed by Cyclin-dependent kinase-5 (CDK5), Glycogen synthase kinase-3β (GSK3β), and Protein phosphatase-2 (PP2A). Our results show that viral secreted proteins produced a reduction of neurite extension and branching in PC12 cells during neuronal differentiation. We observed that GSK3β activity increased, while CDK5 and PP2A activities decreased. In addition, we found reduced levels of Tau phosphorylated at Thr¹⁸¹ and increased levels of CRMP-2 phosphorylated at Ser⁵²². No changes in motor proteins or MAP1B phosphorylation were found. Neurotoxic effects of HTLV-1 secreted proteins on neuronal differentiation of PC12 cells include lower CDK5 activity, which could explain the reduced levels of Tau-(pThr¹⁸¹); this could induce conformational changes in Tau protein, altering microtubule dynamics. Increased CRMP-2-(pSer⁵²²) phosphorylation precedes further phosphorylation at Thr⁵⁰⁹/⁵¹⁴ residues by GSK3β. All these phosphorylations are associated with growth cone collapse. The increased CRMP-2-(pSer⁵²²) levels found here suggest that CDK5 activity, even when decreased, is sufficient for this priming phosphorylation. Reduction in PP2A activity could importantly contribute to maintaining the increased phosphorylation in CRMP-2. These results suggest the involvement of extracellular Tax/sSEMA-4D complex in the activation of Plexin1B receptor, activating downstream cascade involving PI3K/AKT/GSK3β/CRMP-2, inducing growth cone collapse.

HIV cure-related clinical research studies often include analytical treatment interruptions (ATIs), in which participants pause antiretroviral treatment (ART). During ATIs, researchers closely monitor laboratory values and adverse events. We assessed and compared the perspectives of two distinct groups of participants: HIV noncontrollers and controllers in a San Francisco-based ATI study focused on identifying biomarkers predicting HIV viral rebound. Data were collected from 2021 to 2024 over five study time points to assess motivations, understanding of the study, decisional regret, and partner protections. All participants (n = 16) endorsed the goal of helping advance HIV research as a motivator, about half were also driven by interest in their body's response to the ATI, and some indicated monetary compensation as a key motivator. Most participants (6 of 10 noncontrollers and 4 of 6 controllers) did not view personal health benefit as a primary study goal. All understood the option for an extended ATI if they had not met ART restart criteria after 28 days. At the study's onset, all sexually active participants (n = 14) were informed about the risk of transmission to sex partners and the need for partner protections during ATIs. Among noncontrollers, 2 of 5 reported using condoms, being abstinent or partner use of pre-exposure prophylaxis (PrEP) during sexual activity. Among controllers, 3 of 5 reported sexual activity: one with a partner on PrEP, one with a partner on ART, and one using other protection methods. Decisional regret about study participation, measured on a scale of 0-100, was low among both noncontrollers (range 1.67-13.57), and controllers (range 8.33-10) during the ATI, and remained low following it (noncontroller M = 5.07, SD = 4.52; controller M = 10.00, SD = 11.31). Participants generally understood the study, highlighted the need for partner protection support during ATI, and reported low decisional regret.