AIDS research and human retroviruses最新文献

DNA methylation is a hallmark of aging; yet, our understanding of epigenetic age acceleration (EAA) in relationship to frailty in people with HIV (PWH) is poor. We conducted an observational study among PWH from the Veterans Aging Cohort Study (VACS) to test the hypothesis that EAA markers were associated with frailty. Epigenome-wide DNA methylation data from blood samples were used to derive EAA markers based on four established epigenetic clocks: Horvath, Hannum, PhenoAge, and GrimAge. Frailty was defined using a previously studied VACS frailty-related phenotype based on ≥1 survey item characterizing frailty factors: exhaustion, slowness, low physical activity, or weight loss. Logistic regression tested the association of participant characteristics and EAA markers with frailty. Adjusted models included each EAA marker as the independent variable, with significant participant characteristics as covariates. Among 1,076 PWH, frailty was evident in 397 (36.9%) individuals. The characteristics associated with frailty included chronological age, CD4⁺ T-cell count, HIV-1 RNA viral load, smoking, and age-related comorbid conditions. GrimAge acceleration (GrimAA), PhenoAge acceleration (PhenoAA), and HannumAge acceleration (HannumAA) were associated with frailty, but HorvathAge acceleration (HorvathAA) was not. The strength of the association was attenuated with adjustment for characteristics but remained significant for the three markers. Age acceleration based on GrimAA (values >0) was independently associated with a 45% increased odds of frailty (OR_adj: 1.45, 95% CI, 1.10, 1.93). In post hoc analyses, only GrimAA was associated with exercise frequency. In conclusion, select EAA markers were associated with frailty, independently of the traditional predictors of frailty. GrimAA, in particular, may be useful in future research to develop treatment strategies for frailty tailored to PWH.

Human immunodeficiency virus type 1 (HIV-1) binds to CD4 receptors. Chemokine receptors such as C-C chemokine receptor type 5 (CCR5), C-C chemokine receptor type 2 (CCR2), and stromal-derived factor (SDF1) are involved in HIV cell entry, and mutations in the genes encoding these chemokine receptors and their ligands may play a role against HIV and acquired immunodeficiency syndrome (AIDS) progression. This study aims to investigate the frequency of the above polymorphisms within the Iranian population, evaluating their contribution to a protective genetic background against HIV acquisition and progression. Two hundred eighty-five healthy individuals and 100 people with HIV were selected. CCR5 genotyping was performed by polymerase chain reaction (PCR). CCR2 and SDF-1 polymorphism were analyzed by tetra-primer amplification refractory mutation system-polymerase chain (Tetra-ARMS-PCR). No CCR5-Δ32 mutants were found in either group. The screening for the CCR2 polymorphism yielded 44 (44%) and 127 (44.6%) heterozygous genotypes in the people with HIV and healthy individuals. Homozygous mutants were seen in 1 (1%) and 28 (9.8%) of the people living with HIV and healthy individuals, respectively, revealing a CCR2-64I allele frequency of 29.7%. CCR2-64I is associated with HIV resistance and reduced AIDS progression (p-value = .018). Among our 385 analyzed samples, 2 (2%) and 12 (4.2%) were found to be SDF1 heterozygous in persons with HIV and healthy individuals, respectively. Three (3%) of the people with HIV and 25 (8.8%) of the healthy individuals carried homozygous mutant variants. The allele frequency of the above polymorphism reached 9.1%, but no statistically significant association was observed, albeit it is borderline (p-value = .062). There are different distributions between people with HIV and healthy individuals, suggesting that CCR2-64I and SDF1-3'A may have a protective effect on HIV and that CCR2-64I (genotype I/I) has an effect on protecting against HIV and delaying progression from HIV status to AIDS. It could be used for prognostic genotyping in people with HIV.

The China-Myanmar border region is recognized as a hotspot for the emergence of HIV-1 recombinant forms. This study identified a novel HIV-1 circulating recombinant form (CRF) in this area, designated CRF184_BC. Near-full-length genome sequences were obtained from four individuals infected through heterosexual contact: one Chinese individual and three Burmese individuals. These sequences formed a distinct monophyletic clade with strong bootstrap support, separate from all known subtypes/CRFs. Recombination analysis revealed a conserved mosaic structure comprising four subtype C segments and three subtype B segments: I_C (790-2897), II_B (2898-3208), III_C (3209-5983), IV_B (5984-6435), V_C (6436-8821), VI_B (8822-8969), and VII_C (8970-9468). Bayesian Markov chain Monte Carlo analysis indicated that CRF184_BC emerged between the mid-2000s and the early 2010s. Identifying emerging CRFs highlights the ongoing dynamic evolution of HIV-1 in this region and emphasizes the need for enhanced molecular surveillance to inform effective public health strategies and vaccine development efforts.

The collection, storage, and transport of plasma, the ideal specimen for HIV-1 genotyping, is plagued by technical difficulties in resource-limited settings. We aimed to compare corresponding bio-samples for HIV-1 genotypic drug resistance testing. A total of 87 matched specimens of plasma, dried blood spots (DBS), and peripheral blood mononuclear cells (PBMCs) collected from 29 persons living with HIV (PLWH) in clinical, immunological, and/or virological failure were included. Drug resistance genotyping was done by nested PCR amplification and Sanger sequencing of the HIV-1 pol gene. The clinical reporting was based on the Stanford University HIV Drug Resistance Database. Amplification and genotyping success rates from the three sample types were compared. The level of agreement between the sample types was assessed using Cohen's kappa coefficient. In total, 89.7% (n = 26) of samples were amplified in plasma, 69% (n = 20) in DBS, and 100% (n = 29) in PBMC. In samples with plasma viral load >1,000 copies/mL, 96.2% were amplified in plasma, 73.1% in DBS, and 100% in PBMCs. The median number of mutations detected in plasma, DBS, and PBMCs was 6.5 (interquartile range [IQR]: 2-8.25), 5 (IQR: 0-6), and 5 (IQR: 2-7), respectively. The difference in the number of mutations across the three sample types was not statistically significant (p = 0.221). The agreement between the sample types was calculated based on susceptibility and resistance to different antivirals. The kappa values for nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors ranged from 0.70 to 0.88 and 0.75 to 0.87, respectively. Six samples showed discordance in HIV-1 drug resistance profiles when compared across the three compartments. DBS is a promising alternative to plasma for HIV-1 genotypic testing in resource-limited settings owing to the ease of sampling, storage, transportation, human resource efficiency, and cost-effectiveness. However, no single specimen type can satisfy all requirements and purposes. Selecting an appropriate specimen for a setting requires careful consideration of the practical constraints, logistical capacity, and application needs.

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.