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In Sub-Saharan Africa, young women 15-24 years of age account for nearly 30% of all new HIV infections, however, biological and epidemiological factors underlying this disproportionate infection rate are unclear. In this study, we assessed biological contributors of SIV/HIV susceptibility in the female genital tract (FGT) using adolescent ( n  = 9) and adult ( n  = 10) pigtail macaques (PTMs) with weekly low-dose intravaginal challenges of SIV. Immunological variables were captured in vaginal tissue of PTMs by flow cytometry and cytokine assays. Vaginal biopsies were profiled by proteomic analysis. The vaginal microbiome was assessed by 16S rRNA sequencing. We were powered to detect a 2.2-fold increase in infection rates between age groups, however, we identified no significant differences in susceptibility. This model cannot capture epidemiological factors or may not best represent biological differences of HIV susceptibility. No immune cell subsets measured were significantly different between groups. Inflammatory marker MCP-1 was significantly higher (adj p  = .02), and sCD40L trended higher (adj p  = .06) in vaginal cytobrushes of adults. Proteomic analysis of vaginal biopsies showed no significant (adj p  < .05) protein or pathway differences between groups. Vaginal microbiomes were not significantly different between groups. No differences were observed between age groups in this PTM model, however, these animals may not reflect biological factors contributing to HIV risk such as those found in their human counterparts. This model is therefore not appropriate to explore human adolescent differences in HIV risk. Young women remain a key population at risk for HIV infection, and there is still a need for comprehensive assessment and intervention strategies for epidemic control of this uniquely vulnerable population.

Objective: Syndemic conditions have been linked to engagement in receptive condomless anal sex (CAS) and HIV seroconversion. However, little is known about the biological pathways whereby syndemics could amplify vulnerability to HIV and other sexually transmitted infections (STIs)., Design: HIV-negative sexual minority men (i.e. gay, bisexual and other MSM) were recruited from four STI clinics in South Florida for a cross-sectional study., Methods: Participants completed assessments for four syndemic conditions: depression, posttraumatic stress disorder, hazardous alcohol use and any stimulant use (i.e. any self-reported use or reactive urine toxicology results). Cytokine and chemokine levels were measured using LEGENDplex from the rectal swabs of 92 participants reporting receptive CAS and no antibiotic use in the past three months., Results: After controlling for age, race/ethnicity, preexposure prophylaxis (PrEP) use and number of receptive CAS partners, a greater number of syndemic conditions was associated with higher levels of rectal cytokines/chemokines relevant to immune activation, inflammation and the expansion and maintenance of T-helper 17 target cells, including rectal interferon-gamma (β = 0.22; P = 0.047), CXCL-8 (β = 0.24; P = 0.025) and interleukin-23 (β = 0.22; P = 0.049). Elevations in rectal cytokine or chemokine levels were most pronounced among participants experiencing two or more syndemic conditions compared with those experiencing no syndemic conditions. PrEP use was independently associated with elevations in multiple rectal cytokines/chemokines., Conclusion: Syndemic conditions could increase biological vulnerability to HIV and other STIs in sexual minority men by potentiating rectal immune dysregulation., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Despite the efficacy of antiretroviral-based pre-exposure prophylactics (PrEP) in men who have sex with men, studies in women have produced widely varying outcomes. Recent evidence demonstrates that vaginal microbial communities are associated with increased HIV acquisition risk and may impact PrEP efficacy. Here, we investigate the mechanisms underlying how vaginal bacteria alter PrEP drug levels and impact HIV infection rates ex vivo. Using cervicovaginal lavages (CVLs) from women with or without bacterial vaginosis (BV), we identified microbial metabolism of PrEP drugs in BV samples through LC-MS/MS analysis of soluble drug levels and metabolite formation in dual T-cell cultures. CVL samples were assessed for microbiome analysis using sequencing of bacterial 16S rRNA genes. We also observed non-Lactobacillus bacteria that are associated with BV may potentially impact PrEP efficacy through increased HIV infection rates in co-cultures containing Lactobacillus or BV bacteria, PrEP drugs, CEM-GFP cells, and HIV-1LAI virus. Finally, we used these data to develop a novel predictive mathematical simulation modeling system to predict these drug interactions for future trials. These studies demonstrate how dysbiotic vaginal microbiota may impact PrEP drugs and provides evidence linking vaginal bacteria to PrEP efficacy in women., Competing Interests: The authors have declared that no competing interests exist.

Gastrointestinal (GI) mucosal dysfunction predicts and likely contributes to non-infectious comorbidities and mortality in HIV infection and persists despite antiretroviral therapy. However, the mechanisms underlying this dysfunction remain incompletely understood. Neutrophils are important for containment of pathogens but can also contribute to tissue damage due to their release of reactive oxygen species and other potentially harmful effector molecules. Here we used a flow cytometry approach to investigate increased neutrophil lifespan as a mechanism for GI neutrophil accumulation in chronic, treated HIV infection and a potential role for gastrointestinal dysbiosis. We report that increased neutrophil survival contributes to neutrophil accumulation in colorectal biopsy tissue, thus implicating neutrophil lifespan as a new therapeutic target for mucosal inflammation in HIV infection. Additionally, we characterized the intestinal microbiome of colorectal biopsies using 16S rRNA sequencing. We found that a reduced Lactobacillus: Prevotella ratio associated with neutrophil survival, suggesting that intestinal bacteria may contribute to GI neutrophil accumulation in treated HIV infection. Finally, we provide evidence that Lactobacillus species uniquely decrease neutrophil survival and neutrophil frequency in vitro, which could have important therapeutic implications for reducing neutrophil-driven inflammation in HIV and other chronic inflammatory conditions., Competing Interests: The authors have declared that no competing interests exist.

Background: Cannabis is a widely used drug in the United States, and the frequency of cannabis use in the human immunodeficiency virus (HIV)-infected population is disproportionately high. Previous human and macaque studies suggest that cannabis may have an impact on plasma viral load; however, the relationship between cannabis use and HIV-associated systemic inflammation and immune activation has not been well defined., Methods: The impact of cannabis use on peripheral immune cell frequency, activation, and function was assessed in 198 HIV-infected, antiretroviral-treated individuals by flow cytometry. Individuals were categorized into heavy, medium, or occasional cannabis users or noncannabis users based on the amount of the cannabis metabolite 11-nor-carboxy-tetrahydrocannabinol (THC-COOH) detected in plasma by mass spectrometry., Results: Heavy cannabis users had decreased frequencies of human leukocyte antigen (HLA)-DR+CD38+CD4+ and CD8+ T-cell frequencies, compared to frequencies of these cells in non-cannabis-using individuals. Heavy cannabis users had decreased frequencies of intermediate and nonclassical monocyte subsets, as well as decreased frequencies of interleukin 23- and tumor necrosis factor-α-producing antigen-presenting cells., Conclusions: While the clinical implications are unclear, our findings suggest that cannabis use is associated with a potentially beneficial reduction in systemic inflammation and immune activation in the context of antiretroviral-treated HIV infection.

Background Rectal douching is the practice of rinsing the anus and rectum prior to, or after, anal sex. Among gay, bisexual, and other men who have sex with men (sexual minority men), rectal douching is likely to enhance HIV acquisition by amplifying inflammation of the rectal mucosa. This study evaluated the association of rectal douching with rectal inflammation among sexual minority men at risk for HIV infection. Methods HIV uninfected sexual minority men who reported receptive anal intercourse in the past 3 months (N = 197) were recruited from four STI clinics in South Florida, the leading region for new HIV infections among sexual minority men in the United States. A brief survey assessed rectal douching practices and sexual behaviors in the previous 3 months. Rectal inflammation was assessed by measuring 13 human rectal inflammatory cytokines/chemokines in rectal swabs using the LEGENDplex Human Inflammation Panel in a sample of 38 participants who reported douching and condomless receptive anal intercourse (CRAI). Results Average age was 35.8 years (SD=15.4). The sample was multi-ethnic: 42% Caucasian, 38% Hispanic/Latino, 13% Black/African American, and 7% other ethnic minority. Approximately two-thirds of participants (65%) reported any rectal douching in the past 3 months and the median number times participants douched was five. Participants who douched had more CRAI partners (Cohen's d = 0.4587; P < 0.01), and more CRAI partners to ejaculation (Cohen's d = 0.4813; P < 0.01) compared with participants who did not douche. Participants who reported douching five or more times in the past 3 months displayed significantly higher levels of IL-8 (Cohen's d = 0.79; P = 0.02) than those who douched less than five times. Conclusion Among sexual minority men who engage in CRAI, more frequent douching is associated with higher levels of rectal inflammation. Assessment of rectal douching should be included when evaluating HIV prevention interventions among sexual minority men, as those who douche are more likely to engage in CRAI and are at higher risk for acquisition of HIV and other sexually transmitted infection. Further mechanistic studies are needed to assess the role of rectal douching in promoting rectal inflammation. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Simian-human immunodeficiency viruses (SHIVs) have been utilized to test vaccine efficacy and characterize mechanisms of viral transmission and pathogenesis. However, the majority of SHIVs currently available have significant limitations in that they were developed using sequences from chronically HIV-infected individuals or uncommon HIV subtypes or were optimized for the macaque model by serially passaging the engineered virus in vitro or in vivo. Recently, a newly developed SHIV, SHIV.C.CH505.375H.dCT (SHIV.CH505), which incorporates vpu-env (gp140) sequences from a transmitted/founder HIV-1 subtype C strain, was shown to retain attributes of primary HIV-1 strains. However, a comprehensive analysis of the immunopathology that results from infection with this virus, especially in critical tissue compartments like the intestinal mucosa, has not been completed. In this study, we evaluated the viral dynamics and immunopathology of SHIV.CH505 in rhesus macaques. In line with previous findings, we found that SHIV.CH505 is capable of infecting and replicating efficiently in rhesus macaques, resulting in peripheral viral kinetics similar to that seen in pathogenic SIV and HIV infection. Furthermore, we observed significant and persistent depletions of CCR5+ and CCR6+ CD4+ T cells in mucosal tissues, decreases in CD4+ T cells producing Th17 cell-associated cytokines, CD8+ T cell dysfunction, and alterations of B cell and innate immune cell function, indicating that SHIV.CH505 elicits intestinal immunopathology typical of SIV/HIV infection. These findings suggest that SHIV.CH505 recapitulates the early viral replication dynamics and immunopathogenesis of HIV-1 infection of humans and thus can serve as a new model for HIV-1 pathogenesis, treatment, and prevention research. [ABSTRACT FROM AUTHOR]

An altered intestinal microbiome during chronic human immunodeficiency virus (HIV) infection is associated with mucosal dysfunction, inflammation, and disease progression. We performed a preclinical evaluation of the safety and efficacy of fecal microbiota transplantation (FMT) as a potential therapeutic in HIV-infected individuals. Antiretroviral-treated, chronically simian immunodeficiency virus (SIV)-infected rhesus macaques received antibiotics followed by FMT. The greatest microbiota shift was observed after antibiotic treatment. The bacterial community composition at 2 weeks post-FMT resembled the pre-FMT community structure, although differences in the abundances of minor bacterial populations remained. Immunologically, we observed significant increases in the number of peripheral Th17 and Th22 cells and reduced CD4+ T cell activation in gastrointestinal tissues post-FMT. Importantly, the transplant was well tolerated with no negative clinical side effects. Although this pilot study did not control for the differential contributions of antibiotic treatment and FMT to the observed results, the data suggest that FMT may have beneficial effects that should be further evaluated in larger studies. [ABSTRACT FROM AUTHOR]