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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.

Liver disease is a leading contributor to morbidity and mortality during HIV infection, despite the use of combination antiretroviral therapy (cART). The precise mechanisms of liver disease during HIV infection are poorly understood partially due to the difficulty in obtaining human liver samples as well as the presence of confounding factors (e.g. hepatitis co-infection, alcohol use). Utilizing the simian immunodeficiency virus (SIV) macaque model, a controlled study was conducted to evaluate the factors associated with liver inflammation and the impact of cART. We observed an increase in hepatic macrophages during untreated SIV infection that was associated with a number of inflammatory and fibrosis mediators (TNFα, CCL3, TGFβ). Moreover, an upregulation in the macrophage chemoattractant factor CCL2 was detected in the livers of SIV-infected macaques that coincided with an increase in the number of activated CD16+ monocyte/macrophages and T cells expressing the cognate receptor CCR2. Expression of Mac387 on monocyte/macrophages further indicated that these cells recently migrated to the liver. The hepatic macrophage and T cell levels strongly correlated with liver SIV DNA levels, and were not associated with the levels of 16S bacterial DNA. Utilizing in situ hybridization, SIV-infected cells were found primarily within portal triads, and were identified as T cells. Microarray analysis identified a strong antiviral transcriptomic signature in the liver during SIV infection. In contrast, macaques treated with cART exhibited lower levels of liver macrophages and had a substantial, but not complete, reduction in their inflammatory profile. In addition, residual SIV DNA and bacteria 16S DNA were detected in the livers during cART, implicating the liver as a site on-going immune activation during antiretroviral therapy. These findings provide mechanistic insights regarding how SIV infection promotes liver inflammation through macrophage recruitment, with implications for in HIV-infected individuals.

BackgroundCannabis 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.MethodsThe 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.ResultsHeavy 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.ConclusionsWhile 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]