HIV-1 infection disrupts the intestinal immune system, leading to microbial translocation and systemic immune activation. We investigated the impact of HIV-1 infection on the intestinal microbiome and its association with mucosal T cell and dendritic cell (DC) frequency and activation, as well as with levels of systemic T cell activation, inflammation and microbial translocation. Bacterial 16S ribosomal DNA sequencing was performed on colon biopsies and fecal samples from subjects with chronic, untreated HIV-1 infection and uninfected control subjects. Colon biopsies of HIV-1 infected subjects had increased abundances of Proteobacteria and decreased abundances of Firmicutes compared to uninfected donors. Furthermore at the genus level, a significant increase in Prevotella and decrease in Bacteroides was observed in HIV-1 infected subjects, indicating a disruption in the Bacteroidetes bacterial community structure. This HIV-1-associated increase in Prevotella abundance was associated with increased numbers of activated colonic T cells and myeloid DCs. Principal coordinates analysis demonstrated an HIV-1-related change in the microbiome that was associated with increased mucosal cellular immune activation, microbial translocation and blood T cell activation. These observations suggest that an important relationship exists between altered mucosal bacterial communities and intestinal inflammation during chronic HIV-1 infection.

HIV-1-associated disruption of intestinal homeostasis is a major factor contributing to chronic immune activation and inflammation. Dendritic cells (DCs) are crucial in maintaining intestinal homeostasis, but the impact of HIV-1 infection on intestinal DC number and function has not been extensively studied. We compared the frequency and activation/maturation status of colonic myeloid DC (mDC) subsets (CD1c+ and CD1cneg) and plasmacytoid DCs in untreated HIV-1-infected subjects with uninfected controls. Colonic mDCs in HIV-1-infected subjects had increased CD40 but decreased CD83 expression, and CD40 expression on CD1c+ mDCs positively correlated with mucosal HIV-1 viral load, with mucosal and systemic cytokine production, and with frequencies of activated colon and blood T cells. Percent of CD83+CD1c+ mDCs negatively correlated with frequencies of IFN-γ-producing colon CD4+ and CD8+ T cells. CD40 expression on CD1c+ mDCs positively associated with abundance of high prevalence mucosal Prevotella copri and P. stercorea, but negatively associated with a number of low prevalence mucosal species including Rumminococcus bromii. CD1c+ mDC cytokine production was greater in response to in vitro stimulation with Prevotella species relative to R. bromii. These findings suggest that during HIV infection, colonic mDCs become activated upon exposure to mucosal pathobiont bacteria leading to mucosal and systemic immune activation.

Energy intake and the prevalence of obesity have increased dramatically. Dietary interventions should focus on decreasing energy intake and potentially by substituting protein for fat or carbohydrates.

OBJECTIVE Gut microbial translocation (MT) is a major driving force behind chronic immune activation during HIV-1 infection. HIV-1-related intestinal dysbiosis, including increases in mucosa-associated pathobionts, may influence MT and contribute to mucosal and systemic inflammation. Thus, it is critical to understand the mechanisms by which gut microbes and their metabolic products, such as butyrate, influence immune cell function during HIV-1 infection. DESIGN A cross-sectional study was performed to compare the relative abundance of butyrate-producing bacterial species (BPB) in colonic biopsies and stool of untreated, chronic HIV-1 infected (n=18) and uninfected (n=14) study participants. The effect of exogenously added butyrate on gut T cell activation and HIV-1 infection was evaluated using an ex vivo human intestinal cell culture model. METHODS Species were identified in 16S ribosomal RNA sequence datasets. Ex vivo isolated lamina propria (LP) mononuclear cells were infected with CCR5-tropic HIV-1Bal, cultured with enteric Gram-negative bacteria and a range of butyrate doses, and LP T cell activation and HIV-1 infection levels measured. RESULTS Relative abundance (RA) of total BPB and specifically of Roseburia intestinalis, were lower in colonic mucosa of HIV-1 infected versus uninfected subjects. In HIV-1 infected study participants, R. intestinalis RA inversely correlated with systemic indicators of MT, immune activation and vascular inflammation. Exogenous butyrate suppressed enteric Gram-negative bacteria-driven LP T cell activation and HIV-1 infection levels in vitro. CONCLUSIONS Reductions in mucosal butyrate from diminished colonic BPB may exacerbate pathobiont driven gut T cell activation and HIV replication, thereby contributing to HIV-associated mucosal pathogenesis.

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