CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Conclusions: Bacterial gut microbiota composition differs by HIV-1 phenotype and is affected by ART and immune recovery. Initiation of ART while CD4+ remain >500 cells/mm 3 and, particularly, during the first 6 months following HIV-1 infection preserve the gut bacterial content.

262 Butyrate Reduces Pathobiont-Associated HIV-1 Infection and Activation of Gut T Cell Jon Kibbie ; Stephanie Dillon; Eric Lee; Charles Robertson; Daniel N. Frank; Martin McCarter; Cara C.Wilson University of Colorado Anschutz Medical Campus, Aurora, CO, US

Background: We previously reported that untreated chronic HIV-1 infection is associated with an altered intestinal microbiome that was linked to mucosal and systemic inflammation. HIV-1-infected (HIV+) subjects had increased abundances of pathobionts (e.g. Prevotella) and decreased abundances of bacterial families that contain butyrate- producing bacterial species (BPB). Butyrate is a short chain fatty acid important in intestinal immune regulation. We hypothesized that butyrate would decrease pathobiont-driven mucosal inflammation and investigated this using an ex vivo intestinal cell model. Methods: Species identification was performed on bacterial 16S ribosomal DNA sequences previously obtained from colon biopsies of 17 untreated chronic HIV+ and 14 uninfected (HIV-) subjects. For analysis, the percent abundances of known colonic BPB (n=15 species) were pooled for each subject. Lamina propria mononuclear cells (LPMC) from normal human intestinal tissue (n=7) were infected with HIV-1 BaL and cultured with P. stercorea and butyrate: 0mM, 0.2mM (low) or 2mM (physiologic). Measurements of CD4 T cell activation (CD38+HLA-DR+) and infection (intracellular Gag-p24; ip24) were performed by flow cytometry. Levels of T cell-associated cytokines IFN γ , IL-17 and IL-2 were measured by ELISA. t-tests were used for statistical analysis. Results: Abundances of BPB were lower in HIV+ subjects compared to HIV- controls (p=0.009). In HIV-1 BaL -infected LPMC, without butyrate, P. stercorea increased T cell activation (p=0.005), induced IFN γ (p=0.005), IL-17 (p=0.001) and IL-2 (p=0.03) production and increased frequencies of ip24 + CD4 T cells (p<0.0001). With 2mM butyrate, P. stercorea - associated T cell activation was decreased by 85% (p<0.05), production of IFN γ (p<0.01), IL-17 (p<0.01) and IL-2 completely abrogated, and T cell infection levels decreased 3-fold (p=0.01). Lower butyrate concentrations failed to inhibit P. stercorea -induced T cell activation and infection, induced a 2-fold decrease in IFN γ and IL-17 (p<0.05), but increased IL-2 production. Conclusions: Untreated, chronic HIV+ subjects have decreased abundances of BPB in the colonic mucosa. In an ex vivo intestinal cell model, physiological levels of butyrate decreased T cell activation, cytokine production and HIV infection induced by P. stercorea , a pathobiont increased in the colonic mucosa of HIV+ subjects, whereas lower levels did not. These findings suggest that a loss of BPB in the gut microbiome may contribute to HIV-associated mucosal pathogenesis. 263 Maraviroc Does Not Induce Changes in the Gut Microbiome of HIV-Infected Individuals Andrej Vitomirov ; David M. Smith; Susanna R.Var; Maile Karris; Parris Jordan; Douglas D. Richman; Susan Little; Josué Pérez-Santiago University of California San Diego, La Jolla, CA, US Background: HIV preferentially depletes CD4 T cells in the gut-associated lymphoid tissue during acute infection, likely associated with high levels of CCR5 expression. Maraviroc (MVC) blocks HIV entry by binding CCR5. The consequences of MVC treatment on the gut microbiome have not been investigated. Here, we evaluated the impact of antiretroviral treatment (ART) plus MVC intensification on the gut microbiome during primary HIV infection. Methods: Thirteen recently HIV infected persons in the San Diego Primary Infection Cohort were randomized to receive early ART (atazanvir, ritonavir, tenofovir and emcitritabine) with or without MVC. Anal swabs were collected prior to the start of ART and approximately every 4 weeks thereafter for 48 weeks. Stool DNA was extracted from the swabs and the V6 region of the 16s rDNA gene was pyrosequenced. We classified bacterial sequences at the order level and evaluated microbiome profile differences cross-sectionally and longitudinally between persons who did (MVC+) or did not (MVC-) receive MVC. All analyses were performed with R statistical software. Results: We classified 13 orders of bacteria that were shared among all participants at baseline. We then compared each order of bacteria between MVC+ (n=6) and MVC- (n=7) individuals at weeks 4, 24, and 48 after initiation of ART. The distribution of bacterial orders between groups did not differ statistically (p>0.05) at any time point (Mann-Whitney test). In a paired analysis comparing baseline bacterial levels with weeks 4, 24, and 48 between MVC groups, we found no differences in the levels of each order of bacteria (Wilcoxon test); however, there was a trend for a reduction of the order of Actinomycetales from baseline to week 48 (p=0.06). When we evaluated the full microbiome of all participants at all time points measured using principal component analysis, there were no clusters based on MVC intensification (see figure).

Poster Abstracts

229

CROI 2015