CROI 2020 Abstract eBook
Background: Changes in the intestinal microbiome, known as dysbiosis, and its metabolites promote inflammation and systemic immune activation in persons living with HIV, which may contribute to the persistence of HIV during ART. Methods: To define the major factors that drive dysbiosis we contrasted the diversity and composition of the fecal microbiome of persons living with HIV before beginning ART (HIV+ naïve; 13 patients) with those on ART (57 patients) for 133 months (HIV+ ART+) by16S rRNA sequencing. Results were compared to the microbiome in 55 healthy HIV-uninfected controls. Results: Overall, 76 %were males of median age of 44. Groups were similar in demographics. HIV+ ART+ had a median CD4 count of 685 and 88% had HIV-1 RNA of < 20. Principal component analysis (PCA) of the intestinal microbiome at the phylum level reveals that b-diversity of the microbial composition in HIV+ naïve and HIV+ ART+ individuals is similar and quite distinct from the uninfected controls. Individual a-diversity, as measured by the Shannon index, and richness, reported by the Chao-1 index, are decreased in HIV+ naive patients (p=0.009) and are partially reversed after ART treatment. However, the balance in the abundance of the core microbiota, Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Verrucomicrobia, distinguishes HIV+ naïve from HIV+ ART+ individuals. The HIV+ naïve population exhibits decreased Actinobacteria (p = 0.04) and Proteobacteria (p=0.009) compared to the uninfected group. The decrease in abundance of these communities in the HIV+ naïve group is exchanged for a significant increase in Actinobacteria (p=0.008) and Firmicutes (p=0.008), and a decrease in Bacteroidetes (p=0.001), thereby seemingly normalizing bacterial diversity, but not composition in HIV+ ART+ individuals. Conclusion: These results indicate that HIV reduces the diversity and breadth of microbes in the intestine and that after ART, the diversity of the microbiota increases due to an undergrowth of Bacteroidetes and excess colonization by Actinobacteria and Firmicutes. 226 MICROBIOTA MODULATES HIV TARGET-CELL LEVELS AT SITES OF MUCOSAL HIV ACQUISITION Angela Wahl 1 , Baolin Liao 1 , Cara Richardson 1 , Morgan Chateau 1 , Wenbo Yao 1 , Allison Rogala 1 , R. Balfour Sartor 1 , J. V. Garcia 1 1 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Background: Most HIV infections are acquired at the mucosa of the gut or female genital tract (FGT). Given that resident microbiota regulate mucosal immune homeostasis, we hypothesized that microbiota modulates HIV target cell levels at these sites of HIV transmission which could affect HIV acquisition, pathogenesis, persistence, and PrEP efficacy. Methods: We used bone marrow/liver/thymus (BLT) humanized mice to examine the effect of microbiota on HIV target cell levels in the gut and FGT. The systemic presence of human immune cells in BLT mice including the gut and FGT is well documented. Specifically, we bioengineered germ-free (GF) BLT humanized mice using rederived GF immunodeficient NSG mice. GF NSG mice were implanted with human thymus/liver tissue and transplanted with autologous stem cells in a GF surgical isolator. The GF status of mice was monitored by the National Gnotobiotic Rodent Resource Center. BLT mice colonized with microbiome were also constructed. To directly evaluate the effect of microbiota on HIV target cell levels in the gut and FGT, we quantitated the number of human CD4+ T cells and myeloid cells in both models with flow cytometry. We also quantitated the number of CCR5+ CD4+ T cells and activated (HLA-DR+CD38+) CD4+ T cells in the gut. We analyzed the small intestine (S), cecum (C), and large intestine (L) intraepithelial (IEL) and lamina propria (LPL) layers separately. Results: Numbers of human CD4+ T cells were higher in the SIEL (p=0.0001), SLPL (p=0.0009), CIEL (p=0.0232), LIEL (p=0.0005), and LLPL (p=0.0015) of colonized BLT mice compared to GF BLT mice. Numbers of CCR5+ CD4+ T cells were consistently higher in the gut of colonized BLT mice (SIEL p=0.0002, SLPL p=0.0401, CIEL p=0.0004, CLPL p=0.014, LIEL p=0.0005, LLPL p=0.0022). The presence of microbiome also resulted in higher numbers of activated CD4+ T cells in the SIEL (p=0.0011), SLPL (p=0.0279), and CIEL (p=0.0364). Higher numbers of human myeloid cells were observed in the SIEL (p=0.0015) and SLPL (p=0.0005) of colonized BLT mice. In the FGT, the presence of microbiome resulted in higher numbers of human CD4+ T cells (p=0.0079) but had no effect on human myeloid cell levels. Conclusion: Our results provide direct evidence that microbiota modulate HIV target cell levels and in particular, CD4+ T cell levels at key mucosal sites of HIV acquisition.
whether alterations in GMB and related functional groups may contribute to disrupted host metabolite profiles in PWV. M ethods : This study included 185 women (128 with long-standing HIV infection, 88% under antiretroviral therapy; and 57 HIV-uninfected women from the same geographic location with comparable characteristics) from the Women’s Interagency HIV Study. Stool samples were analyzed by 16S rRNA V4 region sequencing. GMB function was inferred by PICRUSt. Plasma metabolomic profiling (133 metabolites including amino acids, biogenic amines, acylcarnitines and lipids) was performed using liquid chromatography tandem mass spectrometry. Linear discriminant analysis effect size (LefSe) and partial least squares discriminant analysis (PLSDA) were used to identify GMB and plasma metabolite signatures of HIV infection, respectively. Results: LefSe identified four predominant bacterial genera associated with HIV infection, with higher abundances of Ruminococcus and Oscillospira and lower abundances of Bifidobacterium and Collinsella in HIV-infected women compared to HIV-uninfected women. PLSDA revealed a distinct plasma metabolite profile (Figure 1A) for HIV-infected women, featured with elevated glycerophospholipid levels, compared to HIV-uninfected women. The two HIV- increased bacterial genera, notably Ruminococcus, showed positive correlations with plasma glycerophospholipids but not with amino acids or biogenic amines (Figure 1B). The two HIV-decreased microbial genera, Bifidobacterium and Collinsella, showed little correlation with plasma metabolites. Functional analyses also indicated that GMB lipid metabolismwas enriched in HIV-infected women. Ruminococcus and Oscillospira were among the top bacterial genera that contribute to the GMB glycerophospholipid metabolism pathway and showed positive correlations with host plasma glycerophospholipid levels. One bacterial functional capacity in the acetate/propionate biosynthesis pathway was identified to be mainly contributed by Bifidobacterium. Conclusion: Our integrative analyses suggested that altered gut microbiota with related functional capacities are associated with disrupted plasma metabolite profiles in HIV-infected women.
225 ART REVERSES LOSS OF DIVERSITY & RICHNESS OF INTESTINAL MICROBIOME IN HIV+ NAIVE
Angelica I. Cruz-Lebron 1 , Ramona M. Johnson 1 , Danielle Labbato 2 , Theresa O. Rodgers 2 , Julia C. Kosco 2 , Grace A. McComsey 2 , Alan D. Levine 1 1 Case Western Reserve University, Cleveland, OH, USA, 2 University Hospitals Cleveland Medical Center, Cleveland, OH, USA
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