Since the HIV virus directly targets and substantially depletes gut CD4+ T cells, HIV infection provides a unique opportunity to study the role of adaptive immunity in shaping the composition of microbes that colonize the gut (the microbiota) in humans. Consistent with the notion that adaptive immunity plays a central role in determining which bacteria will successfully colonize, we and others have found that HIV-infected individuals have profoundly altered and highly characteristic gut microbiota composition. Microbiota inbalance (dysbiosis) has been associated with metabolic disease, and HIV-infected individuals often have metabolic abnormalities including hypertriglyceridemia, low high-density lipoprotein cholesterol, and insulin resistance. Antiretroviral therapy (ART) drugs are associated with these abnormalities and with lipodystrophy (LD;lipoatrophy in the face, extremities and buttocks with or without visceral fat accumulation). However not everyone on ART develops disease and other contributing factors are not well understood. We observed that gut microbiota is often not restored to a state typical of healthy US adults with long-term ART, indicating a potential to contribute to the pathology of ART-linked diseases.
In Specific Aim (SA)1 of this grant, we will use high-throughput sequencing of fecal and rectosigmoid biopsy samples from HIV-positive subjects with and without LD and ART to determine whether individuals with metabolic disease will more likely have HIV-associated dysbiosis and gut inflammation. The goal of SA2 and SA3 is to go beyond the establishment of an association between gut microbiota and metabolic disease in HIV infection to understand underlying mechanisms. Central questions that we will address are 1) Why does HIV infection lead to the specific microbiota compositional changes that we observe? 2) What is the mechanism by which these compositional changes may drive metabolic disease? 3) What specific molecular factors are involved? To do this we will explore the properties of bacterial species that differ in relative abundance with HIV infection and LD, both by identifying genes/operons that are selected for in their genomes (SA2), and by experimental determination of their immune-modulatory properties (SA3). Our preliminary data suggest that beneficial """"""""symbiotic"""""""" bacteria that depend on the induction of FoxP3+ CD4+ T regulatory cells (Tregs) for persistence are preferentially lost with HIV infection. We hypothesize that this may in turn lead to the outgrowth of pro-inflammatory bacteria, chronic inflammation and the development of metabolic disease. Thus, we expect to find that species depleted with HIV infection and/or LD will more likely stimulate Tregs and will more likely have known Treg inducing molecular factors in their genomes. Conversely we expect that HIV and LD-associated species will stimulate relatively high levels of pro-inflammatory cytokines and will have a selection for virulence-associated factors in their genomes. This work will establish whether gain/loss of bacterial drivers/suppressors of inflammation in the gut contributes to metabolic disease in HIV-infected individuals.

Public Health Relevance

This study will determine whether change in the composition of gut bacteria in HIV-infected individuals is related to a high prevalence of chronic gut inflammation and metabolic disease in this population. We will also investigate the immune-modulatory properties of specific bacteria that correlate with disease both by characterizing which functional genes are selected for in their genomes and by stimulating immune cells isolated from blood and gut tissue with bacterial isolates. This work will establish whether gain/loss of bacterial drivers/suppressors of inflammation in the gut contributes to metabolic disease in HIV-infected individuals.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Perrin, Peter J
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University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
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