HIV Reservoir Dynamics Associated with Metabolic Complications of HIV Infection

About This Grant

With continuous antiretroviral therapy (ART) and viral suppression, life expectancy for people with HIV (PWH) is approaching that of people without HIV. Some estimates suggest the mortality gap is 10 years or less, when comparing persons with and without HIV. However, with prolonged survival there have also been increases in non-AIDS defining age-related comorbid diseases. What has now emerged in contemporary HIV clinical care is a convergence of declining mortality with effective ART treatment, combined with the earlier onset of age- related comorbidities. This means a growing portion of the lifespan for PWH involves morbidity and disability from multiple diseases like obesity, diabetes, hepatic steatosis, cardiovascular diseases, and cancer. Several of these comorbidities are related to changes in metabolism, however the mechanism of these changes is not understood but may be unique to HIV. One common link between HIV and these metabolic diseases is that both are associated with chronic immune activation (IA). For example, people who are obese without HIV have elevated levels of circulating pro-inflammatory cytokines such as IL-6 and TNF. The same is true in treated HIV infection. There are several potential causes of IA including an altered microbiome, microbial translocation, and other infections like cytomegalovirus (CMV). However, we and others have shown that HIV RNA+ cells persist in lymphatic tissues despite fully suppressive ART, and we think this is a significant contributing cause of IA in PWH. Our primary hypothesis is that the size of this dynamic reservoir of HIV RNA+ cells is a primary driver of IA which, in turn, leads to development of these metabolic comorbidities. We will test this hypothesis in 2 ways. We will first explore the natural history of metabolic dysfunction in HIV using a large tissue repository of gut and lymph nodes (LN) we have collected over the last 20 years in multiple studies. We will measure the size of the HIV reservoir in gut and LN and frequency of hormone producing cells (e.g., GLP-1, PYY, GIP) in HIV negative people and PWH before and during ART and when viral recrudescence with treatment interruption. We will measure markers of IA and microbial translocation in mononuclear cells from those tissues as well as plasma that was collected at the time of the biopsy. Collectively, these data will provide insight into how metabolism is altered in HIV infection and the relationship to the size of the HIV viral reservoir. Our second approach is to focus on obesity as one of the most common comorbidities in PWH. We will enroll PWH with and without obesity (BMI30) and HIV-negative people with and without obesity into an 18-month prospective observational study. We will collect LNs, ileal, and colonic samples as well as PBMC and plasma at the baseline and 18-month timepoint. We will collect functional metabolic data with DXA and MRI scans to measure fat distribution throughout the body and we will do extensive metabolomics and functional genomics on these same tissues. We will apply machine learning algorithms to this extensive data set to determine the relationship of viral reservoirs to development of obesity as well as other predictors of obesity.