Center For AIDS Research

Yan Sun, PhD

Funded by: NIH CFAR Administrative Supplement

Project Period: 8/1/19 - 7/31/20

Metabolic Markers of Renal Failure among Individuals of African Ancestry after ART

Project Summary
Although antiretroviral therapy (ART) results in successful suppression of HIV and a decrease of AIDS progression, people with HIV (PWH) experience a higher incidence of chronic diseases and shorter expectancy of life. Chronic kidney disease (CKD), which emerged as a common complication of both HIV infection and its treatment, has been a critical cause of shortened life span in PWH. The pathogenesis of HIV-related CKD is multifactorial, linked to direct exposure to HIV viremia, superinfections, the systemic immune response to infection and ART regiments, as well as to traditional CKD risk factors. Both genetic and environmental factors play a role in the development and progression of CKD, and affect metabolic functions and pathways. The metabolome is the global collection of all small molecules that are produced by cells during metabolism. It provides a direct functional readout of cellular activity and physiologic status, and reflects the combined systemic effects of environmental and genetic factors. Current high-throughput technology allows for the measurement of thousands of metabolites in peripheral blood, offering a new opportunity to understand biological systems and pathways linking the environment, genomics, and CKD, and to predict the disease progression, particularly important among ART-treated PWH. In a well characterized sample of African ancestry treated by a single ART regimen, we will investigate over 20,000 metabolomic features to identify metabolic predictors of kidney function using both targeted and untargeted metabolomic approach (Aim 1). We will also examine genetic determinants of metabolomic associations with kidney function to understand genetic effects of APOL1 G1/G2 risk variants (known genetic risk for kidney disease) on metabolites (Aim 2a), and to evaluate the causal relationship between metabolites and kidney function using Mendelian Randomization method (Aim 2b).

By identifying novel metabolic targets related to kidney disease progression, and establishing potential causal relationship, this integrative metabolomic study will shed light on novel intervention and prevention strategy to improve long-term outcomes, and promote precision medicine among PWH, particularly among African ancestry.