Impact of microbial metabolites and their roles in HIV-associated neurocognitive disorders

About This Grant

Project summary Despite the success of antiretroviral therapy (ART) in extending the life expectancy of people with HIV (PWH), nearly half of this population continues to experience chronic HIV-related conditions, including HIV-associated neurocognitive disorders (HAND). HAND persists even with effective viral suppression and is recognized as a chronic neurological condition. Emerging evidence suggests that the gut microbiome and its metabolites play key roles in shaping host immunity and neurological health in PWH. However, our understanding of the microbial metabolites involved in HAND pathogenesis remains limited due to limited functional studies and incomplete annotation of the metabolome. During my postdoctoral research, I identified thousands of previously uncharacterized N-acyl lipids and bile acids–classes of microbially derived molecules that are significantly altered in PWH and individuals with HAND. However, due to the widespread use of ART in human cohorts, it is still unclear whether these molecular changes are driven by HIV, ART, or their interaction. Moreover, their microbial producers and biological functions in the context of HAND remain largely unknown. Therefore, the objective of this proposal is to investigate the functional roles of microbial metabolites in HAND by integrating metabolomics, metagenomics, in vitro and in vivo assays, and computational approaches. In Aim 1, I will use the HIV-1 transgenic (HIV-1Tg) rat model to determine how ART affects the metabolome, microbiome, behavior, and tissue distribution of microbial metabolites, particularly N-acyl lipids and bile acids. In Aim 2, I will evaluate the neuroinflammatory potential of N-acyl lipids and bile acids using stem cell–derived microglia (iPSC-MG), identify their microbial sources by culturing a synthetic gut community (111 strains) and individual strains, and integrate multi-omic data to establish microbe-metabolite correlations in different cohorts. Finally, in Aim 3, I will expand this approach to discover additional classes of microbial metabolites relevant to HIV and HAND and build a publicly accessible, web-based functional atlas to systematically catalog microbial metabolites associated with HIV and HAND. Together, these aims will address a critical knowledge gap in neuroHIV by defining specific microbial metabolites that contribute to HAND and providing tools for biomarker discovery and mechanistic insight. During the K99 phase, this work will be conducted at the University of California San Diego, where I will receive training from Dr. Pieter Dorrestein (expert in metabolomics and data mining), Dr. Rob Knight (expert in microbiome research), Dr. Karsten Zengler (expert in microbial communities), and Dr. Ronald Ellis (expert in neuroHIV), along with a team of multidisciplinary collaborators with large expertise in the in vivo and in vitro experiments proposed. Their combined expertise and strong record of transitioning postdoctoral researchers to faculty positions make them an ideal mentorship team for my goal of becoming an independent group leader working on the microbiome-brain axis.