Mitochondrial Impact on Inflammaging and Cognitive Impairment in HIV and Substance Use

About This Grant

PROJECT SUMMARY This proposal responds to NIDA RFA-DA-26-009 and aims to characterize the mitochondrial regulation of inflammaging in immune cells and neurons, along with their translational effects on cognitive function among people with HIV (PWH) who use substances (SU). It is estimated that 30-60% of PWH will develop cognitive impairment, which is associated with numerous critical adverse outcomes such as frailty, increased hospitalization rates, and elevated mortality. Among PWH, persons who inject drugs (PWID) represent one of the most vulnerable groups for cognitive impairment, as substances like cocaine and heroin exhibit pronounced neurotoxicity and are directly linked to cognitive decline. A primary cause of cognitive impairment among PWH is inflammaging, characterized by persistent low-grade inflammation and immune activation. Mitochondria, central to adenosine triphosphate (ATP) production, regulate bioenergetic processes and signaling pathways across nearly all organ systems but are susceptible to oxidative stress and inflammation. Our ongoing research indicates that mitochondrial DNA copy number (mtDNA-CN), a marker of mitochondrial integrity, is associated with HIV infection, T-cell senescence, and cognitive impairment, and is further reduced by active heroin and cocaine use. Additionally, mitochondrial genetic variation has been closely linked with multiple aging-related outcomes specifically in PWH, suggesting interactions between mitochondrial genetics and HIV infection. Therefore, we hypothesize that mitochondrial function and genetics independently and jointly influence immune dysfunction and cognitive impairment following HIV infection and substance use. Clarifying the interplay between these factors may yield therapeutic insights capable of improving brain health among PWH. Our study will address the following aims: 1) To characterize the association of cell type-specific MT function with immune dysfunction and cognitive impairment as influenced by HIV and SU; 2) To identify mtDNA genetic variation associated with immune dysfunction and cognitive impairment, and whether HIV and SU modify these associations; 3) To quantify the effects of HIV and SU on MT function, inflammaging, and nuclear DNA methylation in induced pluripotent stem cell (iPSC)-derived cortical neurons from PWIDs.