Impact of opioid use disorder on mitochondrial dysfunction among antiretroviral therapy-receiving aging people with HIV.

About This Grant

Use of antiretroviral therapy (ART) has considerably increased life expectancy for people with HIV (PWH) resulting in increased risk of age-related non-AIDS-defining health burden, including inflammaging, a low-grade chronic proinflammatory immune response, among the older population of PWH compared to the general population. A large proportion of PWH are often found to be addicted to synthetic or non-synthetic opioids, resulting in opioid use disorder (OUD), which can also add to proinflammatory immune response. However, little is known about the consequences of long-term ART and OUD on inflammaging in this aging PWH. Interestingly, a common denominator for aging, HIV and OUD is that they all cause mitochondrial dysfunction in immune cells as indicated by various previous reports. Mitochondria are highly dynamic organelles, essential for cellular metabolism, stress responses and homeostasis maintenance and are considered as the hub for biochemical processes including oxidative phosphorylation (oxphos), adenosine triphosphate (ATP) production, intracellular reactive oxygen species (ROS) generation, fatty acid synthesis and calcium (Ca2+) homeostasis. Our previously published data have shown that mitochondrial ROS increased with mitochondrial depolarization in people with HIV. Moreover, our exciting preliminary data indicated that mitochondrial ROS in immune cells is further increased in older PWH with age ≥50years compared to younger PWH with age <50 years. In addition, PWH with OUD had more mitochondrial ROS+ and reduced mitochondrial membrane potential in immune cells compared to PWH without OUD. Also, we found increased inflammatory immune markers in plasma of PWH with OUD. In view of this evidence, we hypothesize that OUD aggravates inflammatory immune response by increased mitochondrial dysfunctions in aging PWH. To test our hypothesis, we propose to evaluate the extent of OUD induced mitochondrial dysfunction in aging PWH, by studying mitochondrial mass, mitochondrial superoxide levels, mitochondrial membrane potential, mitochondrial fusion/fission, mitophagy, expression of mitochondrial stress response genes, oxidative phosphorylation and mitochondrial NADH levels in peripheral blood mononuclear cells (PBMC) of ART-treated PWH of age ≥50years, with or without OUD. In addition, we will identify cell specific molecular targets contributing to mitochondrial dysfunction, cellular senescence and inflammaging in PWH with OUD by transcriptomic analysis using single cell RNAseq. Finally, we will investigate if treatment with ROS a scavenger or a NAD+ booster can improve mitochondrial function in immune cells and reduce proinflammatory immune response in aging PWH with OUD. This proposal aims to advance the foundational knowledge about the role of mitochondria in the age-related altered immune cell function in older ART receiving PWH with OUD, which could be leveraged to develop targeted therapies and improve outcomes in people aging with HIV, opioid use and addiction.