Mitochondrial Dysfunction in Aging CD4 T cells in HIV-immune Non-responders.

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SUMMARY - Mitochondrial Dysfunction in Aging CD4 T Cells in HIV Immune Non-Responders Despite effective control of HIV by antiretroviral therapy (ART), a significant number of HIV patients fail to achieve complete immune reconstitution and are deemed immune non-responders (INRs). CD4 T cells from these HIV-INRs exhibit prominent mitochondrial dysfunction and premature aging, which play a major role in HIV latency and increase the incidence of non-AIDS, non-communicable diseases (NCDs). To date, how CD4 T cells develop mitochondrial dysfunction and premature aging is unknown, thus raising an urgent need to uncover these molecular processes. The objective of this administrative supplemental proposal is to elucidate the mechanisms that drive mitochondrial dysfunction in aging CD4 T cells during HIV infection. During our parent award entitled “HIV infection- induced mitochondrial dysfunction and premature T cell aging”, our studies revealed significant changes in mitochondrial functions in aging CD4 T cells from HIV patients (especially in INRs), including decreases in mitochondrial respiration, ATP production, and mitochondrial (mt)DNA content, and increases in the synthesis of reactive oxygen species (ROS) and expression of aging markers. Importantly, we found that these functionally impaired, aging CD4 T cells display significant repression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α) and mitochondrial transcription factor A (mtTFA) - two mitochondrial master regulators - along with differential expression of specific non-coding RNAs (ncRNAs), which control the expression of target genes at the post-transcriptional level. Based on these new findings, we further hypothesize that mitochondrial regulatory proteins PGC1a and mtTFA are epigenetically dysregulated by ncRNAs during HIV infection, leading to mitochondrial dysfunction and CD4 T cell aging. We propose two aims to test this hypothesis. Aim 1 will investigate how PGC1α and mtTFA are repressed in CD4 T cells during latent HIV infection. Aim 2 will determine the impact of PGC1α and mtTFA repression on CD4 T cell aging during latent HIV infection. This translational research is novel and will answer clinically relevant questions: how HIV infection induces mitochondrial dysfunction and aging in CD4 T cells; and whether targeting the mitochondrial regulatory machinery can restore mitochondrial functions and reprogram the CD4 T cell aging process. Information gained from this study will fill major knowledge gaps in understanding of the pathogenesis of HIV latency and facilitate the development of novel HIV immunotherapy. Thus, this proposal is significant and will have a potentially high impact on HIV and aging research. Because this administrative supplemental application is based on our funded parent project, will add participants (including elderly Veterans) with HIV to our ongoing study where such participants were not enrolled in sufficient numbers to make meaningful comparations between groups for exploration of new measures to elucidate the role and mechanisms of master mitochondrial regulators in T cell mitochondrial regulation, this administrative supplemental application is relevant to HIV and aging research, meets the eligibility criteria, and fits within the scope of our existing award.