Exploring the Molecular Link between Bioenergetics, Latency, and Neuro-cognitive Impairment during HIV-associated progressive Aging - Abstract Aging is an inevitable biological process characterized by continuous deterioration of physiological, molecular, cellular, biochemical, and functional changes. The effects of aging are critical to the population of people living with HIV (PLWH), as the overall cohort of infected individuals is getting older, with over 4 million over the age of 50, and the number is increasing. While PLWH are experiencing improved life expectancy due to significant advancements in the combinatorial antiretroviral therapy (cART), they continue to face a higher burden of aging- associated co-morbidities like diabetes, cancer, frailty, and neurological disorders, which led researchers to believe that HIV infection leads to a form of early aging. Aging and HIV infection have been shown to have negative impacts on the form and function of the central nervous system (CNS). Combinatorial ART’s poor penetrance across the blood-brain-barrier leads to continuous low-level viral replication in the CNS and could result in premature aging in PLWH. Though the brain makes up only 2% of the body’s weight, it consumes over 20% of the oxygen the body takes in, a 10-fold greater energy requirement than any other organ. The brain undergoes a steady decline in energy metabolism during normal aging, and HIV infection adds another level of complexity to it. The changes in the brain energy level could be one key contributing factor in accelerated aging in PLWH. Whether HIV alone, cART alone, or both HIV and cART acting synergistically contribute more to the aging-associated perturbations is not well studied because of limitations regarding longitudinal clinical sample availability and suitable human-aging mimicking animal models. Approaches to visualize and comprehend neuroimmune dysfunction, brain bioenergetics, and associated cognitive deficits in the setting of new-age cART are the knowledge gap. Thus, deciphering how chronic ART-treatment affects aging and the brain immune homeostasis will provide a clue to understand the mechanism involved in accelerated aging in PLWH and ultimately its therapeutic targeting. Recently, we used chronically HIV-1-infected CD34-NSG humanized mice to model older people living with HIV and uncover associations between HIV-1 infection and aging (PMID:38399364). We are the first to report human aging-associated gene changes in the brains of hu-mice using transcriptomics by maintaining the HIV-infected mice for more than one year without ART. With an appropriate model in hand and new preliminary data sets, we propose to study progressive aging and associated changes in the CNS during chronic, clinically relevant oral cART and injectable long-acting ART regimens. How much brain bioenergetics, latency, and cART regimens would contribute to premature aging (we termed as BLAAGING) and functional neuro-immune interaction at the molecular and behavioral level will be answered. By employing the proposed animal model under highly suppressive cART treatment regimens, the proposed three aims will measure axonal fiber integrity, neuronal metabolites, using diffusion tensor imaging and CEST-MRI, and brain functional deficits using behavior analysis, gene-level changes using transcriptomics, and bioenergetics changes from brain-derived mitochondria during progressive aging. The outcome will help identify new biomarkers of aging in the CNS and will provide mechanistic evidence for future therapeutics to delay the accelerated aging process in PLWH.
