SUMMARY Over 37 million people worldwide are infected with HIV and as many as 50% are affected by some form of neurological dysfunction. Despite effective antiretroviral therapy (ART) extending the lifespans of people with HIV (PWH), treatments to reduce the prevalence of HIV-associated neurocognitive disorder (HAND) and other age-related diseases are lacking. Increased mitochondrial activity in reactive astroglia play a causal role in mitochondrial dysfunction in neurons and this may be a targetable mechanism underlying neuronal dysfunction in virally suppressed PWH, particularly in aging populations. Indeed, there is evidence that aging PWH may be susceptible to age-related diseases such as Alzheimer’s disease (AD). Early during HIV infection, HIV-infected monocytes enter the brain and spread infection to resident microglia that then release HIV, HIV proteins, and inflammatory cytokines, which stimulate a proinflammatory phenotype in astroglia. Reactive astroglia are a hallmark of postmortem brain tissues from HAND and AD. Astroglia have many homeostatic functions, which are likely disrupted by chronic low-level HIV infection, long-term exposure to ART and the age- and AD-related protein beta amyloid (Ab). One important function of astroglia is to buffer the concentrations of metabolic substrates (glucose, lactate, and glutamine) available to neurons in the extracellular space. Despite this crucial function to maintain bioenergetic homeostasis in the brain and the well-documented evidence of bioenergetic deficits during HAND and AD, little is known about how these processes are affected in reactive astroglia. We’ve recently discovered that HIV and ART stimulate a switch in astroglia from being primarily glycolytic and secreting the byproduct lactate, to relying on oxidative phosphorylation to meet energy demands. To achieve this increase in mitochondrial activity, reactive astroglia increase levels of the mitochondrial biogenesis factor TFAM, which is associated with a reduction in TFAM expression and viability in neurons. Importantly, this neurotoxicity is blocked by anti-inflammatory compounds that inhibit mitochondrial activity and reduce the inflammatory phenotype of astroglia. However, the mechanistic link between increased mitochondrial activity in reactive astroglia and the reduction in mitochondrial biogenesis in neurons is not understood. We will investigate the role of astroglial metabolism in aging PWH by testing the hypothesis that the age-related protein Aβ synergizes with HIV, ART and inflammatory cytokines in an age- and TFAM-dependent manner to induce reactive astroglia. SA1 will test in human astrocyte cultures from young and aged donors how TFAM knockdown alters mitochondrial activity and inflammatory gene expression in reactive astroglia. SA2 will investigate in postmortem brain tissues from HIV-, HIV- with AD, and in PWH with and without HAND changes in astroglial TFAM and the relationship with Ab plaques. These AIMs addres...