Accelerated aging in the CNS of SIV-infected macaques

About This Grant

PROJECT SUMMARY ABSTRACT HIV infection results in numerous complications across multiple organ systems, with over 75% of patients with chronic HIV disease showing clinical manifestations, even when on long-term successful combination antiretro- viral therapy (ART). Additional inflammatory sequelae have patients on long-term successful ART therapy who suffer from residual and end organ diseases of HIV infection. We posit that astrocyte dysfunction in key brain regions is central to HIV-associated accelerated aging. Activated astrocytes are associated with increased leu- kocyte transmigration, HIV infection, and the establishment of a highly inflammatory environment, which further aggravates HIV-associated disease, including accelerated aging and associated cognitive decline. Thus, as glia are present in all brain regions, and can be exposed to virus and viral proteins during acute infection, glia will be activated before treatment can be administered. Chronic activation of glia are known to impact the blood-brain barrier and can be an underlying cause of fronto-temporal and vascular dementias. Numerous studies are show- ing that the chronic activation of glia following SIV infection leads to an accelerated aging phenotype, including cognitive decline. Long-term ART may diminish the neurodegeneration observed in chronic SIV infection but have minimal impact on accelerated aging in glial cells observed in multiple brain regions. Due to the protean nature of early HIV infection, it is likely that, even under the best of care, ART is administered only after several weeks of infection. However, ART is administered early after exposure in the case of post- exposure prophylaxis (PEP). To date, there are very few studies examining glial activation during PEP. Before attempting a targeted treatment strategy, it will be necessary to tease out the underlying pathways of activation and determine if it is even possible to prevent the aging from happening in the first place. To this end, we are proposing a group of animals that will begin treatment at the very earliest stage of infection. Dysregulation of glial function and associated accelerated aging, especially in the context of successful ART suppression of SIV infection, represents a significant gap in our knowledge. Therefore, there is a critical need to understand the mechanisms of SIV-induced inflammaging and the influence of very early versus ART administration after viral setpoint, including downstream cognitive function. This multidisciplinary R01 application, which piggy-backs on several NIH-funded projects, seeks to address how long-term successful ART influences the activation of astro- cytes, focusing on mechanisms of inflammaging and neurodegeneration in multiple brain regions.