While antiretroviral therapy (ART) has lengthened the life-span of HIV-1-infected individuals, even young treated adults are at increased risk of morbidity and mortality from health outcomes such as frailty, osteoporosis, cardiovascular disease, diabetes, various carcinomas and reduced renal and liver function, all of which are more common in older uninfected adults. These observations have led to speculation that HIV-1- infection, and perhaps even ART, accelerate aging. Despite the fact that aging is a complex, multisystem, biological process fraught with genetic variability and environmental factors, we successfully identified a pattern of DNA methylation that is strongly associated with aging, and is accelerated during HIV-1 infection by ~14 years. Our findings demonstrate that HIV-infection and aging have additive influence on overlapping epigenetic pathways, but the mechanisms by which these changes are triggered remain unclear. The accumulation of senescent and activated CD8+ T-cells, and increasing levels of inflammatory markers, are associated with increased risk of morbidity and mortality, suggesting that inflammatory processes may lie behind aging and HIV-associated epigenetic changes. The experiments we propose will investigate the relationship between ART, HIV-1-infection, aging, inflammation, and biological outcomes. The overall goal is to better define the mechanisms behind the increased risk for aging-related diseases in treated, HIV-infected adults.
Specific Aim 1 will explore the ability of ART to restore epigenetic patterns to age-appropriate status, shedding light on the possible role of methylation as a pathway involved in aging and HIV-1-associated comorbidities, and providing novel insight into genes involved in aging and in HIV-1 and ART pathogenesis.
Specific Aim 2 will explore the relationship between epigenetics, ART and biological outcomes such as grip strength and gait speed, two markers of biological aging known to be associated with functional decline, morbidity and mortality.
Specific Aim 3 will further characterize the development of the aging-related methylation phenotype (ARMP) and explore the relationship between viral load and duration of infection on the ARMP. All three aims will explore associations between methylation status and levels of immune activation and inflammation. Genes implicated in poor biological outcomes can be explored later for associations with various comorbidities, and may provide new targets for novel therapeutic strategies to delay or mitigate the development of those health outcomes during aging with, and without, HIV-1-infection. As many of the comorbidities of aging and of HIV-1-infection result in significant costs to families and society, these experiments have strong
. PUBLIC HEALTH RELEVANCE: Many HIV-infected individuals are now aging while on treatment and are at increased risk of many aging-related diseases that cause increased dependence on healthcare resources and caregivers. These studies are designed to provide novel information that could be utilized to develop therapeutic strategies to delay, or mitigate, aging-related diseases in individuals with, and without, HIV-infection.