The role of CMV in HIV-associated accentuated aging

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ABSTRACT Due to the introduction of combined antiretroviral therapy (ART), AIDS is now rare - instead HIV has become a chronic disease in much of the industrial world. Persons over 50 with controlled HIV (PWH) make up nearly half of all infected individuals (>0.6M people in the US alone) and their numbers are increasing. But these people are not cured: PWH experience multiple comorbid conditions at rates higher than, and earlier in life compared to, uninfected age-matched persons. These HIV-associated non-AIDS conditions (HANA) lead to premature accumulation of physical and cognitive functional deficits that resemble a pronounced/ accelerated aging phenotype. Inflammation and immune function decline accompany both HIV and aging, suggesting that both could potentiate and/or drive aspects of exacerbated aging in PWH. Persistent cytomegalovirus (CMV) infection has been implicated in immune aging and age-related inflammation too, but there are significant inter- person variations and an incomplete understanding of control of CMV with aging. Limited data suggests that the premature “aging” phenotype seen in PWH is only found in those co-infected with CMV, but the control of CMV in PWH remains poorly understood. Therefore, CMV could be a driver of disabilities in older HIV+ individuals, a marker with stratifying and predictive value, or neither. We have developed a battery of tests to measure CMV viral load, anti-CMV NK, T and B cell immunity, and concurrent levels of systemic inflammation, and have found that while <50% of HIV-negative participants exhibit anti-CMV neutralizing Ab (nAb), >90% HIV+ age-matched participants develop nAb. We hypothesize that anti-CMV nAb production is a direct function of CMV load and replication during, and maybe also in the aftermath, of the acute HIV infection. We have also developed and validated the upper extremity flexion (UEF) test that, coupled with cognitive testing, can provide simultaneous assessment of frailty, motility, cardiovascular and cognitive function, all of which provide deep functional insight into quality of life (QOL) and geriatric syndromes. We seek to use these tools to evaluate the impact of CMV and CMV-associated inflammation as biomarkers in predicting trajectories of functional decline in HIV+ individuals with aging. Our hypothesis is that PWH with signs of CMV reactivation (viral loads, high levels of anti-CMV nAb, T and NK cell activation) experienced prolonged and high CMV reactivation during acute HIV disease and/or in its aftermath, with a broad spectrum of immune and inflammatory abnormalities, that predispose them for aggravated chronic conditions and geriatric syndromes such as frailty, mobility/falls and reduced cognitive ability. We will test this hypothesis by multivariate analysis of immune and inflammatory mediators and geriatric assessment in three observational (one prospective) and one anti-CMV drug treatment cohort, including both sexes. This work will dissect the relationship between CMV, inflammation and reduced overall fitness, frailty and accelerated and/or unsuccessful aging in HIV+ individuals and could provide basis for broader anti-CMV treatment of older adults with HIV to improve their healthspan.