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Grant

The Role of CMV in HIV-Associated Accentuated Aging

Sponsored by National Institute on Aging

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$672.5K Funding
4 People
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Abstract

ABSTRACT Due to the introduction of combined antiretroviral therapy (ART) AIDS is now rare - instead HIV hasbecome a chronic disease in much of the industrial world. Persons over 50 with controlled HIV (PWH) make upnearly half of all infected individuals (>0.6M people in the US alone) and their numbers are increasing. Butthese people are not cured: PWH experience multiple comorbid conditions at rates higher than and earlier inlife compared to uninfected age-matched persons. These HIV-associated non-AIDS conditions (HANA) lead topremature accumulation of physical and cognitive functional deficits that resemble a pronounced/ acceleratedaging phenotype. Inflammation and immune function decline accompany both HIV and aging suggesting thatboth 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 thatthe premature aging phenotype seen in PWH is only found in those co-infected with CMV but the control ofCMV 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 tomeasure CMV viral load anti-CMV NK T and B cell immunity and concurrent levels of systemic inflammationand 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 functionof CMV load and replication during and maybe also in the aftermath of the acute HIV infection. We have alsodeveloped and validated the upper extremity flexion (UEF) test that coupled with cognitive testing can providesimultaneous assessment of frailty motility cardiovascular and cognitive function all of which provide deepfunctional insight into quality of life (QOL) and geriatric syndromes. We seek to use these tools to evaluate theimpact of CMV and CMV-associated inflammation as biomarkers in predicting trajectories of functional declinein HIV+ individuals with aging. Our hypothesis is that PWH with signs of CMV reactivation (viral loads highlevels of anti-CMV nAb T and NK cell activation) experienced prolonged and high CMV reactivation duringacute HIV disease and/or in its aftermath with a broad spectrum of immune and inflammatory abnormalitiesthat predispose them for aggravated chronic conditions and geriatric syndromes such as frailty mobility/fallsand reduced cognitive ability. We will test this hypothesis by multivariate analysis of immune and inflammatorymediators and geriatric assessment in three observational (one prospective) and one anti-CMV drug treatmentcohort including both sexes. This work will dissect the relationship between CMV inflammation and reducedoverall fitness frailty and accelerated and/or unsuccessful aging in HIV+ individuals and could provide basisfor broader anti-CMV treatment of older adults with HIV to improve their healthspan.

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