Extracellular vesicles in AD-like pathology in HIV and its potential therapeutics

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Studies of brain tissues from people living with HIV (PLWH) age from 38-60 years, showed increased amyloid plaques and tau hyperphosphorylation compared to age-matched HIV-negative subjects. PLWH who are on antiretroviral therapy (ART) live longer but experience neurodegenerative conditions related to HIV as they age. In 2018, 51% of PLWH in the U.S. were age 50 or older, and in the next 5-10 years, this population will be in their sixties, the prime age when Alzheimer’s disease (AD) symptoms begin to manifest. Further, premature aging with HIV infection is reported to affect neurocognition in PLWH. Since aging is a significant risk factor for AD development and HIV can cause premature aging, it's critically important to examine the relationship between HIV-induced aging and AD. Compared to age-matched HIV-negative subjects, studies of brain tissues from people living with HIV (PLWH) aged 38-60 showed increased amyloid plaques and tau hyperphosphorylation. However, the underlying mechanism by which HIV causes AD-associated neurodegeneration and memory impairment in PLWH is not well studied. Moreover, due to the inability of ARVs to cross the blood-brain barrier (BBB), the current ARV regimens are insufficient in suppressing HIV in the brain, which can further exacerbate neurodegenerative conditions in the aged HIV population. Our preliminary studies have shown that extracellular vesicles (EVs) derived from HIV-infected macrophages carry higher pro-inflammatory cytokines and low antioxidant enzymes. Further, exposure of these EVs from HIV-infected macrophages to SH-SY5Y neuronal cells caused increased toxicity, IL-1β levels, and neuronal loss (MAP2). We have also demonstrated that EVs administered by the intranasal route can bypass the BBB and be detected in the brain. Further, we showed that the elvitegravir (an antiretroviral drug) could be loaded into EVs and delivered across the BBB in an in vitro model. This proposal will elucidate the role of the HIV components packaged in EVs in causing AD-like pathology through the TXNIP inflammatory pathway. We will also use EVs as nanocarriers to improve curcumin (TXNIP inhibitor) and EVG levels across the BBB, thus effectively suppressing inflammation with minimal/tolerable drug toxicity.