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-1ß 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.