PROJECT SUMMARY
The success of combined antiretroviral therapy (cART) has drastically improved the life expectancy of people
living with HIV (PLWH). With improved survival among PLWH, many are suffering from age-related
neurocognitive complications. HIV-associated inflammation has been implicated in premature aging and
increased risk of age-associated comorbidities even in cART-treated individuals. Autophagy, a conserved
lysosomal degradation pathway, is known to increase the lifespan of model organisms. We have previously
shown that the autophagy protein Beclin1 can regulate viral replication and the secretion of neuroinflammatory
molecules in HIV-infected glial cell cultures and an EcoHIV-infected mouse model. Beclin1 interacts via its BH3
domain with the anti-apoptotic Bcl-2 family; thereby inhibiting autophagy. Studies have shown that disrupting the
binding between Beclin1 and Bcl-2 can effectively increase autophagy, preventing premature aging, improving
health span, and promoting longevity in healthy aged mammals. Thus, the goal of this exploratory grant is to
investigate whether increasing autophagy via the inhibition of the Beclin1- Bcl-2 complex formation delays age-
related phenotypes and improves cognitive decline associated with HIV in infected adult and old mice. To test
our goals, an equal number of male and female Becn1F121A/F121A and C57BL/6J (control) mice at 6 months
(Experiment 1) and 16 months of age (Experiment 2) will be infected with EcoHIV or equal volume Saline
(control). After 2 weeks a subset of the EcoHIV-infected and Saline animals will receive a daily cocktail of ART
and a subset will receive equal volume Saline. In Specific Aim 1, we hypothesize that reduction of the Beclin1–
BCL2 complex will improve age-related phenotypes and cognitive decline induced by HIV under ART. In Specific
Aim 2, we hypothesize that disrupting the interaction between Beclin1 and Bcl-2 will reduce the expression of
key markers of inflammation, oxidative stress, glutamatergic neurotransmission, and altered synaptic plasticity
in the pathogenesis of aging and cognitive impairments. The experiments described in this proposal will allow
us to determine the role of autophagy in the prevention of age-related neurocognitive complications associated
with HIV infection. The success of this study will enhance our knowledge of the mechanism of persistence of
neurological complications associated with HIV in the aging population and could lead to the development of a
Beclin1-mediated autophagy hyperactivation therapeutic strategy in the prevention of age-related neurocognitive
complications associated with HIV infection.