Thursday, April 3, 2025
4/3/2025
Reduction of the Beclin1-BCL2 complex in the prevention of HIV and comorbidities associated with aging - 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).