Although the lifespan of individuals living with HIV-1 has increased significantly owing to effective combination anti- retroviral therapy (cART), paradoxically however, in almost 50% of infected individuals there is increased prevalence of HIV-1-associated neurocognitive disorders (HAND), which remains an important comorbidity. It is suggested that persistence of cytotoxic viral protein such as HIV-1 Tat that accumulates despite cART, could likely contribute to this process. Additionally, reports on Alzheimer?s like pathology in patients with HAND are also extant, likely attributable to the action of both HIV-1 infection and the cytotoxic viral Tat protein in neurons and endothelial cells. A recent study from our lab has shown that HIV-1 Tat could also induce amyloidosis in yet another cell type, the astrocytes, via the HIF-1?-BACE1-antisense (AS) pathway in an in vitro model. Validation of these findings was also demonstrated in the brains of SIV-infected macaques & HIV-infected patients? samples, and this amyloids could be an important contributing factor to neurotoxicity associated with HAND. Based on our recent report that astrocytes can produce amyloids following exposure to Tat, we hypothesized that the toxic amyloid forms secreted by Tat-stimulated astrocytes in the astrocyte-derived extracellular vesicles (ADEVs) could be taken up by the neuorns, resulting in exacerbated neuronal injury. The concept of uptake by neurons of astrocyte released amyloids via the ADEVs is a novel idea and has never been explored before. In this exploratory R21 proposal, we will test the hypothesis in two aims:
Aim 1 : a) Determine how HIF-1? regulates HIV-1 Tat-mediated release of ADEVs carrying neurotoxic amyloids (A? 1-42) cargoes which, in turn, can be taken up by the neurons, leading to synaptodendritic injury, and Aim 2: b) Determine how the delivery of HIF-1A siRNA via the ADEV cargoes can inhibit amyloidosis and the associated cognitive decline in two relevant rodent models of HAND- inducible transgenic Tat mice model as well as the humanized mice model of HIV infection. These findings could have ramifications for future development of adjunctive therapeutic interventions targeting astrocytic HIF-1? for treatment of neurological disorders in HIV patients on cART therapy.
A recent study from our lab have identified the contribution of astrocytes in the Alzheimer?s like pathology (which is a co-morbidity of HIV), in patients who are on combined antiretroviral therapy (cART), with lower/ undetectable viral titre, however, the role of astrocyte derived extracellular vesicles carrying this amyloid cargoes in HIV associated neurological disorders, remains an enigma. In the proposed project, we will assess how HIF-1? regulates HIV-Tat mediated release of extracellular bodies from these astrocytes carrying amyloids which can lead to neuronal injury resulting in cognitive dysfunction, and additionally, how delivery of HIF-1 siRNA via ADEVs in the humanized mice model of infection can lead to protection of amyloidosis and cognitive dysfunction. These findings could have ramifications for future development of adjunctive therapeutic interventions targeting astrocytic HIF-1? for treatment of neurological disorders in HIV patients on cART therapy.
