Antiretroviral therapeutic (ART) drugs have greatly increased the lifespan of people living with HIV-1/AIDS. However, these same people experience ~50% prevalence rates of HIV-1 associated neurocognitive disorders (HAND). Increasingly noted in HIV-1 infected individuals are clinical manifestations and pathological features of Alzheimer?s disease (AD) including cognitive impairment, increased levels of amyloid beta protein (A?), increased levels of phosphorylated tau protein (p-tau), and synaptic dysfunction. Not only is the pathogenesis of HAND unclear, but relatively little is known about the extent to which HIV-1, HIV-1 proteins, and/or ART drugs act as ?aging and AD accelerators?. The objective for this Alzheimer?s-focused Administrative Supplement (NOT-AG-20-008) is to determine the extent to which and mechanisms by which HIV-1 Tat protein contributes to the development of AD-like pathology. Our central hypothesis is that HIV-1 Tat interacts with the SLC38A9 arginine sensor in endolysosomes, promotes the disassembly of the v-ATPase proton pump in endolysosomes, and causes AD-like pathology. Guided by our preliminary findings, this novel hypothesis will be tested by pursuing two specific aims. (1) Determine the extent to which and mechanisms by which Tat causes v-ATPase disassembly. (2) Determine the extent to which and mechanisms by which Tat induced v- ATPase disassembly causes AD-like pathology in primary cultured neurons. The proposed studies here will explore novel mechanisms whereby Tat induces disassembly of v-ATPase via a lysosome arginine sensor, and we will focus on how Tat-induced disassembly of v-ATPase contributes to AD-like pathogenesis. Further, we expect that promoting the assembly of v-ATPase will attenuate Tat-induced AD-like pathology. The proposed studies are within the scope of the awarded R01 (MH119000-01) that is focused not on AD or its related dementias, but rather an involvement of v-ATPase in Tat endolysosome escape and HAND. Results of the proposed studies will not only lead to novel mechanistic insights into the co-pathogenesis of HAND and AD, but also provide rationale for developing endolysosome-acidifying agents as novel therapeutic strategies.
The proposed research is relevant to public health, because the long-term survival of HIV-1 infected individuals (due to combined antiretroviral therapy) is accompanied by a high prevalence of HIV-1 associated neurocognitive disorder (HAND) as well as clinical manifestations and pathological features of Alzheimer?s disease (AD). The proposed studies are focused to determine the molecular mechanisms by which Tat induces disassembly of v- ATPase and the extent to which Tat-induced disassembly of v-ATPase contributes to AD-like pathogenesis. The results are expected to provide us with new targets and rationale for preventative and therapeutic interventions against HAND and AD. Thus, the outcome of the proposed studies could have a substantial impact economically, socially and clinically.
