Combined antiretroviral therapy has increased dramatically the life span of HIV-1 infected individuals, but damaging effects of HIV-1 persist throughout the nervous system, and the prevalence of HIV-1 associated neurocognitive disorder (HAND) is greater than 50% of HIV-1 infected people in the USA. Our long-term goal is to understand the pathogenesis of HAND and develop therapeutic interventions. The proposed studies are focused to determine the novel endolysosome-dependent mechanisms whereby HIV-1 transactivator of transcription protein (HIV-1 Tat) contributes to the development of HAND. Our central hypothesis is that HIV-1 Tat induces synaptic disruption and neuronal injury by elevating endolysosome pH and activating a novel endolysosome-dependent calcium regulatory mechanism. Guided by our preliminary findings, this novel hypothesis will be tested by pursuing three specific aims. (1) Determine, in vitro, the extent to which HIV-1 Tat activates a novel endolysosome-dependent calcium regulatory mechanism. (2) Determine, in vitro, the extent to which the above endolysosome-dependent calcium regulatory mechanism underlies HIV-1 Tat-induced neuronal injury. (3) Determine, in vivo, the extent to which the above endolysosome mechanism contributes to disrupted synaptic integrity in HIV-1 Tat transgenic mice. Our results are expected to demonstrate that endolysosomes play a critical role in HIV-1 Tat-induced synaptic disruption and neuronal cell death through a novel endolysosome-dependent calcium regulatory mechanism that is upstream of previously described effects of HIV-1 Tat. Such results are expected to link together unified mechanisms causing early pathological features of HAND. Results from this work will lead to a greater understanding of HAND pathogenesis and the possible development of new therapeutics.
The proposed research is relevant to public health, because the prevalence of human immunodeficiency virus (HIV)-1 associated neurocognitive disorder (HAND) is greater than 50% of HIV-1 infected people in the USA. The proposed studies are focused to determine the extent to which Tat, an HIV-1 viral protein, activates novel endolysosome-dependent calcium regulatory mechanisms that contribute to synaptic loss and neurotoxicity, and results of these studies are expected to provide us with new targets and rationale for preventative and therapeutic interventions against HAND. Thus, the proposed research is highly relevant to the mission of this particular funding opportunity announcement (PA-11-041) of NIH, whose stated purpose is to define the pathogenic mechanisms involved in HAND and identify therapeutic strategies to treat and prevent the neurobehavioral and neurological effects of HIV-1 on the central nervous system.
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