Aged HIV+ individuals represent a large proportion of the HIV population as lifespans are extended significantly by successful anti-retroviral medications. However, increased age in the presence of HIV infection creates a unique set of central nervous system complications that include more rapid onset and progression of age- related diseases, loss of protein quality control and accumulation of aberrant proteins. One such protein that accumulates in the brain in neurodegenerative diseases like HIV encephalitis and Alzheimer's is hyperphosphorylated Tau (hpTau). Accumulation of hpTau causes neuronal dysfunction that can lead to cognitive impairments. Aberrant activation of kinases such as integrin linked kinase (ILK), AKT, GSK3? and others contribute to the phosphorylation of Tau. Likewise, dysregulation of phosphatases including protein phosphatase 1-? (PP1?) and integrin linked associated phosphatase (ILKAP) prevent de-phosphorylation of Tau. Although the mechanisms for this are unclear, it is known that the HIV protein Tat induces hpTau formation. Tat is produced in the brain during HIV infection and enters into neurons where it alters signaling of the kinases and phosphatases involved in Tau phosphorylation. In this context, we have discovered a protein called PINCH that binds ILK, PP1? and mediates AKT and GSK3? kinases activities. Tat increases PINCH expression in neurons and disrupts PINCH's normal control of kinases and phosphatases. Moreover, Tat binds directly to PP1? and competes with ILKAP for cell survival signaling. Our new studies show that in HIV patients' brains and cerebrospinal fluid, PINCH and hpTau increase significantly and bind to one another. Cell culture and mouse models of HIV confirm these findings. However, if we block PINCH expression in the presence of Tat, less hpTau is detected. These data led us to hypothesize that in HIV infection, Tat disrupts the normal functions of the PINCH pathway leading to increased hpTau and neuronal dysfunction. We propose 3 Specific Aims to test our hypothesis at biochemical, behavioral, and neuropathological levels that link with clinical parameters in HIV patient populations. The goal of these studies is to link biochemical pathways to our findings in HIV patient populations. These results may open new directions to study HIV-associated tauopathy and will provide opportunities for therapeutic interventions in age- and disease-related pathologies.

Public Health Relevance

A large proportion of the HIV-infected population is over 50 years of age. Increased age in the presence of HIV infection brings a unique set of central nervous system complications that include more rapid brain disease such as accumulation of hyperphosphorylated Tau (hpTau). We have discovered that in HIV infection, the viral protein Tat disrupts the normal functions of PINCH protein signaling leading to increased hpTau in the brain. Since inhibiting PINCH decreases hpTau accumulation, we will investigate biological consequences of manipulating PINCH levels in cell culture, mouse models and link this with clinical findings in HIV patients' brains.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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NeuroAIDS and other End-Organ Diseases Study Section (NAED)
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Rao, Vasudev
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Temple University
Schools of Medicine
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Natarajaseenivasan, Kalimuthusamy; Cotto, Bianca; Shanmughapriya, Santhanam et al. (2018) Astrocytic metabolic switch is a novel etiology for Cocaine and HIV-1 Tat-mediated neurotoxicity. Cell Death Dis 9:415
Liu, Charles; Russin, Jon; Heck, Christianne et al. (2017) Dysregulation of PINCH signaling in mesial temporal epilepsy. J Clin Neurosci 36:43-52