DESCRIPTION (provided by applicant): 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, GSK3β and others contribute to the phosphorylation of Tau. Likewise, dysregulation of phosphatases including protein phosphatase 1-α (PP1α) 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, PP1α and mediates AKT and GSK3β kinases activities. Tat increases PINCH expression in neurons and disrupts PINCH's normal control of kinases and phosphatases. Moreover, Tat binds directly to PP1α 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.