Role of cellular prion protein in the pathogenesis of NeuroAIDS HIV infection of the central nervous system (CNS) results in the development of a spectrum of neurological complications known as HIV associated neurologic disorders (HAND) in a significant number of individuals. The basis of HAND is not well understood. Although associated with early viral infiltration of the CNS, the number of activated macrophages appears to be a much better indicator of HAND in individuals with HIV rather than viral load, suggesting that dysregulation of adhesion molecules, blood brain barrier (BBB) integrity and leukocyte infiltration and impairment are tightly correlated. The process by which infected monocytes cross the BBB and infiltrate the CNS parenchyma is mediated, in part, by the interactions of a variety of molecules, including adhesion proteins. This inflammatory process is critical to the development of HAND as it brings both infected and uninfected cells into the brain where they activate and infect macrophages/microglia and effect damage to the BBB and other cells within the CNS, including neurons. One such molecule shown to mediate monocyte transmigration across the systemic vasculature is PrPc. However, the role of PrPc in the context of the neuropathogenesis of HIV has not been examined. Our data demonstrate that PrPc expression and release are altered in the brains of HIV-infected individuals with cognitive impairment as compared to uninfected or HIV- infected individuals without cognitive compromise. We also showed PrPc in the brain tissue of macaques infected with SIV. We demonstrated in humans infected with HIV that release of soluble PrPc (sPrPc) into the CSF, but not to the sera, is a biomarker of cognitive decline. These results were independent of viral load, age, gender and CD4 counts. We demonstrated that macrophages, PBMC, monocytes, endothelial cells, neurons and astrocytes release low levels of sPrPc that can be significantly increased by treatment with CCL2 or HIV-infection. Thus, we identified two mediators, HIV and CCL2, that, depending on the cell type analyzed, resulted in release of PrPc. We also demonstrated that sPrPc (sPrPc) is an inflammatory factor that alters secretion of CCL2 and IL-6. It is therefore our hypothesis that HIV infection of the CNS alters PrPc expression and release, resulting in inflammation and subsequent cognitive impairment. Thus, CSF levels of sPrPc are a biomarker of cognitive decline/dementia in individuals infected with HIV. To address this hypothesis we will expand our preliminary data using longitudinal studies of HIV- infected individuals in correlation with cognitive status to examine sPrPc as a biomarker of cognitive impairment in the HIV-infected population, as well as brain tissue sections from individuals with MCMD, HAD and who are infected but cognitively normal. We will also examine the mechanisms of PrPc release and the consequences of the soluble isoform on neuronal survival, astrocyte function and BBB integrity. PUBLIC HEALTH RELEVANCE: HIV infection and HIV neurocognitive impairment are major emerging global health problems. The prevalence of HIV associated neurocognitive disorders (HAND) is increasing as people with AIDS are living longer due to success of antiretroviral therapies. Currently, there are no studies of the role of PrPc, the cellular non pathogenic isoform of the prion protein, in the context of HIV and neurocognitive impairment. We propose that PrPc is a biomarker of cognitive impairment in individuals infected with HIV and that soluble PrPc plays a key role in the pathogenesis of HAND. Our preliminary data demonstrate that PrPc in the CSF of individuals infected with HIV may be a biomarker of cognitive impairment and that soluble PrPc is an inflammatory molecule within the CNS. We will determine whether CSF PrPc in HIV infected individuals can be used as a biomarker of cognitive decline. We will also identify the mechanism by which PrPc is shed/released from CNS cells and the additional consequences of this shed/released protein on CNS function. We propose that PrPc can be a novel target for therapies to reduce HIV CNS impairment.