Program Director/Principal Investigator (Last, First, Middle): Hauser, Kurt F. & Knapp, Pamela E. HIV-associated neurocognitive disorder (HAND) remains a serious clinical problem even in patients receiving cART, and HIV-infected persons who abuse opiates are at greater risk for HAND. Opiates can act directly via µ-opiate receptors (MOR) on glia to amplify secondary neurotoxic effects. The concept that damage to oligodendroglia (OLs) adds to neurologic deficits in HIV is largely unexplored, even though white matter deficits occur quite early after infection. Importantly, our experimental work shows that OLs are vulnerable to viral protein or HIV exposure. A 7 d co-exposure of transgenic mice to HIV-1 Tat ± morphine damages OLs, which exhibit cytoarchitectural/ultrastructural anomalies, and elevated caspase-3 and TUNEL expression, the latter indicating OL death (69; Fig 1). OLs are the only CNS cell type that die in situ in response to acute Tat and morphine coexposure. In vitro, Tat kills developing OLs, while mature OLs instead show a loss of myelin membrane; both outcomes are related to Ca2+- and GluR-mediated mechanisms (84). OL damage, in addition to vascular/blood brain barrier damage, would contribute to myelin pallor consistently noted in imaging studies. Our central hypothesis is that HIV-1 Tat interacts with opiates to directly injure MOR-expressing OLs. Since immature OLs express MOR and are preferentially vulnerable to HIV/Tat, we predict that myelin repair processes are especially vulnerable. Herein, we propose a comprehensive morphological and functional assessment of the time course of OL and myelin damage caused by acute and chronic (≤3 month) HIV/Tat and morphine coexposure. Opiate exposure is intermittent to better model the exposure of injection drug users (IDUs) who contract HIV. Studies are done in both sexes, as myelination is influenced by sex steroids. The central hypothesis is tested in 3 related aims. Aim 1 develops a thorough picture of opiate-related OL and myelin damage in situ using an HIV-1 Tat model. Function is assessed using electrophysiology; damage to white matter tracts and OLs is assessed by histology, high resolution DT-MRI and tractography/connectivity, stereology, and electron microscopy. Vascular changes as assessed by blood-brain barrier leakiness are monitored histologically and correlated with areas of demyelination. In Aim 2, MOR is deleted from OLs to test whether opiate interactions occur via direct actions on OLs in vivo; the direct effects of morphine ± HIV, Tat and gp120 on MOR-expressing, human OLs are compared in vitro. Aim 3 tests structural and functional recovery after morphine is withdrawn. These comprehensive studies answer critical questions about OL/myelin vulnerability and the potential for their recovery after combined HIV/Tat and opiate insults. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page