MOLECULAR BASIS OF RETROVIRUS INDUCED NEUROLOGIC DISEASE

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Human retroviruses, such as HIV-1, are an important and growing cause of central nervous system (CNS) disease. Intensive studies over the past ten years have successfully defined the clinical symptoms and neuropathology of these infections, but have failed to elucidate the molecular basis for these effects. In view of the inherent difficulties of obtaining and working with retrovirus infected human CNS tissue several animal models have been developed. Our laboratory has isolated and molecularly defined isolates of murine leukemia virus (MuLV) that display well defined CNS tropism and neuropathology. This proposal focuses on the further dissection of MuLV within the TR-MuLV subfamily. TR-MuLV are uniformly tropic for cerebral vessel endothelial cells (CVEC), and may establish either benign infection, or chronic to acute neuropathology which is regulated by a single nucleotide substitution within the envelope gene. These molecular changes are linked to the expression of a syncytium (SI) versus non-syncytium inducing (NSI) phenotype within CVEC. TR-MuLV are an excellent model for analysis of the events of retrovirus entry and pathology within the CNS, and more specifically, present an exciting system of in vivo and in vitro syncytium formation. The goal of this proposal is to elucidate the molecular events that regulate retrovirus dependent syncytium formation and neurologic disease. This goal will be achieved through completion of the following specific aims: Aim 1. TO EXAMINE COMMON MECHANISMS OF CELL-TO-CELL AND VIRUS FUSION WITHIN MULV FAMILIES Aim 2: TO DETERMINE THE MECHANISM WHEREBY CHANGES IN ENVELOPE SU MEDIATE ENHANCED CELL FUSION Aim 3: TO DETERMINE THE REGULATION OF SYNCYTIUM FORMATION BY THE mCAT-1 ECOTROPIC RECEPTOR Aim 4. TO DETERMINE THE IMPACT OF RETROVIRUS INFECTION ON ENDOTHELIAL CELL FUNCTION