The ability of cytomegalovirus (CMV) to induce sensorineural hearing loss, labyrinthitis and encephalitis in SCID (severe combined immunodeficiency) mutant mice provides a useful model for the auditory system pathologies observed in patients with acquired immune deficiency syndrome (AIDS). Peripheral and central auditory system pathologies are common features of AIDS patients. These sensory system disorders arise primarily from the opportunistic coinfections which develop in these immunocompromised patients, and not from direct infection with the human immuno-deficiency virus (HIV). CMV is by far the most common of these opportunistic pathogens. While CMV retinitis is the most widely recognized sensory system pathology in AIDS, occurring in approximately 45% of all cases, recent data suggest that more than 20% of AIDS patients also experience CMV induced peripheral and central auditory system pathologies. CMV is species-specific, and therefore it has not been possible to develop an animal model using human virus. However, we have recently demonstrated that intrathecal (i.e., CSF) inoculation of SCID) mice with 100 PFU of murine CMV (MCMV) produces labyrinthitis and sensorineural hearing loss at two weeks postinfection which closely resemble human disease. In contrast, comparable inoculations in immunocompetent congenic BALB/c mice do not produce auditory system pathologies. We propose to utilize our SCID/MCVM model to investigate the following basic questions: l) How is the pathogenesis of MCMV labyrinthitis and central nervous system infection different in immunocompetent and immunocompromised mice? 2) What is the role of cell mediated immunity in the development of MCMV infections in the peripheral and central auditory system? 3) How do changes in cytokine, adhesion molecule, integrin and MHC antigen expression relate to MCMV clearance and neuropathogenesis in the auditory system? 4) How closely do the clinical signs of MCMV infections in immunocompromised mice resemble AIDS-associated pathologies of the auditory system in humans? 5) Does the SCID/MCMV model system provide a bioassay to test the efficacy of antiviral therapy? An interdisciplinary approach will be used to investigate the clinical symptoms, immunologic, virologic, histopathologic, molecular biologic and electrophysiologic aspects of MCMV infections within the peripheral and central auditory system of immunodeficient SCID) vs. immunocompetent BALB/c mice.
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