HYPOTHESIS: The purpose of this study is to test the hypothesis that virally encoded immunomodulatory genes play a role in cytomegalovirus (CMV)-related hearing loss. OBJECTIVE: Cytomegalovirus is the leading cause of infectious-related congenital sensorineural hearing loss worldwide. Unfortunately, little is known about the pathophysiology of CMV-related injury to the developing ear. METHODS: Viral mutagenesis techniques were developed that allow the deletion of a specific viral immunomodulatory gene, macrophage inflammatory protein (MIP) 1α homolog. We assessed the extent to which this gene product contributed to auditory pathologic findings in the guinea pig (GP) model. Eighteen weanling GPs (250-350 g) were used under an Institutional Animal Control and Use Committee-approved protocol. We analyzed preinoculation hearing using auditory brainstem response recordings. Intracochlear inoculations were performed on one group of six GPs with sterile viral media, 6 GPs with wild-type (WT) CMV virus, and 6 GPs with mutant "knockout" (KO) virus (with deleted MIP-1α homolog). Auditory brainstem responses were then obtained on postinoculation Days 7, 14, 21, and 28. RESULTS: There was a significant difference in hearing between the KO group and the WT group, with significantly better hearing in the KO group. A comparison of the KO group to the sham group revealed no significant hearing differences between the groups. The WT group had significant threshold shifts by dose at all frequencies meeting our criteria of hearing loss (>30 dB). There were no statistical differences in the sham or KO group. CONCLUSION: Virally encoded immunomodulatory genes such as MIP-1α seem to play a significant role in CMV-related hearing loss. This study is the first demonstration of the role of specific viral immune modulation genes in the in vivo pathogenesis of CMV-induced hearing loss in a relevant animal model.