Mouse retroviruses cause a variety of diseases with varying degrees of similarity to retrovirally-induced conditions in other animal species, including man. In this application a murine retrovirus-induced disease will be used to characterize: 1) novel viral translational products, and their specific roles in the mechanism of viral pathogenesis and 2) protective T-cell immune responses to an immunodominant epitope encoded by these novel viral proteins. The LP-BM5 retroviral isolate includes replication competent helper viruses and a defective virus (BMSdef) that is the direct cause of disease. LP-BM5 retrovirus infection of susceptible mouse strains leads to a dramatic disease syndrome, including a generalized severe immunodeficiency with consequent susceptibility to progressive infection and mortality by opportunistic pathogens, and increased incidence of tumors, particularly terminal B-cell lymphomas. Because of several similarities to AIDS, other investigators have named this syndrome """"""""murine AIDS/MAIDS."""""""" But in addition to sharing certain aspects with AIDS, MAIDS is also a very intriguing disease itself. The pathogenesis of LP-BM5 induced MAIDS is incompletely understood. Our recent studies have concentrated on defining the early cellular and molecular interactions required for establishing disease and the protective antiviral CD8 CTL response. Our novel findings have included demonstrating that the gag gene of BMSdef also encodes a unique +1 NT extended alternative gag open reading frame (ORF2). ORF2 encodes an immunodominant, protective CTL epitope whose identification lead to the discovery of the extended ORF2 that contains it. Extended ORF2 codes for a putative protein of up to 193 amino acids that our recently published mutational analyses have shown is required for induction of MAIDS. Based on these findings, the specific aims are designed to: 1) examine in detail the protective CTL response to this ORF2 encoded immunodominant epitope as a potential model for alternative ORF-derived CDS T cell-defined determinants, and 2) identify and characterize the viral gag ORF2 extended translational product(s): the host or other viral proteins with which they interact, their subcellular location, and their potential organization by functional domains. In addition to further defining the mechanisms of LP-BM5 retroviral pathogenesis and protective immunity in this system, these studies should add to the general understanding of how retroviral encoding of alternative ORF sequences can affect both the immune response and viral pathogenesis. These studies may thus have broad relevance in other retroviral diseases to various aspects of the mechanisms of disease induction and host defense, including vaccine design approaches.
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