IMMUNE CONTROL OF CAE LENTIVIRUS

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This proposal tests the hypothesis that a focused cell mediated immune response to immunization with a purified lentiviral surface (SU) glycoprotein will control virus replication and disease following challenge infection with homologous and heterologous virus. The research plan is to focus antigen specific T helper (Th) 1 lymphocyte responses by enhancing in vivo production of gamma interferon (IFN gamma) at the time of immunization. A vaccinia virus vector and plasmid DNA expressing IFN gamma cDNA will be evaluated to enhance IFN gamma production in vivo. This plan is based on well documented studies in mice demonstrating that crossregulatory cytokines specify the differentiation of Th1 and Th2 lymphocyte subsets from a common precursor at the time of antigen presentation, overriding the effects of other variables such as antigen dosage and MHC class II genotype. The lentiviral system to be studied is caprine arthritis-encephalitis virus (CAEV) in Saanen goats. The utility of the CAEV model for evaluating the role of Th1 responses to SU in immune control of lentivirus replication and disease is enhanced by preliminary data supporting the following: (1) CAEV infected goats have at least two populations of SU responsive CD4+ T lymphocytes with dichotomous antigen specific proliferative responses and patterns of IFNgamma gene expression analogous to Th1 and Th2 cells. (2) Dominance of CAEV SU responsive Th1 cells is specifically associated with restricted virus load and lack of disease progression. (3) The extent of CAEV replication and disease may be determined by differential activation of SU responsive Th1 or Th2 lymphocyte subsets at or near the time of infection. Thus, the anticipated results of this research will demonstrate the feasibility of using recombinant cytokines to focus antigen specific Th lymphocyte pathways in outbred species and provide an opportunity to directly examine the role of Th1 responses in immune control of a persistent lentivirus infection.