The overall objective of this work is to employe feline leukemia virus- induced immunodeficiency syndrome as a model to study the molecular mechanisms of immunosuppression produced by retroviruses. We have identified a naturally occurring strain of feline leukemia virus (FeLV- FAIDS) which induces immunodeficiency disease in virtually all inoculated cats. By restriction site mapping molecular cloning, DNA sequence analysis, and in vitro and in vivo analysis of constructed viral chimeras, we have identified the immunodeficiency disease-inducing component of FeLV-FAIDS to be a replication defective major variant genome (clone 61C is the prototype), which coexisted with a genetically closely related, highly replication competent but apathogenic common from viral genome (clone 61C s the prototype), which coexisted with a genetically closely related, highly replication competent but apathogenic common form viral genome (clone 61E is the prototype). The essential pathogenic determinant of the FeLV-FAIDS variant genome is contained within a 7 amino acid segment near the C-terminus of the envelope glycoprotein (gp70) gene. Here we propose to extend these studies to define the biochemical, immunologic, and genetic features which distinguish the gp70 of the pathogenic clone 61C from that of clone 61E. The location and type of oligosaccharide side chains and disulfide bridges will be determined. Whether unique structural alterations in the 61C gp70 impart unique antigenic properties will be determined by using monoclonal antibodies to 61C/61E gp70 sequences. Peptides and reactive antibodies will be analyzed for their capacity to block viral infectivity and cell killing. We will also seek to identify the viral target call receptor(s) and genes, characterize the kinetics of gp70 receptor interaction, and determine the effect of viral infection on receptor processing and expression. Finally, to gain insight into the pathogenetic mechanisms involved in the evolution of the progressive and fatal immunologic deficit induced by FeLV-FAIDS in vivo, we will study the target cells for the 61C and 61E viruses in SPF cats inoculated with thee viruses. Newly developed monoclonal antibodies will be employed to segregate the feline homologues of the human CD4, CD8, and pan T lymphocyte subsets for in vitro studies of viral susceptibility and cytopathicity, to identify the feline lymphocyte subsets which are the targets for viral infection and cytopathic depletion in vivo, and to investigate the nature and evolution of functional immunologic deficits produced by FeLV-FAIDS.
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