The long-term goal of this program is to identify the multiple events that interplay in the pathogenesis of lymphoid malignancies in the domestic cat. This outbred species has the highest incidence of leukemia-lymphoma of any animal, and horizontal infection of the naturally occurring feline leukemia virus (FeLV) is responsible for its increased susceptibility to leukemogenesis. Much remains to be discovered for the events that occur during the prolonged viremic period. Current evidence suggests recombinational events between the infectious FeLV and non-infectious endogenously inherited FeLV-like elements which generate highly pathogenic variant viruses. It is likely that the recombinant viral surface glycoproteins which provide recognition of the prospective target cell by the virus may also have independent effect in the same or variant forms on cell proliferation/blastogenesis and cytopathicity. Other factors that contribute to neoplastic disease include the insertionally activated cellular genes such as c-myc and flvi-2 and the gaining of increased strength in transcriptional activity through mutations in viral transcription regulatory elements. Impaired immunologic activity in FeLV- infected cats also has consequences in tumor development. It is proposed to continue the studies on the molecular understanding of the recombinational parameters that dictate target cell tropism, disease specificity, and immunosuppressive properties. Individual recombinant viruses will be molecularly cloned from pathogenic virus mixtures and from selected naturally occurring lymphosarcomas for the scrutiny of their genetic structure, and in vitro and in vivo biological and pathological properties. Experiments have been designed to examine the potential that chimeric viral glycoproteins contribute to pathogenesis by directly or indirectly influencing cell proliferation, differentiation or apoptosis. In addition, appropriate feline lymphosarcoma specimens representing mostly uncharacterized provirus insertion sites have been identified and selected, analysis of which should provide clues to novel genes in FeLV- induced neoplastic disease. These interconnected studies, in combination, should lead to new insights into the pathogenesis of retrovirus-induced lymphoid cancer in an outbred animal species.
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