The overall goal of our research effort is to define the genetic basis for infection and pathogenesis by particular feline leukemia virus (FeLV) variants. Experiments designed to address this question will be conducted using molecularly cloned FeLVs that we obtained directly from the tissues of cats with fatal immunodeficiency disease. These cloned variants have diverse pathogenicities in vitro and in vivo. The abilities of these variants to induce cytopathic effects (CPE) in a feline T cell line predicts their abilities to induce immunodeficiency disease in cats, thus providing an in vitro assay to study the pathogenic mechanisms of FeLV induced immunodeficiency disease. Several preliminary studies suggest that high levels of replication by immunodeficiency inducing FeLVs contributes to the cytopathic effects of these variants. Our results also suggest that the T cell cytopathic potential of FeLV variants may be determined at the level of transcription, splicing of viral RNA, and processing of the envelope polyprotein precursor. The proposed project will explore whether differences at the level of transcription and/or postranscriptional modification are determinants for the distinct pathogenicities of an immunodeficiency inducing FeLV(61C) and a closely related, but minimally pathogenic FeLV(61E). Viral sequences that determine differences in the cytopathic potential of these FeLVs will be identified. If the pathogenic potential of FeLV variants is determined at the level of transcription, the cellular and/or viral factors that enhance expression of immunodeficiency inducing FeLV variants in feline T cells and their viral responsive sequences will be identified and characterized. Experiments in progress suggest that a defect in the processing of the envelope polyprotein (gp85) may play a role in the delayed kinetics of cell killing by a FeLV variant (61B) that induces immunodeficiency in cats only after a prolonged asymtomatic period. We will pursue studies to precisely identify the viral genetic basis for the defect in processing of 61B and determine if alterations in the processing of the 61B envelope precursor are responsible for attenuation of this variant. The FeLV system offers a unique model in which to study the mechanisms of retroviral induced T cell cytopathicity and immunodeficiency disease using closely related molecularly cloned virus variants. The pathogenicity of these viruses have been characterized in their natural host, and several variants that induce feline immunodeficiency as well as FeLVs that do not induce immunodeficiency have been identified. In addition, an in vitro assay has been developed that predicts the ability of FeLV to induce immunodeficiency in cats. Understanding the mechanism of FeLV induced disease and the relationship of viral genetic variation to pathogenicity should facilitate the design of effective therapies against immunodeficiency inducing retroviruses that can ultimately be tested in this model system.
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