Retroviruses, like other RNA viruses, exist in nature not as a single genomic species, but as a complex mixture of closely related genomes. During infection in the natural host, the virus population is continually shaped by selective forces. Minor genomic variations may significantly alter the virus phenotype, and thus provide the substrate on which selective pressures act. Our understanding of the aspects of virus phenotype that drive selection in natural retroviral infection is limited. Feline leukemia virus (FeLV) is an excellent model with which to explore the selective pressures operative in natural retroviral infection because FeLV is a naturally occurring retrovirus endemic in an outbreeding mammalian species, the domestic cat. FeLV is a genetically complex family of viruses, infection with which is associated with clinically variable outcome. In these respects, FeLV infection emulates viral infection in humans. In previous studies, a unique FeLV isolate, termed FeLV-945, was identified in non-thymic lymphomas of the multicentric type. FeLV-945 contains unique sequence elements that are precisely conserved among independent isolates in a geographic cluster. Based on the results of preliminary studies, specific mechanisms are hypothesized that may account for the precise conservation and apparent phenotypic advantage of FeLV-945. Specifically, it is hypothesized that the distinctive structural features of FeLV-945 confer a selective growth advantage to the virus in vivo, and/or a survival advantage to the infected cell. To test this possibility, virus replication will be quantified in infected tissues longitudinally during infection, and proto-oncogenes activated by FeLV-945 in lymphomas will be identified. It is further hypothesized that a requirement for specific protein binding to the unique sequence elements of the FeLV-945 LTR promotes its precise conservation. This possibility will be tested through a structural and functional analysis of protein binding sites in the unique sequence elements. Finally, it is hypothesized that the unique sequence elements of FeLV-945 SU confer a selective phenotypic advantage in altered receptor interactions and/or growth kinetics. This possibility will be tested using a novel single-cycle infection assay. The results will be considered in the context of the range of FeLV variation in natural multicentric lymphomas.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA083823-05S1
Application #
7285528
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Cole, John S
Project Start
2000-02-28
Project End
2007-06-30
Budget Start
2004-02-01
Budget End
2007-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$75,000
Indirect Cost
Name
Tulane University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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Bolin, Lisa L; Ahmad, Shamim; Lobelle-Rich, Patricia A et al. (2013) The surface glycoprotein of feline leukemia virus isolate FeLV-945 is a determinant of altered pathogenesis in the presence or absence of the unique viral long terminal repeat. J Virol 87:10874-83
Bolin, Lisa L; Ahmad, Shamim; Levy, Laura S (2011) The surface glycoprotein of a natural feline leukemia virus subgroup A variant, FeLV-945, as a determinant of disease outcome. Vet Immunol Immunopathol 143:221-6
Bolin, Lisa L; Levy, Laura S (2011) Viral determinants of FeLV infection and pathogenesis: lessons learned from analysis of a natural cohort. Viruses 3:1681-98
Bolin, Lisa L; Chandhasin, Chandtip; Lobelle-Rich, Patricia A et al. (2011) Distinctive receptor binding properties of the surface glycoprotein of a natural feline leukemia virus isolate with unusual disease spectrum. Retrovirology 8:35
Ahmad, Shamim; Levy, Laura S (2010) The frequency of occurrence and nature of recombinant feline leukemia viruses in the induction of multicentric lymphoma by infection of the domestic cat with FeLV-945. Virology 403:103-10
Levy, Laura S (2008) Advances in understanding molecular determinants in FeLV pathology. Vet Immunol Immunopathol 123:14-22
Johnson, C; Marriott, S J; Levy, L S (2007) Overexpression of p101 activates PI3Kgamma signaling in T cells and contributes to cell survival. Oncogene 26:7049-57
Finstad, Samantha L; Rosenberg, Naomi; Levy, Laura S (2007) Diminished potential for B-lymphoid differentiation after murine leukemia virus infection in vivo and in EML hematopoietic progenitor cells. J Virol 81:7274-9
Johnson, Chassidy; Lobelle-Rich, Patricia A; Puetter, Adriane et al. (2005) Substitution of feline leukemia virus long terminal repeat sequences into murine leukemia virus alters the pattern of insertional activation and identifies new common insertion sites. J Virol 79:57-66

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