The overall goal of this project is to extend preliminary studies designed to develop the feline immunodeficiency virus (FIV) system as a relevant and practical experimental animal model of naturally occurring lentivirus-induced immunodeficiency -- a model both relevant to HIV progression and pathogenesis and suited to experimental pathogenesis, therapy, and vaccine studies in a compressed time frame in an accessible nonendangered species. To this end, a subset of 7 rapid/high phenotype in-vivo propagated virus isolates have been isolated from over 20 FIV field strains recovered from naturally infected cats with symptoms of immunodeficiency. Results from preliminary serial In vivo passage studies with these viruses have produced high expression infection manifested by cell-tree and cell-associated viremia, CD4 cell depletion, immune dysfunction, and clinical signs of immune dysfunction within a 3 to 4 month period. We propose here to: (1) characterize the parameters of infection and immune deficits induced by FIVs by serial assay of quantitative parameters of virus burden, immune function, and clinical disease Induction in prospective studies in specific pathogen free cats; (2) determine the genetic diversity among env genes during the natural course of in vivo-propagation of these FIV isolates and through these analyses to correlate virus genotype and env gene radiation with disease induction and progression; (3) clone molecularly defined pathogenic FIV genotypes and assess in vitro biologic activity and in vivo pathogenicity of phenotypically diverse viruses in cats; and (4) to elucidate the cell and tissue tropism of FIV in vivo by use of in situ hybridization to detect viral RNA-bearing cells, immunohistochemistry to define viral protein producing cells, and assess provirus burden via quantitative PCR on sorted serially diluted blood and lymphoid cell phenotypes. This information should reveal significant information about the pathogenesis of FIV infection, it also should provide definitive information regarding the relevance and utility of the FIV infection as an experimental model of HIV infection, and in the process provide lead insights into HIV pathogenesis and immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033773-02
Application #
2068828
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1993-01-01
Project End
1997-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
112617480
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Lehman, Tracy L; O'Halloran, Kevin P; Hoover, Edward A et al. (2010) Utilizing the FIV model to understand dendritic cell dysfunction and the potential role of dendritic cell immunization in HIV infection. Vet Immunol Immunopathol 134:75-81
Lehman, Tracy L; O'Halloran, Kevin P; Fallon, Samantha A et al. (2009) Altered bone marrow dendritic cell cytokine production to toll-like receptor and CD40 ligation during chronic feline immunodeficiency virus infection. Immunology 126:405-12
Sprague, Wendy S; Robbiani, Melissa; Avery, Paul R et al. (2008) Feline immunodeficiency virus dendritic cell infection and transfer. J Gen Virol 89:709-15
Avery, Paul R; Lehman, Tracy L; Hoover, Edward A et al. (2007) Sustained generation of tissue dendritic cells from cats using organ stromal cell cultures. Vet Immunol Immunopathol 117:222-35
Webb, Craig; Bedwell, Cathy; Guth, Amanda et al. (2006) Use of flow cytometry and monochlorobimane to quantitate intracellular glutathione concentrations in feline leukocytes. Vet Immunol Immunopathol 112:129-40
de Rozieres, Sohela; Mathiason, Candace K; Rolston, Matthew R et al. (2004) Characterization of a highly pathogenic molecular clone of feline immunodeficiency virus clade C. J Virol 78:8971-82
Avery, Paul R; Hoover, Edward A (2004) Gamma interferon/interleukin 10 balance in tissue lymphocytes correlates with down modulation of mucosal feline immunodeficiency virus infection. J Virol 78:4011-9
Burkhard, Mary Jo; Mathiason, Candace K; O'Halloran, Kevin et al. (2002) Kinetics of early FIV infection in cats exposed via the vaginal versus intravenous route. AIDS Res Hum Retroviruses 18:217-26
Burkhard, M J; Mathiason, C K; Bowdre, T et al. (2001) Feline immunodeficiency virus Gag- and Env-specific immune responses after vaginal versus intravenous infection. AIDS Res Hum Retroviruses 17:1767-78
Frey, S C; Hoover, E A; Mullins, J I (2001) Feline immunodeficiency virus cell entry. J Virol 75:5433-40

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