The investigator proposes to use mucosal feline immunodeficiency virus (FIV) infection as a model to study the earliest stages of HIV/lentivirus pathogenesis and evaluate means to tip the initial virus:host balance in favor of the host. Building upon findings from the original grant period they will address four major issues which are difficult to resolve in HIV-infected people. 1) The first aim will define the pathway of entry by identifying the earliest target cells in the mucosal and regional lymph nodes during the first hours following vaginal, rectal and oral exposure of cats to pathogenic FIV. 2) The second aim will examine if early immune modulation toward a type 1 cytokine profile will alter progression of mucosal FIV infection. Characterization of cytokine mRNA expression in purified lymph node cell phenotypes will evaluate the ability of treatments designed to drive a type 1 response to alter cytokine profiles and disease progression. 3) The third aim will evaluate if selective pressure on the FIV genome over time are a function of env sequence subtype. Viral env and gag sequences will be studied in sequential PBMC and regional lymph node biopsies after mucosal and parenteral transmission of FIV subtypes A, B and C to determine the frequencies of synonymous and nonsynonymous substitutions. 4) Finally the investigator will use clone feline CCR5 and CXCR4 genes and clinical and cell culture adapted FIV isolates from clades A, B, and C to address the hypothesis that in vivo passaged isolates of FIV employ primarily a CC-chemokine receptor whereas lab culture adapted strains often employ CXC receptors and mucosal entry and initial virus expansion is determined by the receptor repertoire on mucosal cell phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033773-07
Application #
2856011
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Program Officer
Plaeger, Susan F
Project Start
1993-01-01
Project End
2001-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Type
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

Showing the most recent 10 out of 22 publications