We propose to employ a naturally occurring, experimentally reproducible feline model of retrovirus-induced acquired immunodeficiency syndrome to identify the viral genetic determinants and cellular pathogenetic mechanisms responsible for retrovirus-induced AIDS. We have identified a variant feline leukemia virus (FeLV-FAIDS) that induces fatal immunodeficiency syndrome in 100% of experimentally infected specific-pathogen-free cats after incubation periods of 3 months to over 1 year depending on the age of the cats at time of inoculation. Experimental FAIDS, like the natural feline and human diseases, is characterized by viremia, lymphopenia, progressive weight loss, terminal lymphoid depletion preceded by lymphoid hyperplasia, chronic intractable diarrhea, and opportunistic infections such as oral thrush. We have identified a strong correlation between the presence of a characteristic FeLV-FAIDS variant often manifested as high levels of unintegrated viral DNA in bone marrow and the development immunodeficiency. Moreover, the appearance of the FAIDS variant in marrow prefigures the onset of AIDS in asymptomatic animals. We propose here to identify the lymphocytopathic and immunosuppressive determinants of the FeLV-FAIDS by molecularly cloning and sequencing the common and variant form FeLV-FAIDS genomes, identifying regions of sequence divergence between FeLV-FAIDS and cloned, genomes of non-pathogenic FeLV's. To further pinpoint genetic sequences crucial to the pathogenicity of the feline AIDS virus, we will construct recombinant viruses between FeLV-FAIDS and a prototype non-pathogenic FeLV. Chimeric viruses will then be assessed in vitro for cytopathicity in feline lymphoid and hemopoietic colony forming assays and in vivo for capacity to induce FAIDS in inoculated specific-pathogen-free cats. In cats infected with pathogenic molecularly cloned FeLV-FAIDS, we will employ immunofluorescence and molecular hybridization techniques to examine prospectively the sequential emergence and target tissue tropism of the feline AIDS retrovirus variant during the prodromal and early stages of feline AIDS and will correlate its presence with morphologic evidence of lymphoid tissue cytopathicity. We will also employ a concise panel of immune function assays in FeLV-FAIDS infected cats immunized with a standardized antigen to examine prospectively the evolution and nature of the immunologic deficit in feline AIDS infected with FeLV-FAIDS and immunized with single standard antigen. Data from these studies will be directly pertinent to understanding of the early pathogenesis, diagnosis, and therapy of immunosuppressive human retrovirus infections.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043216-02
Application #
3185282
Study Section
Experimental Virology Study Section (EVR)
Project Start
1986-08-01
Project End
1989-07-31
Budget Start
1987-08-01
Budget End
1988-07-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Type
Schools of Veterinary Medicine
DUNS #
112617480
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Quackenbush, S L; Mullins, J I; Hoover, E A (1996) Replication kinetics and cell tropism of an immunosuppressive feline leukaemia virus. J Gen Virol 77 ( Pt 7):1411-20
Quackenbush, S L; Dean, G A; Mullins, J I et al. (1996) Analysis of FeLV-FAIDS provirus burden and productive infection in lymphocyte subsets in vivo. Virology 223:1-9
Ghosh, A K; Mullins, J I (1995) cDNA encoding a functional feline liver/bone/kidney-type alkaline phosphatase. Arch Biochem Biophys 322:240-9
Fontenot, J D; Tjandra, N; Ho, C et al. (1994) Structure and self assembly of a retrovirus (FeLV) proline rich neutralization domain. J Biomol Struct Dyn 11:821-36
Reinhart, T A; Ghosh, A K; Hoover, E A et al. (1993) Distinct superinfection interference properties yet similar receptor utilization by cytopathic and noncytopathic feline leukemia viruses. J Virol 67:5153-62
Fontenot, J D; Tjandra, N; Bu, D et al. (1993) Biophysical characterization of one-, two-, and three-tandem repeats of human mucin (muc-1) protein core. Cancer Res 53:5386-94
Kristal, B S; Reinhart, T A; Hoover, E A et al. (1993) Interference with superinfection and with cell killing and determination of host range and growth kinetics mediated by feline leukemia virus surface glycoproteins. J Virol 67:4142-53
Fontenot, J D; Hoover, E A; Elder, J H et al. (1992) Evaluation of feline immunodeficiency virus and feline leukemia virus transmembrane peptides for serological diagnosis. J Clin Microbiol 30:1885-90
Diehl, L J; Hoover, E A (1992) Early and progressive helper T-cell dysfunction in feline leukemia virus-induced immunodeficiency. J Acquir Immune Defic Syndr 5:1188-94
Ghosh, A K; Bachmann, M H; Hoover, E A et al. (1992) Identification of a putative receptor for subgroup A feline leukemia virus on feline T cells. J Virol 66:3707-14

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