FELINE IMMUNODEFICIENCY VIRUS LTR MUTANTS INFECTION

  • Sparger, Ellen Elizabeth (PI)

Project: Research project

Project Details

Description

The objective of this proposal is to characterize the role of the LTR in
the establishment of virus load in cats infected with the relatively
virulent FIV-pPPR. Infection of naive cats with molecularly cloned
FIV-pPPR results in a productive virus infection with altered CD4+: CD8+
T-cell ratios within 17 months of infection. FIV-pPPR has been found to
replicate in primary feline PBMC, primary feline blood-derived
macrophages, and feline T-cells. The promoter function of the LTR of
FIV-pPPR have been characterized and found to be activated through
specific regulatory domains (i.e., AP-1 and ATF sites) by multiple
cell-signaling pathways including the protein kinase C and the protein
kinase A pathways. The role of regulatory regions within the FIV LTR in FIV replication will
be assessed with infectious FIV-pPPR proviruses containing site-directed
mutations and deletions in the U3 domain of the LTR. Replication of
these LTR mutant viruses will be tested in feline T-cell lines, primary
feline PBMC, and primary feline macrophages. Replication of FIV LTR
mutant viruses in primary feline PBMC and macrophages in varying
activation states as well as resting states will also be assessed.
Replication of FIV-pPPR LTR mutant viruses will be tested in vivo by
infection of specific pathogen free cats and assessment of virus load in
inoculated cats. Virus load will be assessed in PBMC and peripheral
lymph nodes sampled from infected cats by semi-quantitative analysis of
viral DNA and viral RNA by polymerase chain reaction. Infected cats will
be assessed for virus load and for clinical pathological alterations
(i.e., CD4+ and CD8+ T-cell counts) during early infection and in later
stages of infection. Infectious LTR mutant viruses with which infection
is characterized by a significantly reduced virus load, will be assessed
in pilot studies as potential vaccines. The opportunity for direct assessment of viral determinants of
pathogenesis of disease in vivo is provided by animal models such as FIV.
FIV infection in cats presents with immune deficits and CD4+ T-cell
depletion very similar to those observed in humans infected with HIV.
Because of the accessibility of cats, the FIV model provides an
economically feasible working animal model for dissection of the
molecular pathogenesis of lentivirus-induced immunodeficiency, testing
novel vaccine strategies, and testing of therapeutic agents targeting
specific viral determinants.
StatusFinished
Effective start/end date7/15/936/30/98

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)

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