Human immunodeficiency virus (HIV) has an extraordinary survival advantage, confounding existing therapies. With a short generation time, variable antigenicity, and a large number of infective virions, it is hardly surprising that despite the development of anti-viral pharmaceutical compounds, we have managed to only delay the onset of the fatal acquired immunodeficiency syndrome (AIDS). Novel antiviral therapy, specifically the insertion of genes which endow lymphohematopoietic cells with life-long protection against lentivirus infections offers a fresh approach to combating HIV infection. To date, the utility of this therapy has been hampered by the small number of hematopoietic stem cells available for transfection. We are poised to overcome these impediments by using a virtually limitless source of fetal hematopoietic cells (FHC) which are rich in immunologically-naive stem cells. By increasing the cell target numbers for transfection and transplantation we will be able to more rapidly determine the efficacy of stem cell gene therapy for treatment lentivirus infection. The animal model system we will employ is the feline immunodeficiency virus (FIV) in cats. FIV is a naturally-occurring retrovirus of domestic cats that provides valuable resources for understanding mechanisms of pathogenesis and for development of effective antiviral therapy and vaccines with direct relevance to HIV. The current proposal is to develop ribozyme based antiviral gene therapy against FIV infection in cats by targeting the regulatory gene rev and its cognate recognition sequences, rev response element (RRE), which are critical for virus replication. Antiviral sequences against rev and RRE will be delivered into cats using retroviral vectors by way of FHC. The long term goal of this research is to use this animal-model of HIV infection to determine whether decreasing retrovirus burden by myeloablation of a life-long source of blood cells, which are prophylactically protected against retrovirus infection, might provide a new therapy for individuals infected with HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042563-04
Application #
6373785
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Miller, Roger H
Project Start
1998-07-01
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
4
Fiscal Year
2001
Total Cost
$259,948
Indirect Cost
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Carreno, Abigail D; Mergia, Ayalew; Novak, Janelle et al. (2008) Loss of naive (CD45RA+) CD4+ lymphocytes during pediatric infection with feline immunodeficiency virus. Vet Immunol Immunopathol 121:161-8
Novak, Janelle M; Crawford, P Cynthia; Kolenda-Roberts, Holly M et al. (2007) Viral gene expression and provirus load of Orf-A defective FIV in lymphoid tissues and lymphocyte subpopulations of neonatal cats during acute and chronic infections. Virus Res 130:110-20
Kolenda-Roberts, Holly M; Kuhnt, Leah A; Jennings, Ryan N et al. (2007) Immunopathogenesis of feline immunodeficiency virus infection in the fetal and neonatal cat. Front Biosci 12:3668-82
Johnson, Calvin M; Gengozian, Nazareth; Mergia, Ayalew (2004) Hematopoiesis in the feline fetal liver: an assessment by flow cytometry. Vet Immunol Immunopathol 99:53-62
Norway, R M; Crawford, P C; Johnson, C M et al. (2001) Thymic lesions in cats infected with a pathogenic molecular clone or an ORF-A/2-deficient molecular clone of feline immunodeficiency virus. J Virol 75:5833-41
Crawford, P C; Papadi, G P; Levy, J K et al. (2001) Tissue dynamics of CD8 lymphocytes that suppress viral replication in cats infected neonatally with feline immunodeficiency virus. J Infect Dis 184:671-81
Orandle, M S; Crawford, P C; Levy, J K et al. (2000) CD8+ thymic lymphocytes express reduced levels of CD8beta and increased interferon gamma in cats perinatally infected with the JSY3 molecular clone of feline immunodeficiency virus. AIDS Res Hum Retroviruses 16:1559-71
Park, J; Mergia, A (2000) Mutational analysis of the 5' leader region of simian foamy virus type 1. Virology 274:203-12