A safe efficacious vaccine that prevents the spread of human immunodeficiency virus (HIV) will be essential to arresting the spread of the AIDS epidemic. Studies in non-human primates with simian immunodeficiency virus (SIV) and chimeric HIV/SIV virus (SHIV) have demonstrated that live-attenuated nef-deleted viruses are highly effective; however, such vaccines maintain a low level of pathogenicity. We have established a body of Preliminary Results demonstrating that vaccination of cats with a DNA vaccine containing an feline immunodeficiency virus (FIV) provirus encoding a large deletion within the accessory gene vif will induce immunity protective against infection with wild type FIV. Secondly, other recent studies in non-human primates have shown that co-expression of fusion protein interleukin-2/Ig with DNA vaccines expressing SIVmac239 Gag and HIV-1 Env to enhance protection against clinical disease in vaccinated macaques when challenged with pathogenic SHIV-89.6P. Based on these observations, we hypothesize that the efficacy of a vif-deleted FIV proviral DNA vaccine may be enhanced by co-expression of cytokine genes. FIV mutant proviruses expressing cytokines such as feline interferon-gamma, interleukin-2, or granulocyte- macrophage colony stimulating factor (GM-CSF), will be constructed and tested as attenuated virus DNA vaccines in challenge studies in cats. A second vaccine approach will involve co-inoculation of cats with a FIV deltavif proviral DNA vaccine and a mammalian expression vector encoding an cytokine gene. Lastly, a third approach involving a FIVdeltavif DNA vaccine vector that co-expresses an cytokine gene boosted with a killed whole virus vaccine composed of a heterologous FIV isolate will be characterized for its ability to enhance vaccine efficacy. Importantly, the proposed projects in the FIV/cat model will conduct extensive investigations of antiviral immune responses in DNA vaccinated animals. Thus, it may be possible to identify correlates of protective immunity. Accordingly, knowledge gained in this project from this animal model will provide valuable information for evaluation of DNA vaccines for preventing HIV-1 infection and AIDS in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040896-06
Application #
6510714
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Ahlers, Jeffrey D
Project Start
1997-06-01
Project End
2005-05-31
Budget Start
2002-07-01
Budget End
2003-05-31
Support Year
6
Fiscal Year
2002
Total Cost
$282,150
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Maksaereekul, Saipiroon; Dubie, Robert A; Shen, Xiaoying et al. (2009) Vaccination with vif-deleted feline immunodeficiency virus provirus, GM-CSF, and TNF-alpha plasmids preserves global CD4 T lymphocyte function after challenge with FIV. Vaccine 27:3754-65
Shen, Xiaoying; Leutenegger, Christian M; Stefano Cole, Kelly et al. (2007) A feline immunodeficiency virus vif-deletion mutant remains attenuated upon infection of newborn kittens. J Gen Virol 88:2793-9
Gupta, Soumi; Leutenegger, Christian M; Dean, Gregg A et al. (2007) Vaccination of cats with attenuated feline immunodeficiency virus proviral DNA vaccine expressing gamma interferon. J Virol 81:465-73
Gupta, Soumi; Leutenegger, Christian; Dean, Gregg et al. (2006) Construction and characterization of feline immunodeficiency virus proviral mutants that coexpress interferon gamma and green fluorescent protein. AIDS Res Hum Retroviruses 22:342-9
Gemeniano, Malou C; Sawai, Earl T; Sparger, Ellen E (2004) Feline immunodeficiency virus Orf-A localizes to the nucleus and induces cell cycle arrest. Virology 325:167-74
Gemeniano, Malou C; Sawai, Earl T; Leutenegger, Christian M et al. (2003) Feline immunodeficiency virus ORF-Ais required for virus particle formation and virus infectivity. J Virol 77:8819-30
Lockridge, K M; Chien, M; Dean, G A et al. (2000) Protective immunity against feline immunodeficiency virus induced by inoculation with vif-deleted proviral DNA. Virology 273:67-79