This grant proposal is submitted in response to the INTEGRATED PRECLINICAL/CLINICAL AIDs VACCINE DEVELOPMENT program [PAR-97-056]. It has been shown repeatedly that infection with attenuated SIV protects monkeys from challenge with virulent SIV. Although live-attenuated HIV vaccines may never be safe enough for clinical use, understanding the mechanism by which attenuated viruses confer protection will provide critical information for use in designing safe and effective HIV vaccines. We have recently demonstrated that animals immunized by vaginal inoculation with attenuated-SHIV 89.6 are protected from vaginal challenge with virulent SIVmac, Appendix A. Animals that had been infected with the attenuated SHIV for more than one year had antiviral cytotoxic T lymphocytes (CTL) and were protected from challenge with virulent SHIV, while those that were infected with the attenuated SHIV for approximately six months did not have detectable CTL and were riot protected. This association between the presence of CTL and the ability to resist superinfection with pathogenic SIV may partially explain the efficacy of attenuated viruses as vaccine in the SIV model, but it is unlikely to be the complete explanation. Although there are numerous questions, including safety, breadth of protection and route of administration, which need to be addressed in regard to attenuated virus vaccines, Project 1 will test two related hypotheses: 1) The type of cells and the anatomic distribution of cells infected with attenuated SHIV 89.6 changes between six and twelve months of infection. 2) This shift in the distribution of the attenuated virus infection produces a fundamental change in the nature of the antiviral immune response. The change in the immune response is manifested by altered helper T and effector T cell responses and by the generation of an environment within lymphoid tissues which is hostile to virus replication. This hostile environment is due to increased expression of antiviral cytokines (IFN- a, IFN-b, IFN-g and TNF) and chemokines (MIP1a, MIPlb and Rantes). We recognize that attenuated virus vaccines may not be acceptable for clinical use and we will use other vaccines to assess and compare the immune responses of those and attenuated virus. Project will test the ability of DNA vaccines to elicit protection from vaginal SIV challenge. We have chosen to focus on DNA immunization because the intracellular expression of the viral genes most closely resembles an attenuated virus infection and because naked DNA may offer a method for delivering an attenuated viral vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044480-05
Application #
6511095
Study Section
Special Emphasis Panel (ZAI1-VSG-A)
Program Officer
Butler, Robert C
Project Start
1998-05-01
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2004-04-30
Support Year
5
Fiscal Year
2002
Total Cost
$797,663
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
Genescà, Meritxell; Ma, Zhong-Min; Wang, Yichuan et al. (2012) Live-attenuated lentivirus immunization modulates innate immunity and inflammation while protecting rhesus macaques from vaginal simian immunodeficiency virus challenge. J Virol 86:9188-200
Genescà, Meritxell; McChesney, Michael B; Miller, Christopher J (2010) Depo-provera treatment does not abrogate protection from intravenous SIV challenge in female macaques immunized with an attenuated AIDS virus. PLoS One 5:e9814
Stone, Mars; Keele, Brandon F; Ma, Zhong-Min et al. (2010) A limited number of simian immunodeficiency virus (SIV) env variants are transmitted to rhesus macaques vaginally inoculated with SIVmac251. J Virol 84:7083-95
Genescà, M; McChesney, M B; Miller, C J (2009) Antiviral CD8+ T cells in the genital tract control viral replication and delay progression to AIDS after vaginal SIV challenge in rhesus macaques immunized with virulence attenuated SHIV 89.6. J Intern Med 265:67-77
Lederer, Sharon; Favre, David; Walters, Kathie-Anne et al. (2009) Transcriptional profiling in pathogenic and non-pathogenic SIV infections reveals significant distinctions in kinetics and tissue compartmentalization. PLoS Pathog 5:e1000296
Favre, David; Lederer, Sharon; Kanwar, Bittoo et al. (2009) Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection. PLoS Pathog 5:e1000295
Stone, Mars; Ma, Zhong-Min; Genescà, Meritxell et al. (2009) Limited dissemination of pathogenic SIV after vaginal challenge of rhesus monkeys immunized with a live, attenuated lentivirus. Virology 392:260-70
Genesca, M; Skinner, P J; Bost, K M et al. (2008) Protective attenuated lentivirus immunization induces SIV-specific T cells in the genital tract of rhesus monkeys. Mucosal Immunol 1:219-28
Genesca, Meritxell; Skinner, Pamela J; Hong, Jung Joo et al. (2008) With minimal systemic T-cell expansion, CD8+ T Cells mediate protection of rhesus macaques immunized with attenuated simian-human immunodeficiency virus SHIV89.6 from vaginal challenge with simian immunodeficiency virus. J Virol 82:11181-96
Genesca, Meritxell; Rourke, Tracy; Li, Jun et al. (2007) Live attenuated lentivirus infection elicits polyfunctional simian immunodeficiency virus Gag-specific CD8+ T cells with reduced apoptotic susceptibility in rhesus macaques that control virus replication after challenge with pathogenic SIVmac239. J Immunol 179:4732-40

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