A vaccine is urgently needed to prevent HIV transmission and AIDS in children born to the rapidly increasing number of HIV-infected women throughout the developing world. In addition to exposure during gestation and the process of birth, most children of HIV-infected women are exposed daily to HIV in breast milk for many months or even for several years. A vaccine to prevent AIDS in children must be safe to give at birth and must rapidly elicit virus-specific immunity in the presence of maternal antiviral antibodies to protect against the multiple exposures to HIV through breast feeding. HIV vaccines currently being evaluated in adults appear to elicit immunity too slowly to be effective in infants. This proposed project will use the SIV/neonatal rhesus macaque model of human pediatric HIV/AIDS to generate information needed to fill important gaps in developing an HIV vaccine to prevent AIDS in children. Our experiments will test the hypothesis that the protective ability of an anti-HIV/SIV pediatric vaccine is directly related to the speed with which the vaccine can elicit virus-specific immune responses in the primate neonate. The overall goals of the project are (1) to enhance the rate of vaccine induced SIV-specific immune responses in rhesus neonates and, (2) to evaluate the ability of replicating and non-replicating vaccines to generate SIV-specific immunity that can prevent, delay or substantially modify disease in SIV-infected infant macaques. To achieve these goals we propose three Specific Aims. We will determine whether an SIV vaccine regimen administered at birth can: 1) Elicit rapid, protective immunity against oral SIV infection or disease (challenge at 4 weeks of age) in rhesus neonates: a) lacking SIV antibodies or b) with passively acquired SIV antibodies (by injection of SIV hyper-immune serum). 2) Provide long-term protection against oral SIV infection or disease (challenge at 1 year of age).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046320-05
Application #
6649197
Study Section
Special Emphasis Panel (ZRG1-VACC (07))
Program Officer
Black, Roberta J
Project Start
1999-09-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2005-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$548,955
Indirect Cost
Name
University of California Davis
Department
Type
Other Domestic Higher Education
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Abel, Kristina; Pahar, Bapi; Van Rompay, Koen K A et al. (2006) Rapid virus dissemination in infant macaques after oral simian immunodeficiency virus exposure in the presence of local innate immune responses. J Virol 80:6357-67
Van Rompay, Koen K A; Kearney, Brian P; Sexton, Jonathan J et al. (2006) Evaluation of oral tenofovir disoproxil fumarate and topical tenofovir GS-7340 to protect infant macaques against repeated oral challenges with virulent simian immunodeficiency virus. J Acquir Immune Defic Syndr 43:6-14
Greenier, Jennifer L; Van Rompay, Koen K A; Montefiori, David et al. (2005) Simian immunodeficiency virus (SIV) envelope quasispecies transmission and evolution in infant rhesus macaques after oral challenge with uncloned SIVmac251: increased diversity is associated with neutralizing antibodies and improved survival in previously Virol J 2:11
Van Rompay, Koen K A; Abel, Kristina; Lawson, Jonathan R et al. (2005) Attenuated poxvirus-based simian immunodeficiency virus (SIV) vaccines given in infancy partially protect infant and juvenile macaques against repeated oral challenge with virulent SIV. J Acquir Immune Defic Syndr 38:124-34
Van Rompay, Koen K A; Singh, Raman P; Pahar, Bapi et al. (2004) CD8+-cell-mediated suppression of virulent simian immunodeficiency virus during tenofovir treatment. J Virol 78:5324-37
Van Rompay, Koen K A; Singh, Raman P; Brignolo, Laurie L et al. (2004) The clinical benefits of tenofovir for simian immunodeficiency virus-infected macaques are larger than predicted by its effects on standard viral and immunologic parameters. J Acquir Immune Defic Syndr 36:900-14
Pahar, Bapi; Li, Jun; Rourke, Tracy et al. (2003) Detection of antigen-specific T cell interferon gamma expression by ELISPOT and cytokine flow cytometry assays in rhesus macaques. J Immunol Methods 282:103-15
Van Rompay, Koen K A; Greenier, Jennifer L; Cole, Kelly Stefano et al. (2003) Immunization of newborn rhesus macaques with simian immunodeficiency virus (SIV) vaccines prolongs survival after oral challenge with virulent SIVmac251. J Virol 77:179-90
Van Rompay, Koen K A; Schmidt, Kimberli A; Lawson, Jonathan R et al. (2002) Topical administration of low-dose tenofovir disoproxil fumarate to protect infant macaques against multiple oral exposures of low doses of simian immunodeficiency virus. J Infect Dis 186:1508-13
Kern, E R; Rybak, R J; Hartline, C B et al. (2001) Predictive efficacy of SCID-hu mouse models for treatment of human cytomegalovirus infections. Antivir Chem Chemother 12 Suppl 1:149-56