We hypothesized earlier that an effective vaccination strategy against HIV-induced AIDS should focus on priming cell-mediated immunity (CMI) by employing a cocktail of highly conserved epitopes identified to be reactive with multiple MHC haplotypes. Our long-term goal is to formulate a synthetic peptide-based vaccine against HIV because it offers the advantage of being defined, safe and economical. To achieve this goal, we proposed an innovative approach that included employing autologous dendritic cells (DC) for presenting the peptide cocktail and inducing efficient CMI responses for control of infection and pathology by SHIV in a rhesus monkey model. The vaccine consisted of a mixture of six synthetic peptides corresponding to highly conserved regions in the HIV envelope protein gpl60 that we identified in our previous studies, in a series of animal models (murine, rhesus and chimpanzee) and samples from HIV infected people (including long-term nonprogressors), to be capable of inducing HIV-specific CMI responses. The SHIV-rhesus model is best suited for testing the protective efficacy of the peptide-cocktail because, SHIV, a chimeric virus comprised of HIV envelope and SIV core, induces AIDS-like disease in macaques, and thus provides the best alternative for testing HIV env-based vaccines and therapeutics. Our study design for the innovation HIV vaccine proposal involved immunizing rhesus monkeys initially with the peptides in Freund's adjuvant followed later by infusions of peptide-pulsed autologous DC that resulted in efficient induction of proliferative and CTL responses in the vaccinated animals. Importantly, upon challenge with SHIV KU -2, efficient clearance of virus infected cells in circulation and reduction in plasma infectivity were observed in all the vaccinated animals but not in the controls, despite uniform infection in all the monkeys initially. In one of the control monkeys this coincided with a precipitous drop in CD4+ cells to below 50 in three weeks, and signs of wasting by week 34, typical of AIDS. These results serve as proof of the principle for a peptide-based vaccine against HIV. Now, we propose to use the same six-peptide cocktail as a vaccine in combination with autologous DC, as sole adjuvant, for priming protective immunity in the SHIV-rhesus model. Additionally, we propose to adopt the SHIV-rhesus model to test the immunogenicity and efficacy of the six-conserved HIV env peptide cocktail for mucosal vaccination strategies employing adjuvants based on novel bacterial toxins that are modified to eliminate toxicity but retain adjuvant capacity. We obtained pilot data showing the effectiveness of mutated forms of cholera toxin and a hitherto untested cytotoxic enterotoxin from Aeromonos hydrophila, as model mucosal adjuvants for inducing HIV env-specific Th and CTL responses in mice. Finally, we propose to formulate a DNA vaccine, consisting of a cocktail of plasmids with mini-gene constructs encoding the six conserved HIV env peptides, and test immunogenicity and protective efficacy in the SHIV-rhesus model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046969-03
Application #
6511214
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Bradac, James A
Project Start
2000-04-01
Project End
2004-01-14
Budget Start
2002-04-01
Budget End
2004-01-14
Support Year
3
Fiscal Year
2002
Total Cost
$356,375
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Veterinary Sciences
Type
Organized Research Units
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Weaver, Eric A; Nehete, Pramod N; Nehete, Bharti P et al. (2013) Comparison of systemic and mucosal immunization with helper-dependent adenoviruses for vaccination against mucosal challenge with SHIV. PLoS One 8:e67574
He, Hong; Nehete, Pramod N; Nehete, Bharti et al. (2011) Functional impairment of central memory CD4 T cells is a potential early prognostic marker for changing viral load in SHIV-infected rhesus macaques. PLoS One 6:e19607
He, Hong; Courtney, Amy N; Wieder, Eric et al. (2010) Multicolor flow cytometry analyses of cellular immune response in rhesus macaques. J Vis Exp :
Fontenot, Danielle; He, Hong; Hanabuchi, Shino et al. (2009) TSLP production by epithelial cells exposed to immunodeficiency virus triggers DC-mediated mucosal infection of CD4+ T cells. Proc Natl Acad Sci U S A 106:16776-81
Weaver, Eric A; Nehete, Pramod N; Buchl, Stephanie S et al. (2009) Comparison of replication-competent, first generation, and helper-dependent adenoviral vaccines. PLoS One 4:e5059
Courtney, Amy N; Nehete, Pramod N; Nehete, Bharti P et al. (2009) Alpha-galactosylceramide is an effective mucosal adjuvant for repeated intranasal or oral delivery of HIV peptide antigens. Vaccine 27:3335-41
Thapa, Prakash; Zhang, Guodong; Xia, Chengfeng et al. (2009) Nanoparticle formulated alpha-galactosylceramide activates NKT cells without inducing anergy. Vaccine 27:3484-8
Nehete, Pramod N; Nehete, Bharti P; Hill, Lori et al. (2008) Selective induction of cell-mediated immunity and protection of rhesus macaques from chronic SHIV(KU2) infection by prophylactic vaccination with a conserved HIV-1 envelope peptide-cocktail. Virology 370:130-41
Mercier, George T; Nehete, Pramod N; Passeri, Marco F et al. (2007) Oral immunization of rhesus macaques with adenoviral HIV vaccines using enteric-coated capsules. Vaccine 25:8687-701
Sastry, K Jagannadha; Nehete, Pramod N; Nehete, Bharti (2005) Improving the sensitivity of the ELISPOT analyses of antigen-specific cellular immune responses in rhesus macaques. Methods Mol Biol 302:153-66

Showing the most recent 10 out of 14 publications