Vaccine development efforts against human immunodeficiency virus type 1 (HIV-1) are hindered by the high mutation rate of the virus, lack of clear understanding of the nature of the protective immunity, and limitations of available animal models for direct testing of HIV antigens for protection. We tested protective efficacy of a highly conserved HIV envelope peptide cocktail vaccine in Indian origin rhesus macaques by taking advantage of the chimeric virus SHIV, that expresses HIV envelope and causes AIDS in this model thereby allowing for direct testing of HIV vaccines based on envelope sequences. The HIV envelope peptides for the vaccine cocktail were selected through a series of studies in multiple animal models and in vitro studies with cells from HIV-infected long-term non-progressors, for broadly cross reactive T cell responses in the context of multiple MHC haplotypes. Since the peptide cocktail vaccine selectively primes cell-mediated immunity (CMI) in the absence of anti-HIV antibody production, it is possible to test protective efficacy of antiviral TH and CTL responses in this model. Three separate vaccine studies were conducted employing a total of 30 macaques for delivering the peptide cocktail vaccine with Freund's adjuvant and/or autologous dendritic cells (DC). Macaques immunized with ex vivo peptide cocktail-pulsed DC exhibited efficient induction of CMI, and upon challenge with pathogenic strains of SHIV (SHIV[ku2] and SHIV[89.6P]) showed significant reduction in viral set point accompanied by undetectable virus in the blood of majority of vaccinated animals. Importantly, no rebounds were observed in the vaccinated monkeys, some followed for over three years. These results strongly support the vaccine potential of the HIV envelope peptide cocktail and the efficiency of DC loaded ex vivo with peptides for priming protective CMI responses. We hypothesize that FIt3-ligand (FL) treatment followed by delivering the vaccine cocktail in the presence of CpG-containing oligodeoxynucleotides (ODN) will be an effective strategy for targeting the vaccine to DC in vivo. Further we propose that this strategy would entail the HIV envelope peptide cocktail to be a viable vaccine approach applicable to humans. We obtained preliminary data supporting FL-mediated mobilization of multiple subsets of DC with immunogenic properties in murine and primate studies. We will test whether FL treatment of macaques followed by vaccination with the HIV envelope peptide cocktail in CpG-ODN would be effective in priming strong CMI and protection against intravenous challenge using SHIV[KU2]. Since the major route of HIV infection is the mucosal epithelium and is predominantly by macrophage-tropic HIV strains, we will also test the effectiveness of the peptide cocktail targeted to DC in vivo using FL-treatment and CpG-ODN followed by mucosal challenge using SHIV[SF162P], (expressing macrophage-tropic HIV envelope). We will also test a mucosal vaccination strategy for delivering the peptide cocktail using a novel mutant cholera toxin (CT2*) that we observed to be a strong adjuvant for priming systemic and mucosal immune responses to several peptide antigens, including the HIV vaccine peptides in mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI046969-04A2
Application #
6745795
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Ahlers, Jeffrey D
Project Start
1999-12-01
Project End
2006-11-30
Budget Start
2004-01-15
Budget End
2004-12-31
Support Year
4
Fiscal Year
2004
Total Cost
$446,498
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
800772139
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

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