The immunological correlates for protection against human immunodeficiency virus type 1 (HIV-1) infection and development of acquired immunodeficiency syndrome (AIDS) are not clearly understood. The applicants have hypothesized that an effective vaccination strategy against HIV-induced AIDS should involve preferential induction of cell-mediated immunity (CMI). This hypothesis has been supported by recent reports describing presence of helper T-cell responses directed against certain HIV peptides, and/or HIV-specific cytotoxic T lymphocyte (CTL) responses, but not antibodies, in long-term nonprogressors, and in certain individuals who remain HIV-negative despite indulging in high-risk activities. The long-term goal of the application is to formulate a synthetic peptide-based vaccine, for priming HIV-specific CMI, because it offers the advantage of being defined, safe, and economical. In this regard, protection against disease and death induced by certain viruses was demonstrated in animal models using peptide-based vaccines for efficient priming of CMI responses. Using a series of animal models (murine, and rhesus and chimpanzee monkeys), and samples from HIV-infected people, the investigators have previously identified several HIV env peptides, from highly conserved regions, that induce HIV-specific T-cell response in the absence of antibody response. More recently, they have analyzed PBMCs from HIV-seropositive long-term nonprogressors and observed HLA class C-restricted CD8+ CTL responses against the same conserved HIV-1 env peptides. The HIV envelope protein plays a major role in the virus-induced pathogenesis and has been the focus of vaccine strategies. However, the lack of a suitable animal model for HIV-induced AIDS hampered these efforts. The recently developed chimeric virus SHIV, 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. The investigators hypothesize that the conserved HIV env peptides they identified, can function as a vaccine for inducing efficient CMI and protection against pathogenic SHIV challenge in rhesus monkeys. To test their vaccine strategy, they propose two specific approaches involving immunization of rhesus monkeys: (i) with the peptide-mixture in Freund's adjuvant, and (ii) with autologous dendritic cells (DCs), pretreated in vitro with the peptide-mixture. Upon challenge with the pathogenic SHIV, the applicants expect that animals in both experiments will develop efficient virus-specific CMI responses, and resist infection and/or disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI042694-01
Application #
2555248
Study Section
Special Emphasis Panel (ZAI1-VSG-A (O1))
Project Start
1997-09-30
Project End
1999-09-29
Budget Start
1997-09-30
Budget End
1998-09-29
Support Year
1
Fiscal Year
1997
Total Cost
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
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
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
Manuri, Pallavi R; Nehete, Bharti; Nehete, Pramod N et al. (2007) Intranasal immunization with synthetic peptides corresponding to the E6 and E7 oncoproteins of human papillomavirus type 16 induces systemic and mucosal cellular immune responses and tumor protection. Vaccine 25:3302-10
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
Starost, M F; Hill, L R; Nehete, P N et al. (2004) Extramedullary hematopoiesis in the mandibular lymph node of simian-human immunodeficiency virus-infected rhesus monkeys (Macaca mulatta): a report of three cases. Vet Pathol 41:186-90
Lomada, Dakshayani; Gambhira, Ratish; Nehete, Pramod N et al. (2004) A two-codon mutant of cholera toxin lacking ADP-ribosylating activity functions as an effective adjuvant for eliciting mucosal and systemic cellular immune responses to peptide antigens. Vaccine 23:555-65

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