SBIR-STTR Award

Evidence suggests that virus-specific, CD8+ cytotoxic T lymphocytes (CTL) are crucial in the prevention and control of HIV infection. Investigators have shown that CTL recognize 8-10 amino acid peptides bound to MHC class I molecules and that these peptides can he used to induce CTL immunity. Studies using lymphocytic choriomeningitis virus as a chronic disease model have shown that peptide immunization can lead to complete protection. Before a prophylactic vaccine for HIV can be tested in man, preclinical studies in an animal model, such as Simian immunodeficiency virus (SIV) infection of macaque monkeys, must demonstrate potential efficacy.Our goal in the Phase I of this application is to define an optimal length (most antigenic) SIVgag CTL epitope and then to demonstrate that when modified to make it immunogenic, that SIVgag- specific CTL can be induced in rhesus monkeys. If successful, the Phase II of this application will focus on identifying additional gag, envelope and nef CTL epitopes, combining them into a single vaccine, and then evaluating their capacity to induce an SIV-specific CTL response capable of preventing the establishment of SIV infection. The ultimate goal of the Phase II results being to develop sufficient SIV animal model efficacy data to support peptide-based vaccine trials for HIV in man.Proposed commercial application:The commercial application of the research proposed is the development of an HIV vaccine. The studies proposed are designed to combine peptide-based CTL technology with the SIV/monkey model in order to obtain the preclinical "proof of efficacy" required before vaccine studies can be conducted in man.National Institute of Allergy and Infectious Diseases (NIAID)

Specific Aims: Simian immunodeficiency virus (SIV) infection of macaques provides the best non- human primate model for studying AIDS. We will utilize the SIV/macaque model to determine whether the generation of AIDS virus-specific cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTL) can protect against, or alter the course of AIDS virus infection in vivo. Specifically, we will use in vitro binding and immunogenicity assays to identify multiple CTL and HTL epitopes derived from the SIV Mac 251, and restricted by Mamu A*01 and defined DRB alleles Lipopeptides and cDNA minigenes will be utilized to deliver epitopes the identified to rhesus macaques expressing the appropriate MHC types. Challenge studies will examine the prophylactic efficancy of immunization with these constructs, and we correlate each outcome with elicitation of specific HTL responses, CTL responses and potential appearance of viral escape mutants.PROPOSED COMMERCIAL APPLICATION: The overall focus of our research is to develop a vaccine for prevention and treatment HIV and AIDS infection. The proposed research will develop an adequate system for testing the multi epitope approach to immunotherapy in non-human primates. SIV infection of macaques provides the best non-human primate model for studying AIDS.

Thesaurus Terms:
AIDS vaccine, method development, simian AIDS, simian immunodeficiency virus, synthetic vaccine, vaccine development active immunization, cytotoxic T lymphocyte, helper T lymphocyte, leukocyte activation /transformation, vector vaccine Macaca mulatta, tissue /cell culture NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES