With more than 30 million HIV-infected individuals, there can be few other more pressing biomedical priorities than to produce an effective vaccine for HIV. Given the important role that cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs) play in controlling viral replication, it is critical that this vaccine stimulate these cellular responses. Unfortunately, there are few MHC-defined rhesus macaques available for vaccine research. The use of assisted reproductive technologies such as in vitro fertilization (IVF) and micromanipulation in conjunction with selected embryo transfer will result in the production of completely MHC-defined macaques, expressing multiple MHC class I and II molecules for which SIV peptides, tetramers and ELISPOT assays exist. The utility of MHC-defined and genetically- identical MHC-defined animals in a relevant viral challenge model would be enormous and have tremendous impact on our ability to assess vaccine efficacy. We have identified five pairs of rhesus macaques that have multiple offspring. These five pairs of animals will serve as egg and sperm donors for our IVF program and will constitute the founding animals for our MHC-defined breeding program. To define the MHC class I and II molecules of the IVF donors, we will infect the offspring of these five pairs of macaques with SIV and then define the cellular immune response to the virus. This will enable us to synthesize both MHC class I and II tetramers.
In Specific Aim 1 : We will identify at least 15 CTL epitopes and their restricting MHC class I alleles for tetramer synthesis.
In Specific Aim 2 : We will identify at least 10 HTL epitopes and their restricting MHC class II alleles for tetramer synthesis. We plan to develop an innovative, prototypic animal production program that will be central to the future of the Regional Primate Centers. MHC-defined animals produced using assisted reproductive technologies will complement recent developments in tetramer and ELISPOT technologies in the rhesus macaque and provide invaluable animals for AIDS vaccine research. Definition of new MHC/peptide combinations and the production of MHC-defined animals has been a priority of the Baltimore AVRC Committee (see letter of support from Dr. Baltimore; Appendix).
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