application): Progress toward the development of a vaccine for HIV has been hindered by the limited number of animal models with which to study HIV infection of humans. Simian immunodeficiency virus (SIV) infection of the rhesus macaque is an accepted animal model for HIV infection of humans. Although several vaccines tested in rhesus macaques have provided protection against SIV challenge, it has not been possible to determine the correlates of protection in these vaccine trials. There is a strong cytotoxic T lymphocyte (CTL) response to the AIDS virus in both human and rhesus macaques, and CTLs have been implicated in providing protection from infection. Understanding the role of CTLs in AIDS virus-induced disease will be important for the design of effective vaccines. Few CTL epitopes have been defined in SIV and there are no inbred strains of rhesus macaques for CTL adoptive transfer studies. The investigators propose to triple the number of defined SIV CTL epitopes and to develop a rapid MHC class I-typing of rhesus macaques. They propose to find two new epitopes for env and four for nef. These will be characterized for anchor residues, minimal recognizable peptide and MHC class I molecules that bind these epitopes. A PCR-SSP-based technique will be developed for detecting nine restricting rhesus macaque MHC class I alleles. They will produce pairs of MHC-identical rhesus macaques to explore the role of CTLs in AIDS virus infection. This will be done by survey of macaque pedigrees. Female relatives of SIV-infected monkeys will provide ova for in vitro fertilization and nuclear transfer for production of pairs of identical twins. They will produce additional pairs of MHC-defined, identical rhesus macaques for CTL adoptive transfer studies to study correlates of immune protection.
| Schramm, R D; Paprocki, A M; Watkins, D I (2001) Birth of MHC-defined rhesus monkeys produced by assisted reproductive technology. Vaccine 20:603-7 |
| Evans, D T; Jing, P; Allen, T M et al. (2000) Definition of five new simian immunodeficiency virus cytotoxic T-lymphocyte epitopes and their restricting major histocompatibility complex class I molecules: evidence for an influence on disease progression. J Virol 74:7400-10 |
| Evans, D T; O'Connor, D H; Jing, P et al. (1999) Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef. Nat Med 5:1270-6 |
| Vogel, T U; Evans, D T; Urvater, J A et al. (1999) Major histocompatibility complex class I genes in primates: co-evolution with pathogens. Immunol Rev 167:327-37 |
