The role of cytotoxic T lymphocytes in protection from pathogenic simian immunodeficiency virus challenge

With 4x106 new Human Immunodeficiency Virus (HIV) infections in 2006, the need for a vaccine is evident. The Simian Immunodeficiency Virus (SIV) infected rhesus macaque (Macaca mulatta) is the preferred animal model for HIV vaccine development and there is a need to understand the correlates of protection in this non-human primate (NHP) model. This project evaluates the cytotoxic T lymphocyte (CTL) response to SIV in four vaccinated and four unvaccinated rhesus macaques. The animals were observed through four years post-challenge, allowing the study of both acute and chronic phase immune responses. This project includes the first study to apply a previously reported NHP tether system to study viral immunology. The use of the tether during acute infection allows for frequent blood sampling without using restraints or sedation, therefore minimizing the confounding immunological signals generated by sedation or stress. The confirmatory nature of our data indicates the validity of using this tether system for the evaluation of acute phase anti-SIV responses, and is applicable to the study of acute phase immune responses in other viral infections. Monitoring of the chronic phase of infection was accomplished to better understand CTL selection in the context of SIV infection. This study followed the CTL response and its effects on viral evolution in major histocompatability complex (MHC) mismatched animals and identified novel CTL epitopes, which may be useful as tetramer reagents. In addition, we demonstrate that the loss of immune responses to immunodominant epitopes results in more rapid disease progression, despite the presence of other CTL responses. To our knowledge, this is the first report of this phenomenon in an animal with no known protective alleles.;Combined, these observations have contributed to the body of knowledge regarding anti-SIV CTL responses in both acute and chronic infections in this NHP model. This, in turn, contributes to the improvement of the SIV infected rhesus macaque as an animal model, aids in the understanding of immunity in Lentivirus infections, and contributes to the larger issue of HIV vaccine development.