Dissertation

Understanding the antiviral efficacy and breadth of CD8 + T lymphocytes against simian immunodeficiency virus

Loffredo, John Thomas

2006

Overview

There are over 40 million people living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) worldwide. In 2005, there were five million new infections and three million deaths. With greater than 95% of infections occurring in countries unable to afford antiretroviral therapy, the development of a prophylactic HIV vaccine remains one of the world's top public health priorities. The failure of previous vaccines has increased the need for novel approaches in addressing this problem. Many studies illustrate the important role of CD8+ T lymphocytes in controlling HIV and simian immunodeficiency virus (SIV) replication. However, the correlates of immune protection remain unknown. We approached this issue by first defining the breadth of CD8 + responses in the SIV-infected macaque model and then investigating the antiviral efficacy of these CD8+ T lymphocytes. Using major histocompatibility complex (MHC) class I-defined, SIV-infected Indian rhesus macaques (Macaca mulatta) as an animal model for HIV infection, we identified novel CD8+ T lymphocyte epitopes restricted by the MHC class I molecules Mamu-A*02 and Mamu-A*11. The CD8+ T lymphocyte epitopes have been instrumental in understanding the breadth of the CD8+ T lymphocyte responses in vaccinated and SIV-infected macaques. Next, we examined the types of antigen-specific CD8+ T lymphocyte responses that were effective at suppressing SIV replication using a novel viral suppression assay. Recent studies in HIV-infected humans suggested differences in antiviral efficacy between CD8+ T lymphocytes directed against early versus late viral proteins. We initially hypothesized that antigen-specific CD8+ T lymphocytes directed against early proteins would be more effective in suppressing viral replication than CD8+ T lymphocytes directed against proteins expressed later in the viral replication cycle. However, our results suggested that not all CD8+ T lymphocytes responses directed against early proteins are effective at suppressing SIV replication. We also found that a variety of factors likely contribute to the ability of CD8+ T lymphocytes to suppress viral replication including functional avidity, viral escape, epitope location, and disease progression of the animal. This information may be important in determining the CD8+ T cell epitopes to be targeted by vaccination in future HIV studies.

• Publisher: ProQuest Dissertations & Theses
• Subject: Immunology / Microbiology / Virology
• ISBN: 9780542885068, 0542885069