Host and viral genetic factors influencing immunodeficiency virus infection.

摘要

HIV/AIDS is a worldwide pandemic, directly infecting over 33 million people with an estimated 8 million new infections per year. There is no cure for HIV/AIDS. The only available treatment is anti-retroviral drugs; however, treatment is costly and must be taken for life. The development of a prophylactic or therapeutic vaccine provides the best long-term hope for blunting the HIV pandemic; however, efforts to develop a vaccine have not been successful. New approaches for vaccine design are urgently needed. Our research has centered around the observation that major histocompatibility (MHC) class I genotype is one of the most significant predictors of HIV/SIV disease outcome.;MHC class I molecules interact with CD8+ T-lymphocytes and natural killer cells. NK cells interact with MHC class I molecule through killer immunoglobulin-like receptors (KIRs). Specific KIR genotypes associate with control of HIV infection; however, the mechanism underlying this protection has been difficult to study in humans. Many of these obstacles could be overcome by examining NK function in non-human primates; however, this requires a basic understanding of macaque KIR genetics. We present a complete characterization of KIR genetics in Mauritian Cynomolgus macaques, an isolated island population. We further demonstrate that this population can serve as a framework to describe KIRs in other macaque populations, providing a foundation for functional studies.;In the final chapter, we examined viral genetics. We employed next generation sequencing to demonstrate unprecedented complexity in the patterns of CTL escape. This increased sensitivity enabled detection of acute CD8-TL escape as early as 14 days post-infection, representing the earliest published example of CD8-TL escape in macaques. The ability to readily identify and quantify viral variants should permit unprecedented assessment of variant ontogeny, allowing a more nuanced view of the selection, reversion and potential fitness of variants that arise during HIV/SIV infection.