HIV adaptation to immune selection pressures:historic trends and future implications
CIHR - $318,132
Despite HIV's enormous mutational capacity, analyses of contemporaneous HIV sequences have revealed that immune-driven HIV evolution, or "immune escape", occurs along generally reproducible pathways. However, the extent to which HIV has adapted to its human hosts over the course of the pandemic remains poorly understood. Repeated cycles of immune selection and transmission might allow key escape mutations to accumulate in circulating HIV sequences over time, with profound implications. If immune targets in the HIV genome were disappearing over time due to the accumulation of escape mutations, our capacity to generate natural and vaccine-induced protective immune responses would diminish as the epidemic progresses. Furthermore, the extent to which immune escape has influenced HIV pathogenesis remains unknown. Studies investigating the evolution of HIV virulence have largely focused on population-level trends in clinical markers over time, but few have addressed this issue using biological assessments of replication capacity or viral protein function. We propose to undertake the first large-scale investigation of immune-mediated HIV evolution and its pathogenic implications over the past 30-year history of the epidemic in North America. Host and viral sequences from 1979-present will be analyzed to characterize the extent of population-level HIV adaptation over the epidemic's course. Functional assessments of viral replication capacity and protein function will be performed in to determine whether HIV is evolving towards increased virulence, gradual attenuation, or simply adapting to changing host-pathogen pressures over time. With this study we are poised to answer two key questions HIV biomedical research, namely, to what extent the virus has adapted to its hosts since AIDS was first recognized, and what implications this has for the future of the epidemic. Results have the potential to significantly advance HIV vaccine research.