The purpose of this NIH F30 application is to obtain support for the PI, Sushma Boppana, for mentored research and career development activities within her MD/PhD degree training that will strengthen her potential to become a successful physician scientist. The project goal is to develop skills in immunology that will allow the PI to study CD8 cross-reactivity in acute HIV-1 infection using cutting edge laboratory assays and computational techniques. The primary objective of the research proposal is to investigate the impact of cross-reactive CD8 responses in acute HIV-1 infection on viral control and evolution. CD8 T cells play a critical role in viral control during HIV-1 infection and are likely to be an important component of future effective cure therapies. However, the viral latent reservoir represents a major obstacle to achieving functional or complete cure in HIV-1. This reservoir is now known to encode significant numbers of escape mutations, and it is possible that CD8 T cells therapeutically directed towards clearing HIV-1 in infected individuals will need to recognize multiple variants of the same epitopes; in other words, they will need to be cross-reactive. This project seeks to quantify the amount of CD8 cross-reactivity seen in acute infection, to characterize the functionality of these responses, and to establish the impact of these cross-reactive responses on viral control (Aim 1). This proposal will also determine the contribution of individual TCR clonotypes to the overall cross-reactivity of the CD8 responses seen in Aim 1 and will elucidate the impact of CD8 cross-reactivity on viral evolution by correlating cross-reactive responses to diminished viral diversity (Aim 2). The long-term objective of our research is to better understand the role of cross-reactive CD8 T cells in HIV-1 such that future cure strategies can more effectively manipulate the CD8 response to clear a variant-encoding latent reservoir. The proposed training plan for the PI is sponsored by her PhD mentor, Dr. Paul Goepfert. Included in the training plan are experiences that will help the PI develop in three major areas: 1) rigorous immunological research in HIV-1, including developing familiarity with the existing literature, critically evaluating published studies, and training in principles of scientific integrity, responsible conduct of research, and rigor and reproducibility; 2) competence in bioinformatic techniques and biostatistical analysis; and 3) career and professional development, including grant writing, journal article review, clear communication through presentation and manuscript preparation, and translation of research findings to clinical application. The overall goal of this training plan is to provide the PI with a solid foundation for a successful career as a physician scientist, with the ultimate career goal of leading a collaborative research team that bridges the gap between laboratory-based human immunology research and the clinical prevention and treatment of infectious diseases.
CD8 T cells play a critical role in viral control in HIV-1 infection; however, it remains unclear whether the ability of CD8's to cross-react with multiple viral variants contributes to viral control by impeding viral evolution. This study proposes to establish the impact of CD8 cross-reactivity on HIV-1 viral control and evolution by comprehensively studying cross-recognition of natural epitope variants in acute infection and identifying the key molecular players of cross-reactive responses. These data will further our understanding of how CD8 T cells control virus and improve our ability to elicit robust and effective CD8 responses with future HIV-1 curative therapies.
