This is a proposal for a Mid-Career Investigator Award for Katherine Luzuriaga, M.D., a physician scientist with clinical training in pediatric infectious diseases and research training in viral immunology. Over the years, her research has focused on examining the viral and immunopathologies of vertical HIV-1 infection, with the goal of improving prevention and treatment strategies. Ongoing research projects focus on characterizing viral replication and host immune responses in early infection, with a particular emphasis on characterizing HIV-1 specific CD8+ cytotoxic T lymphocyte (CTL) responses in infants. Receipt of a Mid-Career Investigator Award will permit the candidate to devote the majority of her time to patient-oriented research and mentoring the next generation of physician-scientists. The proposed studies address the hypothesis that the role of HIV-1 specific CTL in the control of viremia and protection against disease progression is dependent not only on the time of detection, magnitude, and breadth of the responses but also on CTL functional properties. Novel and extremely sensitive flow- cytometry (MHC-peptide tetramers; intracellular chemokine/cytokine) or modified ELISA (ELISPOT)-based techniques will be used to enumerate HIV-1 specific CTL in serial blood samples from infected infants. The use of monoclonal antibodies to cell surface antigens, along with tetramer staining, will allow evaluation of the in vivo phenotypes and activation state of HIV-1 specific CTL. HIV-1 specific CTL clones will then be derived to evaluate lytic and other functional properties in vitro. As a faculty member at the University of Massachusetts Medical School (UMMS) Dr. Luzuriaga enjoys and is highly committed to training the next generation of physician-scientists. A mentoring plan is outlined which will provide trainees with a range of activities that will prepare them to become independent investigators.
