Betsy Herold, M.D. directs a basic and translational research program, which focuses on the prevention of HIV and HSV and other sexually transmitted infections. Basic research in the lab focuses on defining the cellular signaling pathways that HSV-2 usurps to promote infection. Current work from our laboratory demonstrates that HSV activates calcium (Ca2+), integrin, and phosphorylation signaling pathways and that these pathways play critical roles in the establishment of infection and in cell-to-cell spread of virus. .More recently, the lab has identified a novel cellular protein that plays a key role in the initiation of viral protein expression and could serve as a novel target for prevention strategies. Identification of the viral and cellular factors required for infection has led to development of candidate drugs, which have been formulated for vaginal delivery to prevent both HSV and HIV infection.
Studies with vaginal microbicides have resulted in the expnasion of studies to focus on soluble mucosal immunity in the genital tract. We found that .female genital tract secretions collected from healthy women provide variable, but significant protection against both HSV and HIV. Mechanistic studies suggest that this endogenous activity is mediated by defensins and other antimicrobial peptides. This endogenous activity may serve as a biomarker of a "healthy mucosal immune environment" and thus provide a surrogate marker to evaluate the safety of vaginal microbicides. In addition, identification of the mediators that contribute to this endogenous activity could lead to development of new strategies to boost this host defense and help protect against infection. These studies are being conducted in collaboration with the proteomics core facility at AECOM. Additionally, we are testing the hypothesis that HSV triggers changes in the mucosal environment, which allow it to escape cervical secretion defenses, enhance its own infectivity and facilitate HIV co-infection. Our preliminary observations support the paradigm that HSV disrupts the epithelial barrier by targeting tight junction and adherens junction proteins, and interferes with host defenses by triggering an inflammatory response and a loss in protective proteins such as SLPI. These changes could facilitate both its own infectivity and enhance HIV co-infection.
Results obtained from this bench research are critical to the laboratory's translational studies. The focus of the Translational Microbicide Research Program is to identify optimal combinations of topical microbicides that are safe and target different steps in HIV life cycle, thus reducing the risks of drug resistance and providing greater protection than could be achieved with a single agent, and also target HSV infection. Candidate combinations are evaluated using a multi-tiered approach for anti-viral activity and safety using human cervical cultures, as well as primary T cells and macrophages, in the presence of cervicovaginal secretions and seminal plasma. Leading combinations are then evaluated in human explant cultures (cervical, vaginal) and in murine genital models and a new cotton rat model for anti-viral activity and for the impact on mucosal immunity. If results of these pre-clinical studies suggest that candidate microbicides are safe and effective, the drugs are advanced for regulatory testing, and undergo evaluation in Phase I clinical studies.
Clinical research interests also include prevention of infectious disease complications in transplantation. Members of the research group are involved in studies to optimize pre-emptive prophylaxis for CMV and EBV, vaccine responses in transplantation recipients, and other related infectious complications.
