Regulation of Herpes Simplex Virus (HSV) latency and reactivation and the development of novel therapies to treat HSV recurrent disease
1) Determining the molecular basis of HSV latency and reactivation. A major focus of my laboratory has involved determining the role that virally encoded non-coding RNAs (ncRNAs) play in regulating the ability of HSV to maintain a latent infection in neurons. The HSV-1 latency-associated transcript is an 8.5 kb long ncRNA that is expressed at high levels during latency in some neurons. Mutations that reduce the LAT expression display a variety of phenotypes including decreased reactivation and increased neuronal death or apoptosis. In addition to the LAT, there are 8 microRNAs (miRNAs) that arise from the same region of the genome as well as 2 additional non-coding RNAs that have been recently identified. Our lab has been taking a genetic approach to further map these ncRNAs and to dissect their roles in well established models of HSV latency and reactivation.
2) Identifying the mechanisms of epigenetic regulation of HSV-1 gees during latency and reactivation. This second major focus of my lab centers around identifying the specific chromatin modifying factors that are recruited to the HSV-1 genome during the establishment of latency and reactivation. Our lab was the first to demonstrate epigenetic modifications were associated with the HSV-1 genome during latency and we have and others have shown that the heterochromatin mark H3K27me3 plays an important role in keeping HSV latent by silencing lytic genes. We have recently shown that an inhibitor of the H3K27me3 demethylase significantly reduces the ability of HSV to reactivate. Our work now is focusing on other chromatin modifiers that may be involved in the establishment and reactivation from latency and determining what recruits them to the genome.
3) Developing new therapeutic approaches to prevent HSV recurrent disease. A final area of focus of my lab is aimed at developing novel therapeutic approaches to block the ability of HSV to reactivate. Our approaches include anti-HSV ribozymes (collaborations with Drs. Al Lewin, Sonal Tuli, Greg Schultz and Donna Neumann), TALENs (collaboration with Dr. Bryan Cullen) and CRISPR-Cas9 (Collaboration with Dr. Bryan Cullen and Editas Medicine).
Awards, Professional Service:
Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease Award (2003) , STOP! Children’s Cancer Distinguished Young Investigator (2002) , Nominee, Howard Hughes Medical Institute Investigator, National Multiple Sclerosis Society Postdoctoral Fellowship.
BMS 5300C Medical Microbiology and Infectious Diseases, GMS 6036 Molecular Virology, GMS 7979 Advanced Research, GMS 7980 Doctoral Research.