David M. Knipe
Department of Microbiology and Molecular Genetics
Harvard Medical School
Armenise, Room 530
200 Longwood Avenue
Boston, MA 02115
Tel: (617) 432-1934
Fax: (617) 432-0223
Email: david_knipe@hms.harvard.edu
Web Page: The Knipe Lab Page
8 postdoctoral fellows, 4 graduate students
Our laboratory studies the molecular and cellular biology of herpes simplex virus productive infection and latent infection. We are also studying the mechanisms of immunization by HSV vaccine strains and HSV vaccine vectors for AIDS and West Nile virus.
HSV Lytic versus Latent Infection Decision. We have studied the mechanisms of regulation of HSV gene expression during lytic infection of epithelial cells and latent infection of sensory neurons. We postulate that there is an epigenetic switch that determines the course of the infection in the two types of cells. In epithelial cells a virion protein and an immediate early viral protein reduce chromatin and heterochromatin on viral lytic gene promoters while, in contrast, in sensory neurons, we have shown that the HSV lytic promoters are assembled in heterochromatin during latent infection of sensory neurons through chromatin immunoprecipitation studies. We have also shown that the latency-associated transcript, LAT, promotes the assembly of heterochromatin on the lytic promoters. We are currently studying the mechanisms by which viral proteins promote removal of chromatin while LAT promotes heterochromatin formation and silencing of viral gene expression during latent infection by HSV.
Viral Activation and Inhibition of Host Innate Responses. Viruses activate and modulate host innate immune responses initiated by interaction with Toll-like receptors and cytoplasmic effectors such as RIG-1. We are studying the mechanisms by which herpes simplex virus activates TLR signaling and how the ICP0 protein can modulate TLR signaling and RIG-1 signaling.
Replication-defective mutant viruses as a new form of viral vaccine. We have genetically engineered HSV strains that are mutated in essential genes for viral replication. We have constructed an HSV-2 double deletion mutant virus as a genital herpes vaccine. We are currently studying the ability of this vaccine to induce protective immunity against HSV-2 strains from the Sub-Saharan genital herpes epidemic to determine if this vaccine can impact on the global burden of genital herpes and its promotion of HIV transmission.
References:
- Wang, Q.-Y., C. Zhou, K. E. Johnson, R. C. Colgrove, D. M. Coen, and D. M. Knipe. 2005. Herpesviral latency-associated transcript gene promotes assembly of heterochromatin on viral lytic-gene promoters in latent infection. Proceedings of the National Academy of Sciences, USA. 102: 16055-16059.
- Palliser, D., D. Chowdhury, Q.-Y. Wang, S. J. Lee, R. T. Bronson, D. M. Knipe and J. Lieberman. 2005. An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Nature: 439: 89-94.
- Melroe, G.T., L. Silva, P.A. Schaffer and D.M. Knipe. 2007. Recruitment of activated IRF-3 and CBP/p300 to herpes simplex virus ICP0 nuclear foci: Potential role in blocking IFN-b induction. Virology 360:305-21.
BBS webpage updated 12/02/2009