Project 1: The Impact of IRF-3-Dependent Mechanisms Upon HSV Replication and Virulence.

Director

David A. Leib, PhD.
Professor, Dartmouth Medical School
Department of Microbiology and Immunology
630E Borwell Building
One Medical Center Drive HB 7556
Lebanon, NH 03756.
Tel: 603-650-8616 (office)
Tel: 603-650-8617 (lab)
Fax: 603-650-6223
david.a.leib@dartmouth.edu
http://dms.dartmouth.edu/faculty/facultydb/view.php?uid=3535

COBRE Mentors

Drs WIllliam Green, James Gorham, Richard Enelow.

Mission

Herpes simplex virus (HSV) is a common cause of morbidity and mortality worldwide. In the USA, greater than 80% of the adult population is seropositive for HSV-1, and 20% is positive for HSV-2. HSV-1 causes cold sores and it is a leading cause of viral encephalitis.

There is no cure for HSV despite the availability of effective antiviral drugs, largely due to the ability of the virus to establish lifelong latent infections. Furthermore, no effective HSV vaccine exists. The ability of any microbe to modulate the immune response of its host is a critical aspect of its pathogenic fitness. The innate interferon responses are the first line of defense against virus infection, and as such must be overcome for viruses to be successful pathogens. Experiments using animal models, and clinical studies in humans, have shown that HSV strains unable to counteract the innate interferon (IFN) response are highly attenuated. Interferon regulatory factor 3 (IRF3) is critical in the induction phase of the IFN response. Its role, however, in the control of replication of certain viruses, including HSV-1, is enigmatic. A number of HSV genes interfere with the localization and function of IRF-3 in vitro, suggesting that IRF-3 is critical for controlling HSV replication.

The over-arching goal of this research is therefore to assess the role of IRF3 in the control of HSV replication and pathogenesis.

Background

COBRE facilitated the transition of this project from Washington University in St Louis following Dr. Leib's recruitment to Dartmouth in 2009.

Publications

Menachery, V.D., and Leib, D.A. (2009). Control of herpes simplex virus replication is mediated through an IRF-3-dependent pathway. J. Virol, 83:12399-12406.

Menachery, V.D., Pasieka, T., and Leib, D.A. IRF-3 dependent pathways are critical for control of HSV-1 central nervous system infection. Journal of Virology, Submitted.