Jay C. Brown
- BA, Johns Hopkins University, Baltimore, MD
- PhD, Harvard University, Cambridge, MA
- Postdoc, MRC Lab of Molecular Biology, Cambridge UK
- Professor, Microbiology, Immunology, and Cancer Biology
Structure and Assembly of the Herpes Simplex Virus Capsid.
Project Title: Pathogenesis of Infections by Herpes Simplex Virus
Herpes simplex virus is widespread in the human population with most people exposed during childhood. Nearly all adults have specific antibodies. HSV-1 is best-known as the etiological agent of cold sores and genital lesions, but it also causes a stromal ketatitis, disseminated disease in the newborn and encephalitis in adults. HSV-1 is the leading cause of non-epidemic encephalitis in the U.S. In our laboratory we study the structure and assembly of the HSV-1 virion with the idea that such studies will suggest the nature of novel anti-herpes therapeutic agents directed against the assembly process. Although most of our studies are carried out with HSV-1, it is expected that the results will clarify virus assembly as it occurs in other herpes viruses and perhaps in other virus families as well.
All herpesviruses have a tegument, a layer of protein located between the virus membrane and the capsid. The tegument is composed predominantly of virus-encoded proteins that together can account for up to half or more of the total virion protein. Tegument proteins are thought to be those involved in the early stages of infection before progeny virus proteins are synthesized. The goal of our work is to examine the structure and assembly of the herpesvirus tegument. It is expected that the tegument will offer novel targets for anti-viral therapy and the research is designed to uncover such targets.
Studies are being carried out with HSV-1, the virus in which the tegument has been most thoroughly characterized. Biochemical analysis, for instance, has shown that the HSV-1 tegument is composed of approximately twenty distinct, virus-encoded protein species whose amounts vary considerably. Many of the tegument proteins are required for HSV-1 replication, and functions have been defined for most. Proposed studies are designed to test the hypothesis that tegument structure is organized around UL36, a large protein bound at the capsid vertices. It is proposed that other tegument proteins are attached to the capsid by way of UL36. Additional questions to be addressed include: Which tegument proteins are located furthest from the capsid? Is there temporal and/or spatial specificity to the way tegument components become attached to the capsid? How does the tegument become detached from the capsid as a new infection is initiated? Can intact teguments be isolated away from capsids?
- Mingo R, Han J, Newcomb W, Brown J. Replication of herpes simplex virus: egress of progeny virus at specialized cell membrane sites. Journal of virology. 2012;86(13): 7084-97. PMID: 22532674 | PMCID: PMC3416353
- Newcomb W, Brown J. Internal catalase protects herpes simplex virus from inactivation by hydrogen peroxide. Journal of virology. 2012;86(21): 11931-4. PMID: 22915822
- Newcomb W, Jones L, Dee A, Chaudhry F, Brown J. Role of a reducing environment in disassembly of the herpesvirus tegument. Virology. 2012;431(1): 71-9. PMID: 22695308 | PMCID: NIHMS387811
- Brown J, Newcomb W. Herpesvirus capsid assembly: insights from structural analysis. Current opinion in virology. 2011;1(2): 142-9. PMID: 21927635 | PMCID: PMC3171831
- Kofman A, Marcinkiewicz L, Dupart E, Lyshchev A, Martynov B, Ryndin A, Kotelevskaya E, Brown J, Schiff D, Abounader R. The roles of viruses in brain tumor initiation and oncomodulation. Journal of neuro-oncology. 2011;105(3): 451-66. PMID: 21720806 | PMCID: PMC3278219