Herpes simplex viruses cause considerable morbidity and mortality. They undergo a lytic, productive infection at the mucosal sites and spread into sensory ganglia, where they undergo a latent infection for the life of the host. Reactivation leads to recurrent infection and disease. Antiviral drugs have been defined that inhibit the lytic infection cycle, but there are no approaches that target the latent virus. We hav defined the role of viral gene products such as LAT and ICP0 in modulating the chromatin structure during lytic and latent infection, but further basic information is needed about these mechanisms for discovery of therapeutics that target HSV latent infection. In this application our specific aims are: a. To test hypotheses for possible mechanisms by which the HSV latency-associated transcript reduces lytic gene expression during acute infection and during latent infection of trigeminal ganglia: a. LAT mutations give different phenotypes in different HSV-1 strains. b. LAT acts as a long noncoding RNA that recruits histone-modifying complexes to the viral genome. c. LAT leads to chromatin changes by serving as a precursor to an miRNA that reduces ICP0 expression through studies of miRNA mutant viruses. d. LAT transcription, rather than cis-acting regulatory DNA sequences, promotes chromatin on the viral lytic genes. 2. To define the mechanisms by which the HSV ICP0 protein regulates chromatin structure during acute infection and latent infection of trigeminal ganglia. We have exciting unpublished results that ICP0 mutant viruses have a different chromatin profile on their genome during latent infection. We will test the hypothesis that ICP0 acts to alter the chromatin state by recruiting histone modification enzymes to viral and cellular genes. 3. To define Interactions between LAT and ICP0 in regulating HSV chromatin. We will test the hypothesis that LAT forms duplex RNA with ICP0 transcripts to recruit histone modifying enzymes by mutating the ICP0 promoter or mutating the ICP0 translational initiation site and by constructing LAT and ICP0 double mutant viruses to determine their combinatorial effects on latent infection, and viral chromatin.

Public Health Relevance

Herpes simplex viruses cause considerable genital, ocular and nervous system disease, and genital herpes increases the risk of HIV infection. There are drugs that target the active growth of herpes simplex virus but none that target the latent infection. This research will define basic mechanisms of herpes simplex virus latent infection and new targets for potential drugs to treat the latent infection of these viruses

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - A Study Section (VIRA)
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Challberg, Mark D
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Harvard University
Schools of Medicine
United States
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Cliffe, Anna R; Coen, Donald M; Knipe, David M (2013) Kinetics of facultative heterochromatin and polycomb group protein association with the herpes simplex viral genome during establishment of latent infection. MBio 4:
Knipe, David M; Lieberman, Paul M; Jung, Jae U et al. (2013) Snapshots: chromatin control of viral infection. Virology 435:141-56
Orzalli, Megan H; Conwell, Sara E; Berrios, Christian et al. (2013) Nuclear interferon-inducible protein 16 promotes silencing of herpesviral and transfected DNA. Proc Natl Acad Sci U S A 110:E4492-501