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 ofthe 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 have defined the role of viral gene products such as LAT and ICPO 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: l_AT acts as a long noncoding RNA that recruits histone-modifying complexes to the viral genome, b. LAT leads to chromatin changes by serving as a precursor to an miRNA that reduces ICPO expression through studies of miRNA mutant viruses (with Coen lab), c. LAT regulatory DNA sequences act in a cis-acting manner to promote chromatin on the viral lytic genes, d. LAT leads to differential targeting of the viral genome through studies of genome targeting in cultured neurons with the Leib lab. 2. To define the mechanisms by which the HSV ICPO protein regulates chromatin structure during acute infection and latent infection of trigeminal ganglia. We have exciting unpublished results that ICPO mutant viruses have a different chromatin profile on their genome during latent infection. We will test the hypothesis that ICPO acts to alter the chromatin state by recruiting histone modification enzymes to viral and cellular genes. 3. To define Interactions between LAT and ICPO in regulating HSV chromatin. We will test the hypothesis that LAT forms duplex RNA with ICPO transcripts to recruit histone modifying enzymes by mutating the ICPO promoter or mutating the ICPO translational initiation site and by constructing LAT and ICPO 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

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI098681-02
Application #
8693914
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Knipe, David M; Raja, Priya; Lee, Jennifer (2017) Viral gene products actively promote latent infection by epigenetic silencing mechanisms. Curr Opin Virol 23:68-74
Kurt-Jones, Evelyn A; Orzalli, Megan H; Knipe, David M (2017) Innate Immune Mechanisms and Herpes Simplex Virus Infection and Disease. Adv Anat Embryol Cell Biol 223:49-75
Jiang, Yike; Leib, David (2017) Preventing neonatal herpes infections through maternal immunization. Future Virol 12:709-711
Enquist, Lynn W; Leib, David A (2017) Intrinsic and Innate Defenses of Neurons: D├ętente with the Herpesviruses. J Virol 91:
Jiang, Yike; Patel, Chaya D; Manivanh, Richard et al. (2017) Maternal Antiviral Immunoglobulin Accumulates in Neural Tissue of Neonates To Prevent HSV Neurological Disease. MBio 8:
Katzenell, Sarah; Cabrera, Jorge R; North, Brian J et al. (2017) Isolation, Purification, and Culture of Primary Murine Sensory Neurons. Methods Mol Biol 1656:229-251
Manivanh, Richard; Mehrbach, Jesse; Knipe, David M et al. (2017) Role of Herpes Simplex Virus 1 ?34.5 in the Regulation of IRF3 Signaling. J Virol 91:
Lutz, Gabriel; Jurak, Igor; Kim, Eui Tae et al. (2017) Viral Ubiquitin Ligase Stimulates Selective Host MicroRNA Expression by Targeting ZEB Transcriptional Repressors. Viruses 9:
Pan, Dongli; Pesola, Jean M; Li, Gang et al. (2017) Mutations Inactivating Herpes Simplex Virus 1 MicroRNA miR-H2 Do Not Detectably Increase ICP0 Gene Expression in Infected Cultured Cells or Mouse Trigeminal Ganglia. J Virol 91:
Lee, Jennifer S; Raja, Priya; Knipe, David M (2016) Herpesviral ICP0 Protein Promotes Two Waves of Heterochromatin Removal on an Early Viral Promoter during Lytic Infection. MBio 7:e02007-15

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