- PhD, Edinburgh University, Edinburgh, Scotland, UK
Herpes Simplex Virus Infection of Neurons
Herpes simplex viruses type 1 and type 2 are significant human pathogens. Approximately 65% of the US population are infected with HSV-1 and 20% with HSV-2. The viruses persist in the body for life in the form of a latent, or silent, infection of neurons. Periodically, the viruses reactivate from latency to allow transmission to a new host, which can be associated with disease including cold sores, kerato-conjunctivitis, genital lesions and encephalitis. The Cliffe lab investigates the mechanisms of herpes simplex virus (HSV) latency and reactivation in neurons. We use primary and differentiated neurons along with in vivo models to determine how HSV establishes a latent infection in neurons and how the virus reactivates under conditions of cell stress. Our goals are to understand the following:
1) Why does HSV latency occurs ONLY in neurons? We are investigating the unique properties of neurons that allows HSV to establish a latent infection. Examples of projects include investigating how infection through axons is more repressive than infection through the soma and links between increased resistance to cell death in neurons and enhanced anti-viral responses.
2) How does HSV gene silencing occurs in neurons? During latency, the HSV genome associates with silent, heterochromatin. However, the mechanisms by which heterochromatin is targeted to the viral genome and the proteins associated with the genome are not known. We are investigating how heterochromatin forms on the HSV genome following neuronal infection and the exact nature of the viral chromatin. We are also interested in how differences in the chromatin structure of the latent HSV-1 and HSV-2 genomes influence the ability of the viruses to reactivate.
3) How does the HSV genome become de-repressed during reactivation? In order for HSV to reactivate, the silent heterochromatin on the viral genome needs to be remodeled to allow gene expression to occur. We are investigating links between activation of cell stress pathways in neurons and remodeling of the viral chromatin during reactivation. By understanding how the viral chromatin needs to be remodeled we hope to develop therapies that act on the viral chromatin and prevent reactivation occurring.
- Cliffe A, Wilson A. Restarting Lytic Gene Transcription at the Onset of Herpes Simplex Virus Reactivation. Journal of virology. 2016;91(2). PMID: 27807236 | PMCID: PMC5215350
- Cliffe A, Arbuckle J, Vogel J, Geden M, Rothbart S, Cusack C, Strahl B, Kristie T, Deshmukh M. Neuronal Stress Pathway Mediating a Histone Methyl/Phospho Switch Is Required for Herpes Simplex Virus Reactivation. Cell host & microbe. 2015;18(6): 649-58. PMID: 26651941 | PMCID: PMC4681005
- Gama V, Swahari V, Schafer J, Kole A, Evans A, Huang Y, Cliffe A, Golitz B, Sciaky N, Pei X, Xiong Y, Deshmukh M. The E3 ligase PARC mediates the degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells. Science signaling. 2014;7(334): ra67. PMID: 25028717 | PMCID: PMC4182917
- Cliffe A, Coen D, Knipe D. Kinetics of facultative heterochromatin and polycomb group protein association with the herpes simplex viral genome during establishment of latent infection. mBio. 2013;4(1). PMID: 23322639 | PMCID: PMC3551550
- Cliffe A, Garber D, Knipe D. Transcription of the herpes simplex virus latency-associated transcript promotes the formation of facultative heterochromatin on lytic promoters. Journal of virology. 2009;83(16): 8182-90. PMID: 19515781 | PMCID: PMC2715743
- Hancock M, Cliffe A, Knipe D, Smiley J. Herpes simplex virus VP16, but not ICP0, is required to reduce histone occupancy and enhance histone acetylation on viral genomes in U2OS osteosarcoma cells. Journal of virology. 2009;84(3): 1366-75. PMID: 19939931 | PMCID: PMC2812316
- Cliffe A, Knipe D. Herpes simplex virus ICP0 promotes both histone removal and acetylation on viral DNA during lytic infection. Journal of virology. 2008;82(24): 12030-8. PMID: 18842720 | PMCID: PMC2593313
- Knipe D, Cliffe A. Chromatin control of herpes simplex virus lytic and latent infection. Nature reviews. Microbiology. 2008;6(3): 211-21. PMID: 18264117