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Manipulation of Host Cell Death Pathways by Herpes Simplex Virus

  • Sudan HeEmail author
  • Jiahuai HanEmail author
Part of the Current Topics in Microbiology and Immunology book series


Herpes simplex virus (HSV)-1 and HSV-2 are ubiquitous human pathogens that infect keratinized epithelial surfaces and establish lifelong latent infection in sensory neurons of the peripheral nervous system. HSV-1 causes oral cold sores, and HSV-2 causes genital lesions characterized by recurrence at the site of the initial infection. In multicellular organisms, cell death plays a pivotal role in host defense by eliminating pathogen-infected cells. Apoptosis and necrosis are readily distinguished types of cell death. Apoptosis, the main form of programmed cell death, depends on the activity of certain caspases, a family of cysteine proteases. Necroptosis, a regulated form of necrosis that is unleashed when caspase activity is compromised, requires the activation of receptor-interacting protein (RIP) kinase 3 (RIPK3) through its interaction with other RIP homotypic interaction motif (RHIM)-containing proteins such as RIPK1. To ensure lifelong infection in the host, HSV carries out sophisticated molecular strategies to evade host cell death responses during viral infection. HSV-1 is a well-characterized pathogen that encodes potent viral inhibitors that modulate both caspase activation in the apoptosis pathway and RIPK3 activation in the necroptosis pathway in a dramatic, species-specific fashion. The viral UL39-encoded viral protein ICP6, the large subunit of the virus-encoded ribonucleotide reductase, functions as a suppressor of both caspase-8 and RHIM-dependent RIPK3 activities in the natural human host. In contrast, ICP6 RHIM-mediated recruitment of RIPK3 in the nonnatural mouse host drives the direct activation of necroptosis. This chapter provides an overview of the current state of the knowledge on molecular interactions between HSV-1 viral proteins and host cell death pathways and highlights how HSV-1 manipulates cell death signals for the benefit of viral propagation.


Herpesvirus Cell death suppression RHIM MLKL Innate immunity 



We would like to acknowledge Dr. Edward S. Mocarski at Emory University School of Medicine for critical reading of the manuscript.


This work was supported by the National Natural Science Foundation of China (31671436 and 31830051) and CAMS Initiative for Innovative Medicine (CAMS-I2M, 2016-I2M-1-005).


Sudan He and Jiahuai Han wrote and edited the manuscript. All authors approved the manuscript before it was submitted.

Declaration of Interest

Sudan He and Jiahuai Han declare that they have no conflict of interest.


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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Center of Systems MedicineInstitute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
  2. 2.Suzhou Institute of Systems MedicineSuzhouChina
  3. 3.State Key Laboratory of Cellular Stress Biology, School of Life SciencesXiamen UniversityXiamenChina

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