Molecular Biology Of Varicella Zoster Virus Infection

National Institute Of Allergy And Infectious Diseases

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Abstract

Varicella-zoster virus (VZV) establishes latency in human sensory and cranial nerve ganglia during primary infection (varicella), and the virus can reactivate and cause zoster after primary infection. At present, one zoster vaccine is licensed and available for use in the United States. The recombinant zoster vaccine (RZV) consists of recombinant VZV glycoprotein E formulated in AS01B adjuvant. RZV was approved by the Food and Drug Administration for the prevention of herpes zoster in adults aged 50 years and in October 2017 the Advisory Committee on Immunization Practices recommended RZV for use in immunocompetent adults aged 50 years. At present, it is unknown if patients with chronic lymphocytic leukemia (CLL) who have never been treated for their disease or who are receiving Bruton tyrosine kinase inhibitors, which interfere with B cell signaling pathways and may affect antibody responses, can respond well to RZV or other vaccines. In FY 2022 we used a human stem cell-based neuronal model to characterize cellular factors that mediate entry of VZV into cells. Through transcriptional profiling of infected cells, we identified the cell adhesion molecule nectin-1 as a candidate mediator of VZV entry. Nectin-1 is highly expressed in the cell bodies and axons of neurons. Either knockdown of nectin-1 in the cell or incubation of cells with soluble forms of nectin-1 produced in mammalian cells resulted in a marked decrease in VZV infectivity of neurons. While addition of soluble nectin-1 during viral infection inhibited infectivity, addition after infection had no effect on infectivity. Ectopic expression of human nectin-1 in a cell line resistant to productive VZV infection conferred susceptibility to VZV infection. In summary, we have identified nectin-1 as a neuronal entry mediator of VZV. Identification of nectin-1 as a neuronal VZV entry mediator could lead to improved treatments and preventative measures to reduce VZV related morbidity and mortality.