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 varicella vaccine and one zoster vaccine are licensed and available for use in the United States. The live-attenuated varicella vaccine has reduced the burden of chickenpox; however, the mechanism by which this varicella Oka vaccine (vOka) is attenuated is unclear. While attenuation has been attributed to mutations in the genome acquired during cell culture passage of pOka (parent strain), the precise understanding of attenuation remains unknown. In 2023, we found that that pOka consists of a heterogenous population of virus sequences with two nearly equally represented bases, guanine (G) or adenine (A), at nucleotide 2096 of the ORF31 coding sequence, which encodes glycoprotein B (gB) resulting in arginine (R) or glutamine (Q), respectively, at amino acid 699 of gB. In contrast, 2096A/699Q is dominant in vOka (>99.98%). Glycoproteins gB, gH, and gL are required for fusion of varicella-zoster virus to cells. Transfection of cells with gB 699Q and gH and gL showed significantly less fusion activity than gB 699R and gH and gL in a cell-based fusion assay. Recombinant pOka with gB669Q had a similar growth phenotype as vOka during lytic infection in cell culture including human primary skin cells; however, recombinant pOka with gB669R showed a growth phenotype similar to pOka. Recombinant pOka with gB669R entered neurons from axonal terminals more efficiently than recombinant pOka with gB669Q in the presence of cell membrane-derived vesicles containing gB. Strikingly, when a mixture of pOka with both alleles equally represented was used to infect human neurons from axon terminals, pOka with gB699R was dominant for virus entry. These results identify a variant allele in gB that contributes to attenuation of vOka. Identification of a variant allele in gB, one of the essential herpesvirus core genes, that contributes to its attenuation may provide insights that assist in the development of other herpesvirus vaccines.