PubMed · 16410514
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Joel S Bader, John Chant. 2006-01-13. Systems biology. When proteomes collide.. https://doi.org/10.1126/science.1123221
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BACKGROUND: Two VZV glycoprotein E (gE D150N) mutant strains were collected in North America in 1995 and in 1999. We now report a novel VZV gE mutant virus discovered in Europe in two VZV strains collected in Stockholm, Sweden, in 1990 and 1999. OBJECTIVES: To characterize the two isolates identified among a total of 634 VZV isolates collected over a 15-year period at the Karolinska University Hospital. STUDY DESIGN: VZV genes were amplified by polymerase chain reaction and their sequences were compared to the genomic sequence of VZV-Dumas prototype strain. RESULTS: A mutation within the gE gene in an epitope recognized by the 3B3 monoclonal antibody was identified in both isolates. A different residue was changed (R152S) compared to the North American strains (D150N). CONCLUSIONS: The occurrence of a VZV gE mutant virus is unusual, but probably a recurring event in Europe and North America. It is unknown whether widespread varicella vaccination programs will alter the rate at which these mutant viruses are isolated.
Varicella-zoster virus (VZV) is an alpha-herpes virus that causes varicella (chickenpox), establishes latency in dorsal root ganglia and may reactivate to cause herpes zoster (shingles). Postherpetic neuralgia is the most common debilitating complication of herpes zoster. It is currently supposed that scarring of the dorsal root ganglia and atrophy of the dorsal horn as a result of intense inflammation may play a central role in the pathogenesis of this condition. The exact pathogenesis of the inflammatory reaction leading to persistent ganglion damage is still poorly understood. However, immune suppression is a recognized risk factor for the development of postzosteric neuralgia in zoster patients (increased risk, e.g., in aged patients over 80 years or diabetes mellitus patients). There is some evidence that remote streptococcal and staphylococcal infections may induce immunologic disease mechanisms consequently affecting the central nervous system. Since streptococcal and/or staphylococcal superinfection of skin lesions is common in herpes zoster, we present a hypothesis of immunopathogenesis of postzosteric neuralgia, i.e., as the result of augmentation of local ganglion inflammation due to bacteria-driven clonal expansion of VZV-specific T-cell subsets in the affected skin. Based on the aforementioned hypothesis it is interesting: (1) to study the impact of concomitant systemic antibiotic treatment to the standard antiviral regimen on the rate and severity of both bacterial superinfection of zoster skin lesions and postzosteric neuralgia and (2) to quantify the VZV-specific T-cell response as a function of the degree of bacterial superinfection of zoster skin lesions. Challenging of the present hypothesis should provide an effective means of preventing postherpetic neuralgia by preventing and consequently treating the bacterial superinfection of zoster skin lesions.
IE62, the major transcriptional regulatory protein encoded by varicella-zoster virus (VZV), is associated with the tegument of gradient-purified virions. Here, we show that most, if not all, of the association requires the expression of open reading frame 66 (ORF66), a protein kinase. The association of IE62 with wild-type VZV virions was confirmed using immunoelectron microscopy with IE62-specific antibodies, which reacted with virions in ultrathin sections of VZV-infected cells. Fractionated purified virions from cells infected with recombinant VZV ROka contained substantial levels of the 175-kDa virion IE62 protein and also contained the ORF66 protein. However, virions from cells infected with recombinant VZV ROka66S, in which ORF66 is disrupted, lacked not only the ORF66 protein but also most of the virion 175-kDa IE62 polypeptide. The virion-associated protein kinase activity was still present in ROka66S virions, although the 175-kDa protein substrate for the virion kinase was absent, implying that the virion protein kinase is encoded by genes other than ORF66. The very low levels of IE62 in ROka66S virions indicate that ORF66 protein mediates the redistribution of IE62 to sites of tegument assembly. IE62 was resolved into several species from VZV-infected cells which showed mobility differences between ROka and ROka66S, and a specific form of IE62 was detected in ROka virions. These results are consistent with a role for the ORF66-mediated phosphorylation of IE62 that results in cytoplasmic distribution of the regulatory protein for tegument inclusion. They support a model in which VZV tegument acquisition occurs in the cytoplasm. As such, two unusual features of VZV IE62, namely, its virion inclusion and its phosphorylation and nuclear exclusion by the ORF66 protein kinase, are functionally linked.