Last data update: Jun 24, 2024. (Total: 47078 publications since 2009)
Records 1-7 (of 7 Records) |
Query Trace: Jensen NJ [original query] |
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Analysis of the reiteration regions (R1 to R5) of varicella-zoster virus.
Jensen NJ , Depledge DP , Ng TFF , Leung J , Quinlivan M , Radford KW , Folster J , Tseng HF , LaRussa P , Jacobsen SJ , Breuer J , Schmid DS . Virology 2020 546 38-50 ![]() ![]() The varicella-zoster virus (VZV) genome, comprises both unique and repeated regions. The genome also includes reiteration regions, designated R1 to R5, which are tandemly repeating sequences termed elements. These regions represent an understudied feature of the VZV genome. The R4 region is duplicated, with one copy in the internal repeat short (IRs) which we designated R4A and a second copy in the terminal repeat short (TRs) termed R4B. We developed primers to amplify and Sanger sequence these regions, including independent amplification of both R4 regions. Reiteration regions from >80 cases of PCR-confirmed shingles were sequenced and analyzed. Complete genome sequences for the remaining portions of these viruses were determined using Illumina MiSeq. We identified 28 elements not previously reported, including at least one element for each R region. Length heterogeneity was substantial in R3, R4A and R4B. Length heterogeneity between the two copies of R4 was common. |
Recurrent herpes zoster in the Shingles Prevention Study: Are second episodes caused by the same varicella-zoster virus strain?
Harbecke R , Jensen NJ , Depledge DP , Johnson GR , Ashbaugh ME , Schmid DS , Breuer J , Levin MJ , Oxman MN . Vaccine 2019 38 (2) 150-157 ![]() ![]() Herpes zoster (HZ) is caused by reactivation of varicella zoster virus (VZV) that established latency in sensory and autonomic neurons during primary infection. In the Shingles Prevention Study (SPS), a large efficacy trial of live attenuated Oka/Merck zoster vaccine (ZVL), PCR-confirmed second episodes of HZ occurred in two of 660 placebo and one of 321 ZVL recipients with documented HZ during a mean follow-up of 3.13years. An additional two ZVL recipients experienced a second episode of HZ in the Long-Term Persistence Substudy. All episodes of HZ were caused by wild-type VZV. The first and second episodes of HZ occurred in different dermatomes in each of these five participants, with contralateral recurrences in two. Time between first and second episodes ranged from 12 to 28months. One of the five participants, who was immunocompetent on study enrollment, was immunocompromised at the onset of his first and second episodes of HZ. VZV DNA isolated from rash lesions from the first and second episodes of HZ was used to sequence the full-length VZV genomes. For the unique-sequence regions of the VZV genome, we employed target enrichment of VZV DNA, followed by deep sequencing. For the reiteration regions, we used PCR amplification and Sanger sequencing. Our analysis and comparison of the VZV genomes from the first and second episodes of HZ in each of the five participants indicate that both episodes were caused by the same VZV strain. This is consistent with the extraordinary stability of VZV during the replication phase of varicella and the subsequent establishment of latency in sensory ganglia throughout the body. Our observations also indicate that VZV is stable during the persistence of latency and the subsequent reactivation and replication that results in HZ. |
Revisiting the genotyping scheme for varicella-zoster viruses based on whole-genome comparisons.
Jensen NJ , Rivailler P , Tseng HF , Quinlivan ML , Radford K , Folster J , Harpaz R , LaRussa P , Jacobsen S , Schmid DS . J Gen Virol 2017 98 (6) 1434-1438 ![]() We report whole-genome sequences (WGSs) for four varicella-zoster virus (VZV) samples from a shingles study conducted by Kaiser Permanente of Southern California. Comparative genomics and phylogenetic analysis of all published VZV WGSs revealed that strain KY037798 is in clade IX, which shall henceforth be designated clade 9. Previously published single nucleotide polymorphisms (SNP)-based genotyping schemes fail to discriminate between clades 6 and VIII and employ positions that are not clade-specific. We provide an updated list of clade-specific positions that supersedes the list determined at the 2008 VZV nomenclature meeting. Finally, we propose a new targeted genotyping scheme that will discriminate the circulating VZV clades with at least a twofold redundancy. Genotyping strategies using a limited set of targeted SNPs will continue to provide an efficient 'first pass' method for VZV strain surveillance as vaccination programmes for varicella and zoster influence the dynamics of VZV transmission. |
Herpes zoster caused by vaccine-strain varicella zoster virus in an immunocompetent recipient of zoster vaccine
Tseng HF , Schmid DS , Harpaz R , Larussa P , Jensen NJ , Rivailler P , Radford K , Folster J , Jacobsen SJ . Clin Infect Dis 2014 58 (8) 1125-8 We report the first laboratory-documented case of herpes zoster caused by the attenuated varicella zoster virus (VZV) contained in Zostavax in a 68-year-old immunocompetent adult with strong evidence of prior wild-type VZV infection. The complete genome sequence of the isolate revealed that the strain carried 15 of 42 (36%) recognized varicella vaccine-associated single-nucleotide polymorphisms, including all 5 of the fixed vaccine markers present in nearly all of the strains in the vaccine. The case of herpes zoster was relatively mild and resolved without complications. |
Deep sequencing of viral genomes provides insight into the evolution and pathogenesis of varicella zoster virus and its vaccine in humans.
Depledge DP , Kundu S , Jensen NJ , Gray ER , Jones M , Steinberg S , Gershon A , Kinchington PR , Schmid DS , Balloux F , Nichols RA , Breuer J . Mol Biol Evol 2014 31 (2) 397-409 ![]() Immunization with the vOka vaccine prevents varicella (chickenpox) in children and susceptible adults. The vOka vaccine strain comprises a mixture of genotypes and, despite attenuation, causes rashes in small numbers of recipients. Like wild-type virus, the vaccine establishes latency in neuronal tissue and can later reactivate to cause Herpes zoster (shingles). Using hybridization-based methodologies, we have purified and sequenced vOka directly from skin lesions. We show that alleles present in the vaccine can be recovered from the lesions and demonstrate the presence of a severe bottleneck between inoculation and lesion formation. Genotypes in any one lesion appear to be descended from one to three vaccine-genotypes with a low frequency of novel mutations. No single vOka haplotype and no novel mutations are consistently present in rashes, indicating that neither new mutations nor recombination with wild type are critical to the evolution of vOka rashes. Instead, alleles arising from attenuation (i.e., not derived from free-living virus) are present at lower frequencies in rash genotypes. We identify 11 loci at which the ancestral allele is selected for in vOka rash formation and show genotypes in rashes that have reactivated from latency cannot be distinguished from rashes occurring immediately after inoculation. We conclude that the vOka vaccine, although heterogeneous, has not evolved to form rashes through positive selection in the mode of a quasispecies, but rather alleles that were essentially neutral during the vaccine production have been selected against in the human subjects, allowing us to identify key loci for rash formation. |
Novel genetic variation identified at fixed loci in ORF62 of the Oka varicella vaccine and in a case of vaccine-associated herpes zoster.
Quinlivan ML , Jensen NJ , Radford KW , Schmid DS . J Clin Microbiol 2012 50 (5) 1533-8 ![]() The live attenuated Oka varicella vaccine (vOka), derived from clade 2 wild type (wt) virus, pOka, is used for routine childhood immunization in several countries including the United States (US), causing dramatic declines in varicella incidence. vOka can cause varicella, establish latency and reactivate to cause herpes zoster (HZ). Three loci in varicella-zoster virus (VZV) open reading frame (ORF) 62 (106262, 107252, 108111) are used to distinguish vOka from wt VZV. A 4(th) position (105705) is also fixed for the vOka allele in nearly all vaccine batches. These 4 positions and two vOka mutations (106710 & 107599) reportedly absent from Varivax were analyzed on Varivax-derived ORF62 TOPO TA clones. The wt allele was detected at positions 105705 and 107252 on 3% and 2% of clones, respectively, but was absent at positions 106262 and 108111. Position 106710 was fixed for the wt allele whereas the vOka allele was present on 18.4% of clones at position 107599. We also evaluated the 4 vOka markers in an isolate obtained from a case of vaccine HZ. The isolate carried the vOka allele at positions 105705, 106262 and 108111. However, at position 107252 the wt allele was present. Thus, all of the ORF62 vOka markers previously regarded as fixed occur as the wt allele in a small percentage of vOka strains. Characterization of all four vOka markers in ORF62 and the Clade 2 subtype marker in ORF38 is now necessary to confirm vOka adverse events. |
Regulation of the expression of the varicella-zoster virus open reading frame 66 gene.
Folster JM , Jensen NJ , Ruyechan WT , Inoue N , Schmid DS . Virus Res 2010 155 (1) 334-42 ![]() The varicella-zoster virus (VZV) open reading frame (ORF) 66 encodes a serine/threonine kinase that phosphorylates the major viral transactivator protein, immediate-early (IE) 62, preventing its nuclear importation. Cytoplasmic sequestration of IE62 may alter viral gene transcription and could serve as a mechanism for maintaining VZV latency. We examined the regulation of expression of the ORF66 gene by mapping the promoter region, which was localized to within 150 bases of the start codon. The ORF66 promoter was activated by two viral regulatory proteins, IE62 and IE63. We evaluated the binding of viral regulatory proteins and cellular transcription factors based on recognized cellular transcription factor binding sites identified within the ORF66 promoter. These included Sp1 and TBP binding sites, several of which were essential for optimal promoter activity. Site-directed mutations in Sp1 and TBP binding sites led to varying degrees of impairment of ORF66 gene expression in the context of VZV infection. We also examined the effect of Sp1 and TBP mutations on IE62, Sp1, and TBP binding. These studies reveal that host cell-derived and viral factors contribute to and cooperate in the expression of this important viral kinase gene. |
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