A Herpes Simplex Virus 2 Glycoprotein D Mutant Generated by Bacterial Artificial Chromosome Mutagenesis Is Severely Impaired for Infecting Neuronal Cells and Infects Only Vero Cells Expressing Exogenous HVEM

Wang, Kening; Kappel, Justin; Canders, Caleb P.; Davila, Wilmer F.; Sayre, Dean; Chavez, Mayra; Pesnicak, Lesley; Cohen, Jeffrey I.

doi:10.1128/jvi.01055-12

Cited by 33 publications

(36 citation statements)

References 65 publications

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“…They were initially isolated in human diploid fibroblasts and then passaged twice in Vero cells prior to DNA preparation. The U.S. laboratory strain 333-R519 was propagated as described previously (16). The U.S. strain BethesdaP5 is a fresh human isolate that has been passaged only 4 times and only in human diploid fibroblasts (MRC5 cells).…”

Section: Methodsmentioning

confidence: 99%

Genome Sequencing and Analysis of Geographically Diverse Clinical Isolates of Herpes Simplex Virus 2

Newman

Lamers²,

Weiner

et al. 2015

J Virol

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100

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Herpes simplex virus 2 (HSV-2), the principal causative agent of recurrent genital herpes, is a highly prevalent viral infection worldwide. Limited information is available on the amount of genomic DNA variation between HSV-2 strains because only two genomes have been determined, the HG52 laboratory strain and the newly sequenced SD90e low-passage-number clinical isolate strain, each from a different geographical area. In this study, we report the nearly complete genome sequences of 34 HSV-2 lowpassage-number and laboratory strains, 14 of which were collected in Uganda, 1 in South Africa, 11 in the United States, and 8 in Japan. Our analyses of these genomes demonstrated remarkable sequence conservation, regardless of geographic origin, with the maximum nucleotide divergence between strains being 0.4% across the genome. In contrast, prior studies indicated that HSV-1 genomes exhibit more sequence diversity, as well as geographical clustering. Additionally, unlike HSV-1, little viral recombination between HSV-2 strains could be substantiated. These results are interpreted in light of HSV-2 evolution, epidemiology, and pathogenesis. Finally, the newly generated sequences more closely resemble the low-passage-number SD90e than HG52, supporting the use of the former as the new reference genome of HSV-2. IMPORTANCEHerpes simplex virus 2 (HSV-2) is a causative agent of genital and neonatal herpes. Therefore, knowledge of its DNA genome and genetic variability is central to preventing and treating genital herpes. However, only two full-length HSV-2 genomes have been reported. In this study, we sequenced 34 additional HSV-2 low-passage-number and laboratory viral genomes and initiated analysis of the genetic diversity of HSV-2 strains from around the world. The analysis of these genomes will facilitate research aimed at vaccine development, diagnosis, and the evaluation of clinical manifestations and transmission of HSV-2. This information will also contribute to our understanding of HSV evolution. Herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2) are two closely related human species of herpesviruses in the genus Simplexvirus of the family Herpesviridae (1). HSV-1 is mostly associated with orofacial infections, while HSV-2 is generally associated with genital herpes. Both viruses cause significant human disease, so knowledge of the structure of their DNA genomes and the extent of their genetic variation is very important. A high overall GC content and the presence of highly reiterated repeat regions in both noncoding and coding portions of the genome complicate sequence determination (2).The HSV linear double-stranded DNA genomes consist of two covalent linked components, the long (L) and short (S) components, which invert relative to each other by intramolecular recombination (1). The L component consists of unique sequences (U L ) bounded by inverted repeats (R L and R L =), and the S component consists of unique sequences (U S ) bounded by inverted repeats (R S and R S =) (3). The termini con...

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Section: Methodsmentioning

confidence: 99%

Genome Sequencing and Analysis of Geographically Diverse Clinical Isolates of Herpes Simplex Virus 2

Newman

Lamers²,

Weiner

et al. 2015

J Virol

Self Cite

100

View full text Add to dashboard Cite

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“…HSV-2 mainly infects epithelial cells and causes genital herpes. It also infects neuronal cells and leu-kocytes including dendritic cells (34)(35)(36), leading to encephalitis and disseminated diseases that affect other organ systems (37,38). HSV-2 can establish a lifelong latent infection in sacral ganglia (39), resulting in up to 40% human adults living with HSV-2 latency (40).…”

mentioning

confidence: 99%

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

Zhang

Liu

Wang

et al. 2015

The Journal of Immunology

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HSV-2 is the major cause of genital herpes, and its infection increases the risk of HIV-1 acquisition and transmission. After initial infection, HSV-2 can establish latency within the nervous system and thus maintains lifelong infection in humans. It has been suggested that HSV-2 can inhibit type I IFN signaling, but the underlying mechanism has yet to be determined. In this study, we demonstrate that productive HSV-2 infection suppresses Sendai virus (SeV) or polyinosinic-polycytidylic acid-induced IFN-β production. We further reveal that US1, an immediate-early protein of HSV-2, contributes to such suppression, showing that US1 inhibits IFN-β promoter activity and IFN-β production at both mRNA and protein levels, whereas US1 knockout significantly impairs such capability in the context of HSV-2 infection. US1 directly interacts with DNA binding domain of IRF-3, and such interaction suppresses the association of nuclear IRF-3 with the IRF-3 responsive domain of IFN-β promoter, resulting in the suppression of IFN-β promoter activation. Additional studies demonstrate that the 217–414 aa domain of US1 is critical for the suppression of IFN-β production. Our results indicate that HSV-2 US1 downmodulates IFN-β production by suppressing the association of IRF-3 with the IRF-3 responsive domain of IFN-β promoter. Our findings highlight the significance of HSV-2 US1 in inhibiting IFN-β production and provide insights into the molecular mechanism by which HSV-2 evades the host innate immunity, representing an unconventional strategy exploited by a dsDNA virus to interrupt type I IFN signaling pathway.

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“…HSV2-gD27, also a derivative of BAC clone bHSV2-BAC38, has point mutations (D215G, R222N, and F223I) in gD that impair the ability of gD to interact with the HSV-2 cellular receptor nectin-1, and therefore it is unable to infect cells that do not express functional HVEM (33). HSV2-gD27 was propagated and titrated in B78H1-A10 cells.…”

Section: Cells and Virusesmentioning

confidence: 99%

“…R519 was propagated and titrated in Vero cells. HSV-2 H312-1BB Ϫ (HSV2-⌬BAC38) is a derivative of the HSV-2 bacterial artificial chromosome (BAC) clone bHSV2-BAC38; the BAC cassette was removed when the virus was rescued in Vero cells, and its phenotype is similar to that of R519 in mouse models (33). HSV-2 H312-1BB…”

Section: Cells and Virusesmentioning

confidence: 99%

“…Mutations in one domain can impair the ability of HSV gD to use one receptor but not the other receptor (28,31,32). Accordingly, we constructed an HSV-2 gD mutant virus, HSV2-gD27, in which the nectin-1 binding domain was mutated and the virus was impaired for infecting neuronal cells in vitro and in vivo (33). Here we report the stability and attenuation of the HSV2-gD27 virus and its efficacy in protecting mice from genital herpes after intravaginal challenge.…”

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confidence: 99%

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A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2

Wang

Goodman

et al. 2016

J Virol

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G enital herpes simplex is one of the most prevalent sexually transmitted diseases. In 2012, more than 417 million persons worldwide were reported to be infected with herpes simplex virus 2 (HSV-2), with more than 19.2 million new persons infected in that year alone (1). While HSV-2 disease is mild in most cases, infection can be severe and life threatening in immunocompromised patients and neonates. In addition, genital herpes increases the risk of acquisition of HIV infection 3-fold (2). While HSV-2 traditionally has been the principal cause of genital herpes, more recent studies have shown that HSV-1 may be replacing HSV-2 as the most frequent cause of genital herpes in the United States (3, 4). While both HSV-1 and HSV-2 cause primary and recurrent genital herpes, genital recurrences are much more frequent with HSV-2 than with HSV-1 (5).HSV-2 infects epithelial cells in the vaginal mucosa, replicates in the cells, and enters the nerve endings innervating the mucosa. Viral capsids travel retrograde in axons to the cell body in sensory ganglia, where HSV establishes a latent infection in the nuclei of neurons. Latent HSV can be reactivated by multiple stimuli, such as stress, fever, and exposure to UV light. Viral capsids travel anterograde from the ganglion down the axons to the mucosa, where the virus replicates and is shed in the presence or absence of symptomatic genital lesions. This allows the virus to spread to unin- Citation Wang K, Goodman KN, Li DY, Raffeld M, Chavez M, Cohen JI. 2016. A herpes simplex virus 2 (HSV-2) gD mutant impaired for neural tropism is superior to an HSV-2 gD subunit vaccine to protect animals from challenge with HSV-2.

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A Herpes Simplex Virus 2 Glycoprotein D Mutant Generated by Bacterial Artificial Chromosome Mutagenesis Is Severely Impaired for Infecting Neuronal Cells and Infects Only Vero Cells Expressing Exogenous HVEM

Cited by 33 publications

References 65 publications

Genome Sequencing and Analysis of Geographically Diverse Clinical Isolates of Herpes Simplex Virus 2

Genome Sequencing and Analysis of Geographically Diverse Clinical Isolates of Herpes Simplex Virus 2

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2

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