Intrastrain Variants of Herpes Simplex Virus Type 1 Isolated from a Neonate with Fatal Disseminated Infection Differ in the ICP34.5 Gene, Glycoprotein Processing, and Neuroinvasiveness

Bower, John R.; Mao, Hongyi; Durishin, Catherine; Rozenbom, Edgardo; Detwiler, Michelle; Rempinski, Donald; Karban, Tracy L.; Rosenthal, Ken S.

doi:10.1128/jvi.73.5.3843-3853.1999

Cited by 46 publications

(20 citation statements)

References 40 publications

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“…The amino terminal domain is implicated in virus maturation, by a yet unclear mechanism [8]. The linker region, with a varying number of the triplet repeats, modulates neuroinvasion [9]. The carboxyl terminal domain functions to counteract the PKR response by host cells [6,10].…”

Section: Introductionmentioning

confidence: 99%

A conserved domain of herpes simplex virus ICP34.5 regulates protein phosphatase complex in mammalian cells

et al. 2007

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ICP34.5, encoded by herpes simplex virus 1, is a protein phosphatase 1 (PP1) regulatory subunit that mediates dephosphorylation of the a subunit of translation initiation factor 2 (eIF2a). However, the mechanism of its action remains poorly understood. Here, we show that amino acid substitutions in the arginine-rich motif have differential effects on ICP34.5 activity. The phenotypes parallel with viral protein synthesis and cytopathic effects in virus infected cells. Besides the consensus PP1 binding motif, the Arg-motif appears to enhance the interaction between ICP34.5 and PP1. These results suggest that concerted action between the PP1 binding domain and the effector domain of ICP34.5 is crucial for eIF2a dephosphorylation and viral protein synthesis.

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Section: Introductionmentioning

confidence: 99%

A conserved domain of herpes simplex virus ICP34.5 regulates protein phosphatase complex in mammalian cells

et al. 2007

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“…While cycles of latency and reactivation are a well-established and accepted aspect of herpesvirus biology [1,10], the concept of HSV-1 exhibiting substantial genetic diversity and evolutionary potential within an infected individual has only recently been established [6,11–15]. As with other herpesviruses, HSV-1 has a large double-stranded DNA (dsDNA) genome, and these viruses have generally been considered to be genetically stable in comparison to viruses with an RNA genome [5,16].…”

Section: Introductionmentioning

confidence: 99%

In vitroevolution of herpes simplex virus 1 (HSV-1) reveals selection for syncytia and other minor variants in Vero cell culture

Kuny

Bowen

Renner

et al. 2019

Preprint

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AbstractThe large dsDNA virus HSV-1 is often considered to be genetically stable, however it is known to rapidly evolve in response to strong selective pressures such as antiviral drug treatment. Deep sequencing analysis has revealed that clinical and laboratory isolates of this virus exist as populations that contain a mixture of minor alleles or variants, similar to many RNA viruses. Classical virology methods often used plaque-purified virus populations to demonstrate consistent genetic inheritance of viral traits. Plaque purification represents a severe genetic bottleneck which may or may not be representative of natural transmission of HSV-1. Since HSV-1 has a low error rate polymerase but exhibits substantial genetic diversity, the virus likely uses other mechanisms to generate genetic diversity, including recombination, contraction and expansion of tandem repeats, and imprecise DNA repair mechanisms. We sought to study the evolution of HSV-1 in vitro, to examine the impact of this genetic diversity in evolution, in the setting of standard laboratory conditions for viral cell culture, and in the absence of strong selective pressures. We found that a mixed population of HSV-1 was more able to evolve and adapt in culture than a plaque-purified population, though this adaptation generally occurred in a minority of the viral population. We found that certain genetic variants appeared to be positively selected for rapid growth and spread in Vero cell culture, a phenotype which was also observed in clinical samples during their first passages in culture. In the case of a minor variant that induces a visually observable syncytial phenotype, we found that changes in minor variant frequency can have a large effect on the overall phenotype of a viral population.Author SummaryHerpes simplex virus type 1 (HSV-1) is a common virus, affecting over half of the adult human population, although it presents variable levels of disease burden and frequency of symptomatic recurrence. Antiviral treatments for HSV-1 infections are available, but thus far attempts at vaccine development have been foiled by insufficient immunity and/or viral escape. As a virus with a double-stranded DNA genome, HSV-1 is generally considered to be genetically stable and to have limited evolutionary potential. As these two statements are in conflict, we examined the ability of HSV-1 to evolve in a standardized cell culture setting. We utilized two HSV-1 isolates in this experiment, one with multiple viral genotypes present, which is similar to the viral populations seen in clinical settings, and one with a highly clonal viral population, which is similar to those often used in laboratory settings. After multiple rounds of replication, we analyzed the sequences of each passaged population. We found that the mixed viral population changed substantially over passage, and we were able to track specific genetic variants to phenotypic traits. By comparison, evolution in the clonal virus population was more limited. These data indicate that HSV-1 is capable of evolving rapidly, and that this evolution is facilitated by diversity in the viral population.

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“…Notably, site-specific disruption of the ␥ 1 34.5-PP1 interaction abrogates viral virulence (13,14). HSV ␥ 1 34.5 is also reported to affect glycoprotein processing and viral spread (15,16). Furthermore, evidence suggests that the ␥ 1 34.5 protein displays additional activities.…”

mentioning

confidence: 99%

Selective Editing of Herpes Simplex Virus 1 Enables Interferon Induction and Viral Replication That Destroy Malignant Cells

Xing

2019

J Virol

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Oncolytic herpes simplex virus 1 (HSV-1), devoid of the γ134.5 gene, exerts antitumor activities. However, the oncolytic effects differ, ranging from pronounced to little responses. Although viral and host factors are involved, much remains to be deciphered. Here we report that engineered HSV-1 ΔN146, bearing amino acids 147 to 263 of γ134.5, replicates competently in and lyses malignant cells refractory to the γ134.5 null mutant. Upon infection, ΔN146 precludes phosphorylation of translation initiation factor eIF2α (α subunit of eukaryotic initiation factor 2), ensuring viral protein synthesis. On the other hand, ΔN146 activates interferon (IFN) regulatory factor 3 (IRF3) and IFN expression, known to prime immunity against virus and tumor. Nevertheless, ΔN146 exhibits sustained replication even exposed to exogenous IFN-α. In a 4T1 tumor model, ΔN146 markedly reduces tumor growth and metastasis formation. This coincides with viral replication or T cell infiltration in primary tumors. ΔN146 is undetectable in normal tissues in vivo. Targeted HSV-1 editing results in a unique antineoplastic agent that enables inflammation without major interference of viral growth within tumor cells. IMPORTANCE Oncolytic herpes simplex virus 1 is a promising agent for cancer immunotherapy. Due to a complex virus-host interaction, less is clear about what viral signature(s) constitutes a potent oncolytic backbone. Through molecular or genetic dissection, we showed that selective editing of the γ134.5 gene enables viral replication in malignant cells, activation of transcription factor IRF3, and subsequent induction of type I IFN. This translates into profoundly reduced primary tumor growth and metastasis burden in an aggressive breast carcinoma model in vivo. Our work reveals a distinct oncolytic platform that is amendable for further development.

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Intrastrain Variants of Herpes Simplex Virus Type 1 Isolated from a Neonate with Fatal Disseminated Infection Differ in the ICP34.5 Gene, Glycoprotein Processing, and Neuroinvasiveness

Cited by 46 publications

References 40 publications

A conserved domain of herpes simplex virus ICP34.5 regulates protein phosphatase complex in mammalian cells

A conserved domain of herpes simplex virus ICP34.5 regulates protein phosphatase complex in mammalian cells

In vitroevolution of herpes simplex virus 1 (HSV-1) reveals selection for syncytia and other minor variants in Vero cell culture

Selective Editing of Herpes Simplex Virus 1 Enables Interferon Induction and Viral Replication That Destroy Malignant Cells

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