The BglII-N fragment of herpes simplex virus type 2 contains a region responsible for resistance to antiviral effects of interferon.

Narita, Masaya; Ando, Yumiko; Soushi, Sumi; Kurata, Takeshi; Arao, Yujiro

doi:10.1099/0022-1317-79-3-565

Cited by 11 publications

(6 citation statements)

References 36 publications

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“…The data in this study suggest that major determinants of corneal resistance to viral invasion are the IFNs, since KOS was capable of robust replication in corneas and ganglia of nonscarified IFNR −/− mice. This is consistent with the idea that different HSV strains may be differentially susceptible to the effects of IFNs ( 11 , 12 ).…”

Section: Discussionsupporting

confidence: 90%

“…Only a few studies have examined a role for the host immune system in influencing the in vivo phenotypes of HSV strains and mutants. For example, infected cell protein (ICP)47 has been shown to influence neurovirulence by blocking CD8 + T cell responses, and certain large genomic fragments of HSV-1 and HSV-2 strains have been shown to confer resistance to IFNs, although specific genes have not been identified ( 5 , 11 , 12 ). This line of investigation is especially relevant to those viruses whose growth in culture is significantly reduced due to mutation of a transactivation function such as ICP0 ( 13 , 14 ), or a DNA replication function such as ribonucleotide reductase ( rr ) or thymidine kinase ( tk ), without which the virus cannot thrive in nondividing cells ( 15 , 16 ).…”

mentioning

confidence: 99%

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Interferons Regulate the Phenotype of Wild-type and Mutant Herpes Simplex Viruses In Vivo

Leib

Harrison

Laslo

et al. 1999

The Journal of Experimental Medicine

314

278

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Mechanisms responsible for neuroattenuation of herpes simplex virus (HSV) have been defined previously by studies of mutant viruses in cultured cells. The hypothesis that null mutations in host genes can override the attenuated phenotype of null mutations in certain viral genes was tested. Mutants such as those in infected cell protein (ICP) 0, thymidine kinase, ribonucleotide reductase, virion host shutoff, and ICP34.5 are reduced in their capacity to replicate in nondividing cells in culture and in vivo. The replication of these viruses was examined in eyes and trigeminal ganglia for 1–7 d after corneal inoculation in mice with null mutations (−/−) in interferon receptors (IFNR) for type I IFNs (IFN-α/βR), type II IFN (IFN-γR), and both type I and type II IFNs (IFN-α/β/γR). Viral titers in eyes and ganglia of IFN-γR−/− mice were not significantly different from congenic controls. However, in IFN-α/βR−/− or IFN-α/β/γR−/− mice, growth of all mutants, including those with significantly impaired growth in cell culture, was enhanced by up to 1,000-fold in eyes and trigeminal ganglia. Blepharitis and clinical signs of infection were evident in IFN-α/βR−/− and IFN-α/β/γR−/− but not control mice for all viruses. Also, IFNs were shown to significantly reduce productive infection of, and spread from intact, but not scarified, corneas. Particularly striking was restoration of near-normal trigeminal ganglion replication and neurovirulence of an ICP34.5 mutant in IFN-α/βR−/− mice. These data show that IFNs play a major role in limiting mutant and wild-type HSV replication in the cornea and in the nervous system. In addition, the in vivo target of ICP34.5 may be host IFN responses. These experiments demonstrate an unsuspected role for host factors in defining the phenotypes of some HSV mutants in vivo. The phenotypes of mutant viruses therefore cannot be interpreted based solely upon studies in cell culture but must be considered carefully in the context of host factors that may define the in vivo phenotype.

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Interferons Regulate the Phenotype of Wild-type and Mutant Herpes Simplex Viruses In Vivo

Leib

Harrison

Laslo

et al. 1999

The Journal of Experimental Medicine

314

278

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“…Genetic studies have mapped IFN resistance to a 7.4-kb region of the HSV-2 genome that contains the vhs gene and portions of two flanking genes (35). Another genetic locus influencing HSV-2 resistance to IFN-␣/␤ has been mapped 60 kb distant from the vhs locus (51).…”

mentioning

confidence: 99%

Herpes Simplex Virus Type 2 Virion Host Shutoff Protein Regulates Alpha/Beta Interferon but Not Adaptive Immune Responses during Primary Infection In Vivo

Murphy¹,

Duerst²,

Smith

et al. 2003

J Virol

109

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Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are ubiquitous human pathogens that cause a variety of serious diseases. Primary HSV infections typically initiate at mucosal surfaces, where lytic replication in epithelial cells generates mucosal lesions. Peripheral replication amplifies the virus load and increases uptake of virus into sensory nerve termini. Establishment of latent infections in sensory neurons secures shelter for the virus throughout the life of the host. Periodic reactivations result in disease recurrence and provide an opportunity for transmission to new hosts.The virion host shutoff (vhs) protein of HSV plays a significant role in promoting pathogenesis at the cell and organismal levels. In the infected cell, vhs possesses both endo-and exonuclease activity (8, 9, 57) and mediates the rapid shutoff of protein synthesis via degradation of both cellular and viral mRNAs (22,23,39,43). As a component of the virion tegument, vhs is released directly into the cytosol and can immediately exert its effects on the newly infected cell. Cellular mRNAs are almost completely degraded within 6 h of infection with HSV-1, and within just 2 h by HSV-2 (19). The activity of HSV-2 vhs is also approximately 40-fold stronger than that of HSV-1 (10, 11). In vivo, vhs null mutants of HSV-1 and HSV-2 are profoundly attenuated, implicating vhs as a virulence factor that helps HSV establish robust infection. HSV-1 lacking vhs activity replicates to 1,000-fold-lower titers in the cornea, trigeminal ganglia, and brain of mice than wildtype virus and has impaired capacity to enter the central nervous system, establish latency, and undergo reactivation (48-50). vhs-deficient HSV-2 strains (333-vhsB or 333d41) also replicate much less efficiently than wild-type virus in the genital mucosa and nervous tissue of mice and cause less disease (47). vhs has been implicated in down-regulating major histocompatibility complex (MHC) class I (18, 54) and class II (55) molecules. This activity has functional implications because it is associated with reduced cytotoxic T-lymphocyte recognition

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“…4) HSV-1 ICP27 can decrease IFN-activated STAT1 phosphorylation and partially block STAT1 translocation to cell nuclei (Johnson and Knipe, 2010; Johnson et al, 2008). 5) The HSV encoded RNase, virion host shutoff (VHS) protein, degrades cellular transcripts and thereby prevents expression of IFN-associated antiviral genes (Chee and Roizman, 2004; Duerst and Morrison, 2004; Murphy et al, 2003; Narita et al, 1998; Su et al, 1993). Mutant viruses that specify deletions in these genes exhibit increased sensitivity to IFNs and are highly attenuated in mouse models (Duerst and Morrison, 2003; Halford et al, 2010; Korom et al, 2008; Leib et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Mutant viruses that specify deletions in these genes exhibit increased sensitivity to IFNs and are highly attenuated in mouse models (Duerst and Morrison, 2003; Halford et al, 2010; Korom et al, 2008; Leib et al, 1999). Although a paucity of direct mechanistic studies exist for HSV-2, genetic mapping and pathogenic studies have indicated that the HSV-2 VHS protein is vital for regulating type-I IFN responses, and therefore, deletion of VHS profoundly attenuates HSV-2 in vivo (Murphy et al, 2003; Narita et al, 1998; Su et al, 1993). …”

Section: Introductionmentioning

confidence: 99%

HSV-2 inhibits type-I interferon signaling via multiple complementary and compensatory STAT2-associated mechanisms

2012

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Type-1 interferon (IFN)-mediated responses are a crucial first line of defense against viral infections and are critical for generating both innate and adaptive immunity. Therefore, viruses have necessarily evolved mechanisms to impede the IFN response. HSV-2 was found to completely abolish type-1 IFN-mediated signaling via multiple STAT2-associated mechanisms. Although the extent and kinetics of this inactivation were indistinguishable between the various cell-lines examined, there were distinct differences in the mechanisms HSV-2 employed to subvert IFN-signaling amongst the cell-lines. These mechanistic differences could be segregated into two categories dependent on the phase of the HSV replicative cycle that was responsible for this inhibition: 1) early phase-inhibited cells which exhibited abrogation of IFN-signaling prior to viral DNA replication; 2) late phase-inhibited cells where early phase inhibition mechanisms were not functional, but viral functions expressed following DNA replication compensated for their ineffectiveness. In early phase-inhibited cells, HSV-2 infection targeted STAT2 protein for proteosomal degradation and prevented de novo expression of STAT2 by degrading its mRNA. In contrast, HSV-2 infected late phase-inhibited cells exhibited no apparent changes in STAT2 transcript or protein levels. However, in these cells STAT2 was not activated by phosphorylation and failed to translocate to the cell nucleus, thereby preventing transactivation of antiviral genes. In primary human fibroblasts, HSV-2 failed to fully degrade STAT2 and therefore, both early and late phase mechanisms functioned cooperatively to subvert IFN-mediated antiviral gene expression. Taken together, these results indicate the importance that HSV-2 has assigned to STAT2, investing significant genomic currency throughout its replicative lifecycle for continuous targeted destruction and inhibition of this protein.

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The BglII-N fragment of herpes simplex virus type 2 contains a region responsible for resistance to antiviral effects of interferon.

Cited by 11 publications

References 36 publications

Interferons Regulate the Phenotype of Wild-type and Mutant Herpes Simplex Viruses In Vivo

Interferons Regulate the Phenotype of Wild-type and Mutant Herpes Simplex Viruses In Vivo

Herpes Simplex Virus Type 2 Virion Host Shutoff Protein Regulates Alpha/Beta Interferon but Not Adaptive Immune Responses during Primary Infection In Vivo

HSV-2 inhibits type-I interferon signaling via multiple complementary and compensatory STAT2-associated mechanisms

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