Vaccinia virus glycoproteins and immune evasion: The Sixteenth Fleming Lecture

Smith, Geoffrey L.

doi:10.1099/0022-1317-74-9-1725

Cited by 72 publications

(41 citation statements)

References 55 publications

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“…The products of VV genes E3L and K3L inhibit the activation and/or activity of PKR (6,8). Moreover, the VV analog of the IFN-␥R encoded by gene B8R competes with and blocks the binding of IFN-␥ to its natural receptor (46,59). We demonstrate here that VV can block IFN-␥ responses by another mechanism, inhibiting the IFN-␥ signal transduction pathway.…”

Section: Discussionmentioning

confidence: 71%

See 1 more Smart Citation

Vaccinia Virus Blocks Gamma Interferon Signal Transduction: Viral VH1 Phosphatase Reverses Stat1 Activation

Najarro

Traktman

Lewis

2001

J Virol

170

145

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We have analyzed the effects of vaccinia virus (VV) on gamma interferon (IFN-␥) signal transduction. Infection of cells with VV 1 to 2 h prior to treatment with IFN-␥ inhibits phosphorylation and nuclear translocation of Stat1 and consequently blocks accumulation of mRNAs normally induced by IFN-␥. While phosphorylation of other proteins in the IFN-␥ pathway was not affected, activation of Stat1 by other ligandreceptor systems was also blocked by VV. This block of Stat1 activation was dose dependent, and although viral protein synthesis was not required, entry and uncoating of viral cores appear to be needed to block the accumulation of phosphorylated Stat1. These results suggest that a virion component is responsible for the effect. VV virions contain a phosphatase (VH1) that is sensitive to the phosphatase inhibitor Na 3 VO 4 but not to okadaic acid. Addition of Na 3 VO 4 but not okadaic acid restored normal Stat1 phosphorylation levels in VV-infected cells. Moreover, virions containing reduced levels of VH1 were unable to block the IFN-␥ signaling pathway. In vitro studies show that the phosphatase can bind and dephosphorylate Stat1, indicating that this transcription factor can be a substrate for VH1. Our results reveal a novel mechanism by which VV interferes with the onset of host immune responses by blocking the IFN-␥ signal cascade through the dephosphorylating activity of the viral phosphatase VH1.Gamma interferon (IFN-␥) plays a key role in host defense (67). It regulates the adaptive immune response by enhancing major histocompatibility complex (MHC) class I expression in most cells and inducing MHC class II expression in antigenpresenting cells and endothelial cells. It is also the major physiological activating factor of macrophages and is responsible for induction of nonspecific immune responses. IFN-␥ acts synergistically with tumor necrosis factor (cytotoxic activity/ inflammatory response) and IFN␣/␤ (antiviral activity). IFNs are essential and functionally nonredundant in successful host responses to certain viruses (48).IFN-␥ exerts its action through its ability to bind to the IFN-␥ receptor (IFN-␥R) and induce dimerization of receptor ␣ and ␤ subunit pairs to form a heterotetramer (18,19). The IFN-␥R ␣ and ␤ chains associate with Janus protein kinases Jak1 and Jak2, respectively (34,37,47,65). Ligand-induced association of the receptor subunits allows these kinases to phosphorylate the IFN-␥R␣. The phosphorylated tyrosine (PTyr) and adjacent residues constitute a docking site for the sh2 domain of Stat1 (p91) (16,22), which is present in the cytoplasm as a latent transcription factor. Once bound to the receptor-Jak complex, Stat1 is phosphorylated (p91-P) (57) and subsequently dissociates from the receptor and homodimerizes, by a process that is not fully understood, to form the IFN-␥ activation factor GAF. The IFN-␥ activation factor is translocated to the nucleus, where it is able to bind to the IFN-␥ activation sequence-GAS-in the promoters of genes whose expression is induced by IFN-␥ (5...

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Section: Discussionmentioning

confidence: 71%

“…VV has evolved mechanisms to neutralize the activity of several host cytokines, including IFN (51,58,59). VV open reading frames (ORFs) E3L and K3L encode intracellular proteins that block the IFN-induced inhibition of protein synthesis by inhibiting the activation and/or action of the dsRNA-activated kinase PKR (6,8).…”

mentioning

confidence: 99%

Vaccinia Virus Blocks Gamma Interferon Signal Transduction: Viral VH1 Phosphatase Reverses Stat1 Activation

Najarro

Traktman

Lewis

2001

J Virol

170

145

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“…It has been previously reported that F13L-deleted viruses are "severely attenuated" (25,26), although the details of those studies have not been presented. Nude and SCID mice were susceptible to intranasal VV-WR challenge even at doses as low as 100 pfu, but survived a F13L-KO challenge with 10 6 pfu and showed no evidence of disease during the 2-month monitoring period.…”

Section: Discussionmentioning

confidence: 96%

Efficacy of ST-246 versus lethal poxvirus challenge in immunodeficient mice

Grosenbach

Berhanu

King

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The threat of smallpox as a bioweapon and the emerging threat of human monkeypox, among other poxviral diseases, highlight the need for effective poxvirus countermeasures. ST-246, which targets the F13L protein in vaccinia virus and its homologs in other orthopoxvirus species, provides full protection from lethal poxviral disease in numerous animal models and seems to be safe in humans. All previous evaluations of ST-246 efficacy have been in immunocompetent animals. However, the risk of severe poxviral disease is greater in immunodeficient hosts. Here we report on the efficacy of ST-246 in preventing or treating lethal poxviral disease in immunodeficient mice. After lethal challenge with the Western Reserve strain of vaccinia, Nude, SCID, and J H knockout mice additionally depleted of CD4 + and CD8 + T cells were not fully protected by ST-246, although survival was significantly extended. However, CD4 + T cell deficient, CD8 + T cell deficient, J H knockout, and J H knockout mice also deficient for CD4 + or CD8 + T cells survived lethal challenge when treated with ST-246 starting on the day of challenge. Delaying treatment until 72 h after infection reduced ST-246 efficacy in some models but provided full protection from lethal challenge in most. These findings suggest that ST-246 may be effective in controlling smallpox or other pathogenic orthopoxviruses in some immunodeficient human populations for whom the vaccine is contraindicated.antiviral | immunodeficiency | ST-246 | smallpox | orthopoxvirus

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“…Virus-encoded factors which interfere with the inflammatory response have been described for other poxviruses (reviewed in Smith, 1993;Pickup, 1994), and it is possible that OV encodes factors which interfere with this response also. The duplication of genes contained in the right terminal region of the variant could increase the amounts of specifically encoded proteins, some of which might interfere with the inflammatory response.…”

Section: Bamhi-gmentioning

confidence: 99%

Genomic analysis of a transposition-deletion variant of orf virus reveals a 3.3 kbp region of non-essential DNA

Fleming

Lyttle

Sullivan

et al. 1995

Journal of General Virology

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Restriction endonuclease analysis of the DNA extracted orfvirus strain NZ2, which had been serially passaged in primary bovine testis cells, revealed a population of variants that had over-grown the wild-type virus. At least three distinct mutant forms were identified in which the right end of the genome had been duplicated and translocated to the left end, accompanied by deletions of sequences at the left end. Sequencing of a single variant isolated from the heterogeneous population revealed that recombination had occurred between non-homologous sequences. In this case, 6-6 kb of DNA at the left end of the genome had been replaced by 19-3 kb from the right end. The transposition resulted in the deletion at the left end of 3.3 kb of DNA encoding three genes and the terminal sequence of a fourth gene. The three genes completely deleted were a homologue of dUTPase, a gene that encodes a protein containing ankyrin-like repeats and a homologue of the 5K gene of the vaccinia virus WR strain. Experimental inoculation of sheep showed that the genes are also non-essential in vivo, but that the size of the lesion was reduced, compared with that induced by the wild-type, and resolved more rapidly.

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Vaccinia virus glycoproteins and immune evasion: The Sixteenth Fleming Lecture

Cited by 72 publications

References 55 publications

Vaccinia Virus Blocks Gamma Interferon Signal Transduction: Viral VH1 Phosphatase Reverses Stat1 Activation

Vaccinia Virus Blocks Gamma Interferon Signal Transduction: Viral VH1 Phosphatase Reverses Stat1 Activation

Efficacy of ST-246 versus lethal poxvirus challenge in immunodeficient mice

Genomic analysis of a transposition-deletion variant of orf virus reveals a 3.3 kbp region of non-essential DNA

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