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Mode of virus rescue determines the acquisition of VHS mutations in VP22-negative herpes simplex virus 1.

ABSTRACT: It has been proposed that herpes simplex virus 1 with VP22 deleted requires secondary mutation of VHS for viability. Here we show that a replication-competent ?22 virus constructed by homologous recombination maintains a wild-type (Wt) VHS gene and has no other gross mutations. By contrast, ?22 viruses recovered from a bacterial artificial chromosome contain multiple amino acid changes within a conserved region of VHS. Hence, the mode of virus rescue influences the acquisition of secondary mutations.

SUBMITTER: Ebert K

PROVIDER: S-EPMC3753997 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Mode of virus rescue determines the acquisition of VHS mutations in VP22-negative herpes simplex virus 1.

Ebert Katja K Depledge Daniel P DP Breuer Judith J Harman Laura L Elliott Gillian G

Journal of virology 20130717 18

It has been proposed that herpes simplex virus 1 with VP22 deleted requires secondary mutation of VHS for viability. Here we show that a replication-competent Δ22 virus constructed by homologous recombination maintains a wild-type (Wt) VHS gene and has no other gross mutations. By contrast, Δ22 viruses recovered from a bacterial artificial chromosome contain multiple amino acid changes within a conserved region of VHS. Hence, the mode of virus rescue influences the acquisition of secondary mutat ...[more]

PMID: 23864617

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Project description:AIM2 is a cytosolic DNA sensor of the inflammasome, which induces critical innate immune responses against various invading pathogens. Earlier biochemical studies showed that the binding of AIM2 to DNA triggered the self-oligomerization of AIM2, which is essential for AIM2 inflammasome activation. We recently reported that VP22, a virion tegument protein of herpes simplex virus 1 (HSV-1), inhibited activation of the AIM2 inflammasome in HSV-1-infected cells by preventing AIM2 oligomerization. VP22 binds non-specifically to DNA; however, its role in HSV-1 replication is unclear. We investigated the role of VP22 DNA binding activity in the VP22-mediated inhibition of AIM2 inflammasome activation. We identified a VP22 domain encoded by amino acids 227 to 258 as the minimal domain required for its binding to DNA in vitro Consecutive alanine substitutions in this domain substantially impaired the DNA binding activity of VP22 in vitro and attenuated the inhibitory effect of VP22 on AIM2 inflammasome activation in an AIM2 inflammasome reconstitution system. The inhibitory effect of VP22 on AIM2 inflammasome activation was completely abolished in macrophages infected with a recombinant virus harboring VP22 with one of the consecutive alanine substitutions, similar to the effect of a VP22-null mutant virus. These results suggested that the DNA binding activity of VP22 is critical for VP22-mediated AIM2 inflammasome activation in HSV1-infected cells.IMPORTANCE VP22, a major component of the HSV-1 virion tegument, is conserved in alphaherpesviruses and has structural similarity to ORF52, a component of the virion tegument that is well-conserved in gammaherpesviruses. Although the potential DNA binding activity of VP22 was discovered decades ago, its significance in the HSV-1 life cycle is poorly understood. Here, we show that the DNA binding activity of VP22 is critical for the inhibition of AIM2 inflammasome activation induced in HSV-1-infected cells. This is the first report to show a role for the DNA binding activity of VP22 in the HSV-1 life cycle, allowing the virus to evade AIM2 inflammasome activation, which is critical for its replication in vivo.

Dataset Information

Mode of virus rescue determines the acquisition of VHS mutations in VP22-negative herpes simplex virus 1.

Publications

Mode of virus rescue determines the acquisition of VHS mutations in VP22-negative herpes simplex virus 1.

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