The Effects of Herpesviruses on Cellular Macromolecular Synthesis

Fenwick, M. L.

doi:10.1007/978-1-4615-1745-0_7

Cited by 41 publications

(35 citation statements)

References 94 publications

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“…Vhs is an endoribonuclease (33,(44)(45)(46)(47) that is a minor component of virions (48)(49)(50). At early times, copies of Vhs from infecting virions accelerate the degradation of many housekeeping and constitutively expressed cellular mRNAs (40,42,48,(51)(52)(53)(54)(55), with a concomitant downturn in the levels of those mRNAs and in the synthesis of the proteins that they encode (52,56,57). Following the onset of viral transcription, Vhs ensures the rapid turnover of most, if not all, viral mRNAs (36,37,(57)(58)(59)(60).…”

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confidence: 99%

mRNA Decay during Herpes Simplex Virus (HSV) Infections: Mutations That Affect Translation of an mRNA Influence the Sites at Which It Is Cleaved by the HSV Virion Host Shutoff (Vhs) Protein

Shiflett

Read

2013

J Virol

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During lytic infections, the herpes simplex virus (HSV) virion host shutoff (Vhs) endoribonuclease degrades many host and viral mRNAs. Within infected cells it cuts mRNAs at preferred sites, including some in regions of translation initiation. Vhs binds the translation initiation factors eIF4H, eIF4AI, and eIF4AII, suggesting that its mRNA degradative function is somehow linked to translation. To explore how Vhs is targeted to preferred sites, we examined the in vitro degradation of a target mRNA in rabbit reticulocyte lysates containing in vitro-translated Vhs. Vhs caused rapid degradation of mRNAs beginning with cleavages at sites in the first 250 nucleotides, including a number near the start codon and in the 5= untranslated region. Ligation of the ends to form a circular mRNA inhibited Vhs cleavage at the same sites at which it cuts capped linear molecules. This was not due to an inability to cut any circular RNA, since Vhs cuts circular mRNAs containing an encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES) at the same sites as linear molecules with the IRES. Cutting linear mRNAs at preferred sites was augmented by the presence of a 5= cap. Moreover, mutations that altered the 5= proximal AUG abolished Vhs cleavage at nearby sites, while mutations that changed sequences surrounding the AUG to improve their match to the Kozak consensus sequence enhanced Vhs cutting near the start codon. The results indicate that mutations in an mRNA that affect its translation affect the sites at which it is cut by Vhs and suggest that Vhs is directed to its preferred cut sites during translation initiation. During lytic herpes simplex virus (HSV) infections, viral and cellular gene expressions are regulated at multiple steps of mRNA metabolism (1, 2), including transcription (2-8), splicing (2, 9-12), transport from the nucleus to the cytoplasm (2, 13-20), translation (21-32), and stabilization of mRNAs in the cytoplasm (33-43). Among the posttranscriptional controls are the regulation of mRNA half-lives (36-42) and translation (23,29) by the HSV virion host shutoff (Vhs) protein (UL41). Vhs is an endoribonuclease (33,(44)(45)(46)(47) that is a minor component of virions (48)(49)(50). At early times, copies of Vhs from infecting virions accelerate the degradation of many housekeeping and constitutively expressed cellular mRNAs (40,42,48,(51)(52)(53)(54)(55), with a concomitant downturn in the levels of those mRNAs and in the synthesis of the proteins that they encode (52,56,57). Following the onset of viral transcription, Vhs ensures the rapid turnover of most, if not all, viral mRNAs (36, 37, 57-60). In so doing, it helps determine viral mRNA levels and facilitates the sequential expression of different classes of viral mRNAs (38). Significantly, during animal infections, Vhs impedes the establishment of an interferon-induced antiviral state (61-67). It blocks the activation of dendritic cells (68-70) and inhibits other components of the innate and adaptive immune responses (41,(71)(72)(73)(74)(75). As su...

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mRNA Decay during Herpes Simplex Virus (HSV) Infections: Mutations That Affect Translation of an mRNA Influence the Sites at Which It Is Cleaved by the HSV Virion Host Shutoff (Vhs) Protein

Shiflett

Read

2013

J Virol

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“…the virus is known to shut off host gene expression as well as host DNA replication (9,51). It is therefore likely to mimic the gene amplification activity of inhibitors of protein synthesis, such as cycloheximide (47), or inhibitors of DNA replication, such as hydroxyurea and aphidicolin (3,18,20,45).…”

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Herpes simplex virus induces the replication of foreign DNA.

Danovich¹,

Frenkel²

1988

Mol. Cell. Biol.

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Plasmids containing the simian virus 40 (SV40) DNA replication origin and the large T gene are replicated efficiently in Vero monkey cells but not in rabbit skin cells. Efficient replication of the plasmids was observed in rabbit skin cells infected with herpes simplex virus type 1 (HSV-1) and HSV-2. The HSV-induced replication required the large T antigen and the SV40 replication origin. However, it produced concatemeric molecules resembling replicative intermediates of HSV DNA and was sensitive to phosphonoacetate at concentrations known to inhibit the HSV DNA polymerase. Therefore, it involved the HSV DNA polymerase itself or a viral gene product(s) which was expressed following the replication of HSV DNA. Analyses of test plasmids lacking SV40 or HSV DNA sequences showed that, under some conditions, HSV also induced low-level replication of test plasmids containing no known eucaryotic replication origins. Together, these results show that HSV induces a DNA replicative activity which amplifies foreign DNA. The relevance of these findings to the putative transforming potential of HSV is discussed. (23)(24)(25). Certain cellular DNA sequences, including the dihydrofolate reductase, human leukocyte antigen, and Ha-ras genes were also amplified, albeit to a lower extent (21,26). The carcinogeninduced SV40 DNA amplification required an intact SV40 DNA replication origin and a functional large T antigen (23,26). It generated a heterogeneous collection of DNA molecules extending from the replication origin (23, 26).Schlehofer et al. (46) have reported that infection of SV40-transformed hamster cells with herpes simplex virus (HSV) also induced amplification of the resident SV40 sequences. Amplification was not observed in one monkey cell line transformed by an originless SV40 construct (33). This indicated that the SV40 DNA replication origin may be required. Studies with inhibitors of HSV DNA polymerase and temperature-sensitive HSV mutants have led to the conclusion that the induced SV40 DNA replication involved the HSV DNA polymerase (32), and the results of studies on the structure of the amplified DNA molecules were consistent with this hypothesis (31). Similar amplification of resident SV40 DNA sequences has been observed in our own studies with SV40-transformed Chinese hamster cells

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“…[23][24][25] In addition to the anatomical data, experiments using mock-as well as control-infected neuronal cultures showed that control vectors can reduce free cytosolic calcium accumulation 6 and reduce metabolism in response to hypoglycemia (both measured at 24 h after the insult). 2 Functional consequences of viral infection could be due to direct effects of the virion on cell metabolism and DNA transcription [33][34][35] or to secondary effects mediated by immune messengers and cytokines. Immune activity stimulated by HSV infection in the central nervous system has been observed [36][37][38] and many immune messengers have the ability to affect hippocampal physiology.…”

Section: Figure 3 Panels Show Expression Patterns In Representative Amentioning

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Delivery of herpes simplex virus amplicon-based vectors to the dentate gyrus does not alter hippocampal synaptic transmission in vivo

Dumas

McLaughlin

et al. 1999

Gene Ther

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Herpes simplex virus type-1 (HSV) amplicon vectors con-(I/O) curves were not altered by infection. Paired-pulse taining neuroprotective genes can alter cell physiology and facilitation at either recording site was also unaffected. Xenhance survival following various insults. However, to gal-positive granule cells surrounded the recording elecdate, little is known about effects of viral infection itself trode (PP-DG recording) and stimulating electrode tracts (independent of the gene delivered) on neuronal physi-(MF-CA3 recording) in animals that received vector, sugology. Electrically-evoked synaptic responses are routinely gesting that we had measured function, at least in part, in recorded to measure functional alterations in the nervous infected neurons. Because of the negative electrophysiolsystem and were used here to assess the potential capaogical result, we sought to deliver a gene with an HSV bility of HSV vectors to disrupt physiology of the hippocamamplicon which would affect the measured endpoints, as pus (a forebrain structure involved in learning that is highly a positive control. Delivery of calbindin D 28k potentiated susceptible to necrotic insult, making it a frequent target in PP-DG synaptic strength, indicating that our recording sysgene therapy research). Population excitatory post-synaptem could detect alterations due to vector expression. tic potentials (EPSPs) were recorded in the dentate gyrus Thus, the data indicate that HSV vectors are benign, in (DG) and in area CA3 in vivo 72 h after infusion of an HSV regard to effects on synaptic function, and support the use vector expressing a reporter gene (lacZ) or vehicle into the of these vectors as a safe method to deliver selected DG. Evoked perforant path (PP-DG) or mossy fiber (MFgenes to the central nervous system. CA3) EPSPs slope values measured across input/output

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The Effects of Herpesviruses on Cellular Macromolecular Synthesis

Cited by 41 publications

References 94 publications

mRNA Decay during Herpes Simplex Virus (HSV) Infections: Mutations That Affect Translation of an mRNA Influence the Sites at Which It Is Cleaved by the HSV Virion Host Shutoff (Vhs) Protein

mRNA Decay during Herpes Simplex Virus (HSV) Infections: Mutations That Affect Translation of an mRNA Influence the Sites at Which It Is Cleaved by the HSV Virion Host Shutoff (Vhs) Protein

Herpes simplex virus induces the replication of foreign DNA.

Delivery of herpes simplex virus amplicon-based vectors to the dentate gyrus does not alter hippocampal synaptic transmission in vivo

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