The herpes simplex virus virion host shutoff protein is targeted to mRNA cleavage sites through interactions with components of the host translational apparatus

The herpes simplex virus virion host shutoff protein is targeted to mRNA cleavage sites through interactions with components of the host translational apparatus

Herpes simplex virus type 1 (HSV-1) is a neurotropic human herpesvirus. Experiments in animals have shown that mice surviving a primary HSV infection in the lumbo-sacral area, can become latently infected in trigeminal ganglia upon reinfection of the orofacial site. Sequences within the terminal repeat of HSV DNA are necessary for the cleavage and packaging reactions, and are also thought to be responsible for high frequency genome isomerization events. The number of a sequences at the termini and at the L-S component junction varies from one to several copies. Furthermore, Rep expression will be automatically suppressed as a consequence of Rep-mediated integration. Substitution of a 2.8-kbp region from the HSV-1 latency-associated transcript (LAT) for native HSV-2 sequences caused HSV-2 to reactivate with an HSV-1 phenotype in both animal models. Thus, the HSV helper activity for productive AAV replication seems to consist of DNA replication functions.
The herpes simplex virus virion host shutoff protein is targeted to mRNA cleavage sites through interactions with components of the host translational apparatus

The ability to express viral genes from plasmids which can be shuttled into and out of the HSV genome in cell-free recombination reactions makes this a powerful method for performing genetic studies of the biologic properties of viral gene products. The herpes simplex virus type 1 (HSV-1) genome is a 152-kb linear duplex DNA molecule composed of two covalently linked components, L and S (Fig.1a) (16, 25, 38). However, blocking later stages of translation initiation only had a modest effect on RNase activity. Results also found that a 5′ cap analog inhibits Vhs site-specific cleavage of mRNA at regions near the 5′ cap. Formation of the infectious virion is the culmination of the lytic herpes simplex virus type 1 (HSV-1) life cycle. The use of alternative cleavage sites during maturation and packaging of concatemeric intermediates can account for the generation of only two isomeric forms from a single monomeric template (25). Results indicated that Vhs requires a free 5′ end for specific cleavage of mRNA that undergoes cap-dependent scanning.

However, Vhs does not require a free 5′ end to specifically cleave a circular RNA that utilizes cap-independent methods for translation initiation. Mutational work, with pBK2 mutants which contained mutations in or surrounding the AUG codon, further supported a mechanism for Vhs cleavage that involved Vhs association with the scanning complex to reach some of its preferred cut sites. Mutating the first AUG to a non-AUG inhibited Vhs specific cleavage of pBK2 mRNA at a region just upstream from the AUG codon. Zinc binding by ICP8 is thought to be involved in its DNA binding activity, because altering residues in the ICP8 zinc finger region results in an abolishment of DNA binding (11). (c) Motifs and regions within the 194-bp Uc-DR1-Ub fragment. To conclude, this work provides several indications that Vhs associates with components of the translational apparatus to access at least some of its cut sites.

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