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Chapter 20 : New Herpes Simplex Virus Replication Targets
Category: Viruses and Viral Pathogenesis; Clinical Microbiology
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The human alphaherpesviruses include human herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV). HSV-1 and HSV-2 are responsible for primary and recurrent herpetic lesions of the mouth and genital tract, as well as more serious and potentially life-threatening infections of the eye and central nervous system. This chapter discusses alternative targets for antiherpesviral therapy. The roles of various viral glycoproteins in the attachment and penetration steps at the outset of the infection cycle are only now being identified; however, as with human immunodeficiency virus (HIV), the processes of attachment, receptor recognition, and penetration are likely be excellent targets for the development of antiviral therapy. Several reports have described a class of agents that inhibit the adsorption of the virus to host cells. Viral genes are classified as immediate early, early, or late and are transcribed from both strands of the viral genome by cellular RNA Pol II. The authors have proposed that recombination-dependent DNA replication plays an important role in viral DNA replication. Procapsids formed in the nucleus are competent to undergo encapsidation of the viral genome accompanied by a major conformational change in its structure from a sphere to a more angular shape.
Domain structure of UL9. The N-terminal helicase domain contains seven motifs shared in superfamily 2 helicases (horizontal lines). The putative PEST sequence (residues 265 to 282) is shown. The DNA binding C-terminal domain is shown in diagonal lines. The nuclear localization signal has been mapped to residues 817 to 851. The region of UL9 that interacts with DNA is indicated by cross-hatching.
The HSV-1 helicase/primase consists of three viral genes, UL5, UL8, and UL52. The UL5 gene is shown with seven black boxes depicting each of the motifs shared within superfamily 1 members. The UL52 gene is shown with the conserved catalytic primase site and the putative Zn binding region. UL8 is a 751-amino-acid protein.
Model for HSV DNA replication. An HSV-1 replication fork would be expected to contain the H/P complex (UL5/ UL52/UL8) at the fork: UL5 would be expected to unwind duplex DNA ahead of the fork, and UL52 would be expected to lay down RNA primers, which could then be extended by the two-subunit DNA Pol (UL30/UL42). The HSV-1 Pol would also be expected to carry out leading strand synthesis. ICP8 (UL29, ssb) would be expected to bind to single-stranded DNA generated during HSV DNA synthesis.