Despite its tremendous success, acyclovir has several drawbacks, including limited potency and efficacy, particularly against herpesviruses other than HSV and VZV, and the frequency at which immunocompromised patients develop resistant infections.
This has led to the development of several new compounds, some of which have entered clinical trials. An interesting antiviral agent, maribavir, inhibits the HCMV protein kinase, UL97, which is important for viral DNA synthesis, particularly in nondividing cells, because it phosphorylates retinoblastoma protein family members Wolf et al. Thus, there is reason for optimism but also for caution regarding the prospects of these newer DNA replication inhibitors.
A major impediment to deeper understanding remains the lack of an in vitro system that reconstitutes origin-dependent replication. More incremental goals for the future are to determine the role of UL9 and other viral and cellular proteins in the initiation of replication, understand the mechanism of replication and the role of repair and recombination in the generation of replication products, and continue probing the structure, function, and functional interactions of the viral replication proteins.
It is hoped that the results of these efforts will help us develop more effective strategies for antiviral therapy to prevent and treat all human herpesviruses. We thank members of our laboratories for helpful suggestions, especially Samantha Marques for help with Figure 1. Editors: Stephen D. Bell, Marcel Mechali, and Melvin L.
National Center for Biotechnology Information , U. Cold Spring Harb Perspect Biol. Sandra K. Weller 1 and Donald M. Coen 2. Donald M.
Author information Copyright and License information Disclaimer. Correspondence: Email: ude. This article has been cited by other articles in PMC. Open in a separate window. Figure 1. Table 1. Formation of Concatemeric DNA Production of HSV concatemeric DNA is an essential step for the generation of progeny virus as the packaging machinery must recognize longer-than-unit-length concatemers during encapsidation.
Efforts to Combat Viral Infections by Targeting DNA Replication Most of the antiviral agents developed to combat herpesvirus infections have targeted the viral polymerase. Footnotes Editors: Stephen D. The crystal structure of the cytomegalovirus DNA polymerase subunit with the C-terminus from the catalytic subunit: Differences in structure and function relative to unliganded UL Point mutations in herpes simplex virus type 1 oriL, but not in oriS, reduce pathogenesis during acute infection of mice and impair reactivation from latency.
Potent and selective inhibition of human cytomegalovirus replication by W94, a benzimidazole L-riboside with a unique mode of action. Reconstitution of uracil DNA glycosylase-initiated base excision repair in herpes simplex virus Herpes simplex virus type 1 DNA polymerase requires the mammalian chaperone hsp90 for proper localization to the nucleus.
Recruitment of polymerase to herpes simplex virus type 1 replication foci in cells expressing mutant primase UL52 proteins. Herpes simplex virus-1 helicase-primase: Roles of each subunit in DNA binding and phosphodiester bond formation.
The R1 subunit of herpes simplex virus ribonucleotide reductase has chaperone-like activity similar to Hsp The ribonucleotide reductase domain of the R1 subunit of herpes simplex virus type 2 ribonucleotide reductase is essential for R1 antiapoptotic function. Herpesviral replication compartments move and coalesce at nuclear speckles to enhance export of viral late mRNA. DNA binding activity of the herpes simplex virus type 1 origin binding protein, UL9, can be modulated by sequences in the N terminus: Correlation between transdominance and DNA binding.
Direct interaction between the N- and C-terminal portions of the herpes simplex virus type 1 origin binding protein UL9 implies the formation of a head-to-tail dimer. The two helicases of herpes simplex virus type 1 HSV Herpes simplex virus type 1 helicase-primase: DNA binding and consequent protein oligomerization and primase activation. Viral DNA polymerases. In DNA replication in eukaryotic cells ed. DePamphilis ML , pp. Antiherpesviral DNA polymerase inhibitors.
In Antiviral research: Strategies in antiviral drug discovery ed. LaFemina R , pp. Association of DNA helicase and primase activities with a subassembly of the herpes simplex virus 1 helicase-primase composed of the UL5 and UL52 gene products. ND10 components relocate to sites associated with herpes simplex virus type 1 nucleoprotein complexes during virus infection. Leading and lagging strand DNA synthesis in vitro by a reconstituted herpes simplex virus type 1 replisome.
Identification of human cytomegalovirus UL84 virus- and cell-encoded binding partners by using proteomics analysis. Phosphorylation of retinoblastoma protein by viral protein with cyclin-dependent kinase function.
Construction and properties of a recombinant herpes simplex virus 1 lacking both S-component origins of DNA synthesis. Phosphorylation of the herpes sVirus type 1 origin binding protein. Mutations that increase DNA binding by the processivity factor of herpes simplex virus affect virus production and DNA replication fidelity.
Numerous conserved and divergent microRNAs expressed by herpes simplex viruses 1 and 2. Human paillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase. Herpesvirus replication compartments originate with single incoming viral genomes. Proliferating cell nuclear antigen uses two distinct modes to move along DNA. Hopping of a processivity factor on DNA revealed by single-molecule assays of diffusion.
Crystal structure of the herpes simplex virus 1 DNA polymerase. Molecular chaperones and alphaherpesvirus infection. In Alphaherpesviruses: Molecular virology ed. Weller SK , Chap.
Oligomerization of ICP4 and rearrangement of heat shock proteins may be important for herpes simplex virus type 1 prereplicative site formation. Recombination-dependent concatemeric viral DNA replication. Functional properties of the herpes simplex virus type I origin-binding protein are controlled by precise interactions with the activated form of the origin of DNA replication.
The herpes simplex virus type 1 origin-binding protein carries out origin specific DNA unwinding and forms stem-loop structures. Most people get HSV-1 herpes simplex type 1 as an infant or child. This virus can be spread by skin-to-skin contact with an adult who carries the virus. An adult does not have to have sores to spread the virus. A person usually gets HSV-2 herpes simplex type 2 through sexual contact.
Some people are more likely to get HSV These people:. Herpes simplex viruses spread from person to person through close contact. You can get a herpes simplex virus from touching a herpes sore. Most people, however, get herpes simplex from an infected person who does not have sores. Most people get genital herpes from HSV-2, which they get during sex.
If someone has a cold sore and performs oral sex, this can spread HSV-1 to the genitals, and cause herpes sores on the genitals. Corey L, Wald A.
Genital Herpes. Sexually Transmitted Diseases. New York: McGraw-Hill; — Trends in seroprevalence of herpes simplex virus type 2 among non-Hispanic blacks and non-Hispanic whites aged 14 to 49 years—United States, to Sex Transm Dis , Mertz GJ.
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