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Replication of Herpes simplex virus Herpes viruses are found in a wide variety of species ranging from molluscs to man. Eight different herpes viruses have man as the natural host: three alfa herpes viruses, herpes simplex virus type I and type II and varicella zoster virus, three beta herpes virus cytomegalovirus, human herpes viruses 6 and 7, two gamma herpes viruses, Epstein-Barr virus and human herpes virus (also referred to as Kaposis sarcoma herpes virus). All herpes viruses share certain features as, for example, the ability to establish life-long latent infections in the host. Virus in latently infected cells can be reactivated and start production of new infectious virus particles. Many of the properties required for production of infectious virus, such as synthesis of virus DNA, processing and encapsidation of viral genomes and formation of a membrane surrounding the capsid and the tegument before the virus is ultimately released from the cell, are all likely to rely on evolutionarily conserved molecular processes. Our research has for some time been directed towards elucidating the molecular mechanisms for replication, recombination and repair of Herpes simplex virus type I DNA. We also study the mechanism by which DNA replication contributes to the tight regulation of the class of genes expressed late during the viral life-cycle. We have discovered an evolutionarily conserved mechanism for initiation of DNA replication common to alfa herpes viruses. We have characterized enzymes involved in synthesis of virus DNA, and, using six purified virus proteins, established an in vitro system capable of simultaneous synthesis of leading and lagging strands. We have examined the contributions of cellular proteins to replication, recombination and repair of Herpes simplex virus DNA. For example, we have found that DNA ligase IV/XRCC4 is needed for circularization of linear viral genomes in the nucleus. We have also seen that inhibition of topoisomerase II by the drug ICRF-193 specifically and efficiently inhibits synthesis of herpes simplex virus DNA. Recently, we have demonstrated how DNA replication and expression of virus genes are affected by UV-induced lesions in HSV-1 DNA. The long-term goal is to acquire detailed understanding of the molecular processes for rapid and accurate synthesis of new herpes virus genomes and how these processes are affected by different forms of antiviral treatment. The mechanisms responsible for synthesis of new genomes generate genetic diversity thereby contributing to development of drug resistance and virus evolution. Insights into the molecular biology of virus replication also allow us to make use of the virus to investigate properties of the host cell. Group members Per Elias, professor Monica Olsson, technician Isabella Muylaert, researcher Alireza Aslani, researcher Ka-Wei Tang, graduate student Zhiyuan Zhao, student Selected publications Muylaert, I., and Elias, P. (2010) Contributions of nucleotide excision repair, DNA polymerase η and homologous recombination to replication of UV-irradiated Herpes simplex virus type I. J. Biol. Chem. (under revision) Olsson, M., Tang, K-W., Persson, C., Wilhelmsson, L.M., Billeter, M., and Elias, P (2009) Stepwise evolution of the herpes simplex virus origin binding protein and origin of replication. J. Biol. Chem. 284, 16246-16255. Muylaert, I., and Elias, P. (2007) Knockdown of DNA ligase IV/XRCC4 by RNA interference inhibits Herpes simplex virus type I DNA replication. J. Biol. Chem. 282, 1086510872. Macao, B., Olsson, M., and Elias, P. (2004) 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. J. Biol. Chem. 279, 29211-29217. Aslani, A., Olsson, M., and Elias, P. (2002) ATP-dependent unwinding of a minimal origin of DNA replication by the origin-binding protein and the single-strand DNA-binding protein ICP8 from Herpes simplex virus type I. J. Biol. Chem. 277, 41204-41212. Falkenberg, M., Lehman, I.R., and Elias, P. (2000) Leading and lagging strand DNA synthesis in vitro by a reconstituted herpes simplex virus type I replisome. Proc. Natl. Acad. Sci. U.S.A. 97, 3896-3900.