Download Replication of Herpes simplex virus

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.