Herpes simplex viruses (HSV) are important pathogens affecting more than 50% of the general population HSV infections can cause aggressive intraoral and extraoral herpetic lesions. The successful treatment of HSV infections is complicated by the increasing prevalence of drug resistant mutants, which is becoming a clinical problem, especially in immunocompromised individuals. This possesses the need for new antiviral drugs and alternate therapeutic strategies against mutant viruses. An understanding of the mechanisms by which DNA is replicated and mutations evolve will be of value for future designs of new antiviral drugs and treatments. DNA polymerase (pol) is the pivotal enzyme involved in DNA replication. It plays the central role controlling the mutation rate by two major steps: selection of the correct nucleotides to be incorporated into the growing primer terminus, and proofreading or editing of the incorrectly incorporated nucleotides. Numerous mutagenesis and kinetic studies of a variety of Pols have already been conducted in vitro to reveal the mechanisms controlling the fidelity of DNA replication. HSV DNA replication has been proven to be an excellent model for the study of DNA replication, since HSV can be genetically amended for in vivo and in vitro characterization. Using this unique property, the effects of mutations in the pol gene can be analyzed in virus-infected mammalian cells. The in vitro characterizations of the same mutant Pol can also be studied by molecular biological and biochemical assays. Therefore, information obtained from the studies of a variety of mutant pols will be of value for a better understanding of the molecular mechanisms of DNA replication and replication fidelity. This information will also shed light on the structure-function relationship of Pol, which will be useful for future studies of new antiviral treatments. Our goals in this project include the following: 1. To examine the mutation spectra in different target genes induced by various HSV pols. 2. To examine sequence context effects on the misinsertion fidelity of HSV pols.
| Burkham, J; Coen, D M; Hwang, C B et al. (2001) Interactions of herpes simplex virus type 1 with ND10 and recruitment of PML to replication compartments. J Virol 75:2353-67 |
