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Repair of DNA following Incorporation of 1-ß-D-Arabinofuranosylcytosine into Herpes Simplex Virus Type I¹

Charles A. Dana Research Institute, Harvard-Thorndike Laboratory of Beth Israel Hospital, and Harvard Medical School, Divisions of Hematology/Oncology [G. J. B., L. E. S.] and Infectious Disease [C. S. C.], Boston, Massachusetts 02215

The nucleoside analogue 1-ß-D-arabinofuranosylcytosine (ara-C) is incorporated into herpes simplex virus type 1 (HSV-1) DNA, and this correlates with inhibition of virus replication. The technique of Weigle-type reactivation (WR) was used to compare the ability of induced cellular DNA repair pathways to recognize or repair ara-C incorporated into HSV-1 DNA and ultraviolet (UV)-irradiated virus DNA (254 nm). Pretreatment of monkey cells withlow-fluenceUVirradiation, growthincis-dichlorodiammineplatinum(II), or growth in ara-C followed by infection after a 24-hr incubation period resulted in enhanced survival of UV-irradiated HSV-1. Under the same experimental conditions, no reactivation of HSV-1 inactivated by growth in ara-C is observed.

Comparisons between uninfected Vero cells exposed to UV irradiation (30 J/m²) or grown in 10^-6 M ara-C demonstrated repair replication in irradiated cells, whereas there was no evidence for DNA repair at various time intervals following removal of the nucleoside analogue. These observations suggest that, once ara-C is incorporated into HSV-1 or eukaryotic DNA, it is not recognized as a repairable lesion within the limits of the DNA repair assays used in these studies.

¹ Supported in part by Grant NIA-1-P01-AG00596 and Contract AI-52530 from the Antiviral Substance Program of the National Institute of Allergy and Infectious Disease. This work was presented in part during the 1983 University of California, Los Angeles, Symposium on DNA Repair, Keystone, CO, April 1983, and at the annual meeting of the American Association for Cancer Research, May 1983, San Diego, CA (28).

² Recipient of support in part from NIH Hematology Training Grant HL-07516 and NRSA CA-07236 awarded by the National Cancer Institute, Department of Health and Human Services. To whom requests for reprints should be addressed, at Beth Israel Hospital, Hematology-Oncology Division, L601, 330 Brookline Avenue, Boston, MA 02215.

Received 8/26/83. Accepted 2/ 6/84.