Resistance of Herpes Simplex Virus to Adenine Arabinoside and E-5-(2-Bromovinyl)-2′-Deoxyuridine: A Physical Analysis

The physical map limits of DNA sequences within the DNA polymerase locus of herpes simplex virus (HSV) type 1 that define resistance mutations to adenine arabinoside (ara-A) and E-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) were determined. Intertypic recombinants between HSV types 1 and 2, generated by marker rescue of temperature-sensitive mutations, had genome structures determined by restriction endonuclease analysis and were used to show that the resistance mutation for ara-Ar-1 is closely linked to the resistance mutations for phosphonoacetic acid (paar-1) and acycloguanosine (acvr-1) within a region of 2.6 kilobase pairs (kbp) in the HSV DNA polymerase locus. The resistance mutation for bvdur'-1 is defined by a 2.9-kbp region that overlaps with the region defining resistance to the other three drugs but that is transferred separately. The DNA polymerase locus also contains a 2.2-kbp region that maps adjacent to and to the left of the region defining the bvdur-1 mutation which can be transferred separately and defines a region determining the HSV-1-specific sensitivity to BVDU in a manner analogous to that to acyclovir.