Complementation between Phosphonoacetic Acid-resistant and -sensitive Variants of Herpes Simplex Viruses: Evidence for an Oligomeric Protein with Restricted Intracellular Diffusion as the Determinant of Resistance and Sensitivity

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Abstract
Complementation between phosphonoacetic acid (PAA)-resistant (Pr) and -sensitive (Ps) variants of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) was studied to provide information on the function of the virus-coded DNA polymerase. Complementation within and between serotypes was demonstrated with the growth of the PS partner in mixed infections becoming relatively more resistant and the Pr partner relatively more sensitive to PAA than in the corresponding single infections. The relative contribution of the Ps partner to the mixed infection had a disproportionately large effect on the resultant sensitivity of the mixed infection which was imcompatible with non-interactive (monomeric) polymerase molecules as determinants of PAA sensitivity and resistance. Although a number of solutions gave equally good fits to the available data, the simplest was obtained by assuming that the functional DNA polymerase was a trimer and that only the (Pr)3 homotrimer was active in the presence of the drug. Yields from mixed infections in the presence of PAA were enriched for the resistant partner relative to yields in the absence of the drug. Thus, the intracellur distribution of resistant DNA polymerase oligomers was evidently non-random with respect to resistant and sensitive template genomes and the resistant polymerase molecules were more likely to encounter and replicate resistant than sensitive genomes. Such an explanation seems to require vectorial nuclear-cytoplasm-nucleus translocation and restricted diffusion of transcript and gene products determining resistance. [Hamster kidney BHK-21/C13 cells were used in these experiments.].