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The Herpes Simplex Virus Type 1 DNA Polymerase Gene: Site of Phosphonoacetic Acid Resistance Mutation in Strain Angelotti is Highly Conserved

Deutsches Krebsforschungszentrum, Institut für Virusforschung, Im Neuenheimer Feld 280, D-6900 Heidelberg, F.R.G.

By comparative sequence analysis of the herpes simplex virus type 1 DNA polymerase gene of strain Angelotti and a phosphonoacetic acid-resistant (PAA^r) derivative, the site of the PAA^r mutation was identified as a single nucleotide (C T) conversion within the mapping limits of the known PAA^r mutations of strains KOS and 17. The conservative amino acid change at residue 719 from alanine to valine results in a radical change in the properties of the polymerase, rendering the mutant enzyme resistant to PAA and various antiviral compounds. Amino acid homologies as well as secondary structure analysis reveal that the PAA^r mutation is contained in a 14 amino acid sequence which is highly conserved, and detected in the central domain of prokaryotic and eukaryotic DNA polymerases.

Keywords: HSV-1 DNA polymerase, PAA resistance, DNA sequence analysis

Received 16 October 1986; accepted 30 January 1987.

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