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Resistance of herpes simplex virus type 1 against different phosphonylmethoxyalkyl derivatives of purines and pyrimidines due to specific mutations in the viral DNA polymerase gene

Laboratory of Antiviral Chemotherapy¹ and Laboratory of Molecular Immunology², Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium

Author for correspondence: Graciela Andrei. Fax +32 16 337340. e-mail graciela.andrei{at}rega.kuleuven.ac.be

Drug-resistant strains of herpes simplex virus type 1 (HSV-1) were selected under the pressure of (S)-3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of cytosine (HPMPC, cidofovir) and adenine (HPMPA) and 2-phosphonylmethoxyethyl (PME) derivatives of adenine (PMEA, adefovir) and 2,6-diaminopurine (PMEDAP). HPMPC-resistant (HPMPC^r) and HPMPA^r strains were cross-resistant to one another, but they remained sensitive to foscarnet (PFA), acyclovir (ACV) and the PME derivatives, while the PMEA^r and PMEDAP^r strains showed cross-resistance to PFA and ACV. The PMEA^r, PMEDAP^r and PFA^r mutants all revealed a single nucleotide change resulting in a Ser-724 to Asn mutation within the conserved region II of the DNA polymerase. Two HPMPA^r clones and one HPMPC^r clone possessed single amino acid changes in the DNA polymerase (HPMPA^r clone D1, Leu-1007 to Met; HPMPA^r clone B5, Ile-1028 to Thr; HPMPC^r clone C3, Val-573 to Met). The HPMPC^r clone A4 contained two mutations, Ala-136 to Thr and Arg-700 to Met. The mutation at position 136, located outside the catalytic domain of the enzyme, was not detected in other HPMPC^r clones, suggesting that this mutation may not be responsible for the resistant phenotype. Residue 573 is located within the 3'5' exonuclease editing domain close to the catalytically important residues Tyr-577 and Asp-581. Similarly, residue 700 is located in the palm subdomain of the catalytic domain, adjacent to the Asp residues 717, 886 and 888 that are vital for polymerase activity. The HPMPA^r mutations at residues 1007 and 1028, beyond the last conserved region, still fall within the thumb subdomain of the catalytic domain. The different drug-resistant mutants varied in neurovirulent behaviour, the HPMPC^r strains showing reduced neurovirulence compared with the wild-type.

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