The antiretroviral agent tenofovir, which has been formulated as a vaginal microbicidal gel, has been shown to reduce the risk of HIV and HSV type 2 (HSV-2) acquisition. The authors were interested in its effectiveness when faced with HSV-2 mutations. They selected HSV type 1 (HSV-1) and HSV-2 mutants for resistance to tenofovir and PMEO-DAPy (6-phosphonylmethoxyethoxy-2,4-diaminopyrimidine, an acyclic nucleoside phosphonate with dual anti-HSV and anti-HIV activity) by stepwise dose escalation. The authors found that tenofovir-resistant and PMEO-DAPy-resistant viruses had specific amino acid substitutions that were associated with resistance, not only to tenofovir and PMEO-DAPy, but also to acyclovir and foscarnet. These amino acid changes (A719V, S724N and L802F [HSV-1], and M789T and A724V [HSV-2]) were also found in clinical isolates that were recovered from patients found to be refractory to acyclovir and/or foscarnet therapy or in laboratory-derived strains. In total, ten (HSV-1) and 18 (HSV-2) well-characterised DNA polymerase mutants were found to decrease susceptibility to tenofovir and PMEO-DAPy. Therefore tenofovir and PMEO-DAPy target the HSV DNA polymerase, and clinical isolates with DNA polymerase mutations caused by therapy with acyclovir and/or foscarnet can lead to cross-resistance to tenofovir and PMEO-DAPy.
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