Herpes simplex virus-2 (HSV-2) is the most common cause of genital ulcers and is a known risk factor for HIV-1 acquisition and transmission. The antiviral drug acyclovir is the primary treatment for symptomatic HSV-2 infection, but to be effective it requires activation by the HSV-2 protein UL23; mutations in the UL23 gene can lead to acyclovir resistance. Three recent Phase III clinical trials looked at the effects of acyclovir treatment on the acquisition and transmission of HIV-1 in HSV-2-infected individuals, primarily in developing countries. The trials found that the drug had no effect on HIV transmission or acquisition, leading some researchers to question whether trial participants developed HSV-2 strains carrying acyclovir-resistant mutations.
To study this question in more detail and provide the first insights into HSV-2 sequence variation in the developing world, VIDD affiliate investigators Anna Wald and David Koelle and colleagues collected HSV-2 samples from 64 participants involved in the three trials, sequenced the UL23 gene from each sample, and looked for mutations within the gene that are known to be associated with resistance to acyclovir. Although they found a high degree of sequence variation, including many newly identified variants, none of the mutations were of the type or in locations known to be associated with resistance. It remains to be determined whether any of these newly identified mutations cause acyclovir resistance, but given prior data on the types of mutation that lead to resistance in developed countries, the failure of acyclovir to reduce HIV transmission is unlikely to be due to HSV-2 developing acyclovir resistance in these individuals.
Watson-Jones D, Wald A, Celum C, Lingappa J, Weiss HA, Changalucha J, Baisley K, Tanton C, Hayes RJ, Marshak JO, Gladden RG, Koelle DM. Use of acyclovir for suppression of human immunodeficiency virus infection is not associated with genotypic evidence of herpes simplex virus type 2 resistance to acyclovir: analysis of specimens from three phase III trials. J Clin Microbiol. 2010 Oct;48(10):3496-503.