The spectrum of human immunodeficiency virus type 1 (HIV-1) protease and reverse transcriptase (RT) mutations selected by antiretroviral (ARV) drugs requires ongoing reassessment as ARV treatment patterns evolve and increasing numbers of protease and RT sequences of different viral subtypes are published. Accordingly, we compared the prevalences of protease and RT mutations in HIV-1 group M sequences from individuals with and without a history of previous treatment with protease inhibitors (PIs) or RT inhibitors (RTIs). Mutations in protease sequences from 26,888 individuals and in RT sequences from 25,695 individuals were classified according to whether they were nonpolymorphic in untreated individuals and whether their prevalence increased fivefold with ARV therapy. This analysis showed that 88 PI-selected and 122 RTI-selected nonpolymorphic mutations had a prevalence that was fivefold higher in individuals receiving ARVs than in ARV-naïve individuals. This was an increase of 47% and 77%, respectively, compared with the 60 PI-and 69 RTI-selected mutations identified in a similar analysis that we published in 2005 using subtype B sequences obtained from one-fourth as many individuals. In conclusion, many nonpolymorphic mutations in protease and RT are under ARV selection pressure. The spectrum of treatment-selected mutations is changing as data for more individuals are collected, treatment exposures change, and the number of available sequences from non-subtype B viruses increases.Identifying the mutations responsible for human immunodeficiency virus type 1 (HIV-1) drug resistance has implications for drug resistance surveillance, HIV-1 genotypic resistance testing, and the biophysical mechanisms by which HIV-1 escapes from selective drug pressure. Many mutations in HIV-1 protease and reverse transcriptase (RT) are considered drug resistance mutations by virtue of emerging during antiretroviral (ARV) selection pressure in vitro or in vivo, reducing drug susceptibility in vitro, or reducing the virological response to therapy. As more sequenced HIV-1 isolates from ARV-exposed individuals are reported, more ARVs are licensed, and a greater proportion of published sequences of HIV-1 protease and RT belong to non-B subtypes, it is expected that new treatment-selected mutations will be identified.We previously identified nonpolymorphic treatment-selected mutations in an analysis of subtype B protease and RT sequences from ϳ6,000 individuals in the HIV Drug Resistance Database (HIVDB) (26). Here, we describe the results of a similar analysis that includes non-B group M sequences and about four times as many individuals than in the 2005 study.
MATERIALS AND METHODSPatients, viruses, and mutations. HIV-1 RT and protease sequences were compiled from published studies in the HIVDB (http://hivdb.stanford.edu) (27) and from previously unpublished sequences from HIV-1-infected individuals in Northern and Southern California as part of an Institutional Review Boardapproved protocol. For the new virus sequences, treatment his...