A novel human immunodeficiency virus type 1 reverse transcriptase mutational pattern confers phenotypic lamivudine resistance in the absence of mutation 184V

We describe a new human immunodeficiency virus type 1 (HIV-1) mutational pa ttern associated with phenotypic resistance to lamivudine (3TC) in the abse nce of the characteristic replacement of methionine by valine at position 1 84 (M184V) of reverse transcriptase. Combined genotypic and phenotypic anal yses of clinical isolates revealed the presence of moderate levels of pheno typic resistance (between 4- and 50-fold) to 3TC in a subset of isolates th at did not harbor the M184V mutation. Mutational cluster analysis and compa rison with the phenotypic data revealed a significant correlation between m oderate phenotypic 3TC resistance and an increased incidence of replacement of glutamic acid by aspartic acid or alanine and of valine by Isoleucine a t residues 44 and 118 of reverse transcriptase, respectively. This occurred predominantly in those isolates harboring zidovudine resistance-associated mutations (41L, 215Y). The requirement of the combination of mutations 41L and 215Y with mutations 44D and 44A and/or 1181 for phenotypic 3TC resista nce was confirmed by site-directed mutagenesis experiments. These data supp ort the assumption that HIV-1 may have access to several different genetic pathways to escape drug pressure or that the increase in the frequency of p articular mutations may affect susceptibility to drugs that have never been part of a particular regimen.