GENOTYPIC AND PHENOTYPIC CHARACTERIZATION OF HIV-1 ISOLATED FROM PATIENTS RECEIVING (-)-2',3'-DIDEOXY-3'-THIACYTIDINE

We attempted to determine whether HIV-1 developed resistance to (-)-2' ,3'-dideoxy-3'-thiacytidine ((-)-3TC or 3TC, lamivudine) in patients w ith advanced human immunodeficiency virus type 1 (HIV-1) infection dur ing therapy with 3TC. Genotypic analysis of HIV-1 strains isolated fro m 6 patients receiving 3TC revealed that as early as 2 months of thera py, HIV-1 developed a Met to Val amino acid substitution at codon 184 (Met(184) --> Val) in the reverse transcriptase-coding region of the p ol gene. A detailed study of a series of HIV-1 strains isolated from a patient demonstrated that Met at codon 184 was first substituted with lle by 2 weeks of 3TC therapy, followed by the substitution with Val by 8 weeks. All HIV-1 strains with the Met(184) --> Val substitution w ere profoundly less susceptible to 3TC (1800- to 5500-fold decreased s ensitivity) as compared to pretherapy virus strains, These strains wer e also moderately less sensitive to 2',3'-dideoxycytidine (4.5- to 9-f old), but more sensitive to 3'-azido-2',3'-dideoxythymidine (2- to 14- fold). A decrease in viremia levels and an increase in CD4 counts were observed early in therapy; however, these changes were only transient . Our data suggest that reversal of such beneficial changes is associa ted with the Met(184) --> Val substitution of the pol gene of HIV-1. T he data also suggest that 3TC, as a single agent, may induce virologic and immunologic improvement in patients with advanced HIV-1 infection , but only transiently.