ENHANCED FIDELITY OF 3TC-SELECTED MUTANT HIV-1 REVERSE-TRANSCRIPTASE

Monotherapy with (-)2',3'-dideoxy-3'-thiacytidine (3TC) leads to the a ppearance of a drug-resistant variant of human immunodeficiency virus- type 1 (HIV-1) with the methionine-184 --> valine (M184V) substitution in the reverse transcriptase (RT). Despite resulting drug resistance, treatment for more than 48 weeks is associated with a lower plasma vi ral burden than that at baseline. Studies to investigate this apparent contradiction revealed the following. (i) Titers of HIV-neutralizing antibodies remained stable in 3TC-treated individuals in contrast to r apid declines in those treated with azidothymidine (AZT). (ii) Unlike wild-type HIV, growth of M184V HIV in cell culture in the presence of d4T, AZT, Nevirapine, Delavirdine, or Saquinavir did not select for va riants displaying drug resistance. (iii) There was an increase in fide lity of nucleotide insertion by the M184V mutant compared with wild-ty pe enzyme.