Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3'-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase.

Abstract

Resistant variants of human immunodeficiency virus type 1 (HIV-1) have been selected by limited passage in MT4 cells of both wild-type and 3'-azido-3'-deoxythymidine (AZT, zidovudine)-resistant strains with the nucleoside analogues (-)-2'-deoxy-3'-thiacytidine (3TC) and (-)-2'-deoxy-5-fluoro-3'-thiacytidine (FTC). Virus variants selected independently were crossresistant to both inhibitors. This rapid in vitro selection of resistant virus has not previously been seen with nucleoside analogues but is reminiscent of that observed with the nonnucleoside reverse transcriptase inhibitors. However, passage of wild-type virus with a combination of AZT and FTC appreciably delayed emergence of FTCresistant virus. DNA sequence analysis of the reverse transcriptase coding region from FTC-resistant virus revealed changes at codon 184 in the highly conserved Tyr, Met, Asp,

Mutational studies of human immunodeficiency virus type 1 reverse transcriptase : the involvement of residues 183 and 184 in the fidelity of DNA synthesis

“…The close proximity of Tyr-183 and Met-184 to the active site of the aspartic acid triad of HIV-1 RT can affect the fidelity of DNA synthesis. It is important to note that modifications of Met-184 in HIV-1 RT were reported to confer resistance to ddCTP, ddlTP and oxathiolane-cytosine nucleotides [34][35][36]. We have found that both the MI84L and Y183F mutants show also a significant reduction in sensitivity to ddNTPs (unpublished results).…”

Human immunodeficiency virus type 1: drug resistance in treated and untreated Brazilian children

“…For the other child receiving AZT and 3TC some relevant resistance codons were missing from evaluation, thus hampering the final result interpretation. However, she also presented the T215Y-mediated AZT resistance, which is reversed by the M184V mutation (Tisdale et al 1993). The T69D was detected in 1 child.…”

A Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutational Pattern Confers Phenotypic Lamivudine Resistance in the Absence of Mutation 184V

“…On the other hand, a mutation may reverse the effect of another mutation occurring concurrently in a viral variant. This is the case for the 3TC resistance mutation M184V, which can reverse the effect conferred by the ZDV mutation T215Y (1,14,28). Thus, although resistance to a particular antiretroviral drug is conferred by a specific mutation(s) associated with a particular drug, this can also be modulated by other mutations present in the background.…”

“…For example, mutations at codons 41, 67, 70, 210, 215, and 219 of reverse transcriptase (RT) typically confer resistance to zidovudine (ZDV) (6,12,13,27). Similarly, mutation M184V in RT has been shown to be specifically associated with high-level (Ն50-fold) phenotypic resistance to lamivudine (3TC) (1,22,28). No "specific" mutation(s) associated with moderate levels of phenotypic resistance (4-to Ͻ50-fold) to 3TC has been described before.…”