Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase.
Monotherapy with (-)2',3'-dideoxy-3'-thiacytidine (3TC) leads to the appearance 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 viral 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 rapid 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 variants displaying drug resistance. (iii) There was an increase in fidelity of nucleotide insertion by the M184V mutant compared with wild-type enzyme.
Wainberg
M A
MA
McGill AIDS Centre, Jewish General Hospital, Montreal, Canada.
Drosopoulos
W C
WC
Salomon
H
H
Hsu
M
M
Borkow
G
G
Parniak
M
M
Gu
Z
Z
Song
Q
Q
Manne
J
J
Islam
S
S
Castriota
G
G
Prasad
V R
VR
D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001482:Base Composition; D001483:Base Sequence; D003854:Deoxyribonucleotides / Q000378:metabolism; D004352:Drug Resistance, Microbial; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000502:physiology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D019259:Lamivudine; D008969:Molecular Sequence Data; D009154:Mutation; D009500:Neutralization Tests; D011804:Quinolines / Q000494:pharmacology; D012194:RNA-Directed DNA Polymerase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019258:Saquinavir; D014779:Virus Replication / Q000187:drug effects; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000998:Antiviral Agents; D003854:Deoxyribonucleotides; D015483:HIV Antibodies; D017320:HIV Protease Inhibitors; D007546:Isoquinolines; D011804:Quinolines; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D016047:Zalcitabine; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D019258:Saquinavir