title: Lamivudine-resistant human immunodeficiency virus type 1 variants (184V) require multiple amino acid changes to become co-resistant to zidovudine in vivo.
abstract: Exposure of human immunodeficiency virus to the nucleoside analogue lamivudine (3TC) rapidly selects for resistant variants with a valine at codon 184 (M184V) in the catalytic site of reverse transcriptase. In vitro, 184V demonstrated increased enzyme fidelity and suppressed zidovudine resistance. Clinical trials demonstrated that 3TC-zidovudine combination therapy results in a strong and sustained antiviral response. To investigate the role of 184V on in vivo virus evolution, the effect of zidovudine addition in 3TC-pretreated patients harboring 184V was studied. In vivo, no significant change in fidelity was observed with 184V, shown by generation of the classical pattern of zidovudine mutations. Of interest, in contrast to zidovudine monotherapy, in which just one substitution is sufficient for in vivo development of significant zidovudine resistance, multiple substitutions are required for the same level of zidovudine resistance in strains harboring 184V. This need for multiple substitutions may be one of the mechanisms explaining the sustained antiretroviral response of the 3TC-zidovudine combination.
authors.affiliation: Eijkman-Winkler Institute, Department of Virology, University Hospital Utrecht, Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Nijhuis
authors.forename: R
authors.initials: R
authors.lastname: Schuurman
authors.forename: D
authors.initials: D
authors.lastname: de Jong
authors.forename: R
authors.initials: R
authors.lastname: van Leeuwen
authors.forename: J
authors.initials: J
authors.lastname: Lange
authors.forename: S
authors.initials: S
authors.lastname: Danner
authors.forename: W
authors.initials: W
authors.lastname: Keulen
authors.forename: T
authors.initials: T
authors.lastname: de Groot
authors.forename: C A
authors.initials: CA
authors.lastname: Boucher
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000235:genetics; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology* / Q000627:therapeutic use; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D012367:RNA, Viral / Q000097:blood; D015215:Zidovudine / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D004279:DNA, Viral; D012367:RNA, Viral; D019259:Lamivudine; D015215:Zidovudine; D054303:HIV Reverse Transcriptase