Novel mutation in the human immunodeficiency virus type 1 reverse transcriptase gene that encodes cross-resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine

Gu, Z; Gao, Qing; Li, X; Parniak, Michael A.; Wainberg, Mark A.

doi:10.1128/jvi.66.12.7128-7135.1992

Cited by 224 publications

(100 citation statements)

References 37 publications

(35 reference statements)

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“…The M184V mutation is a well studied and important HIV-1 drug-resistance mutation [15]. Many resistance algorithms still consider the M184V mutation to confer some degree of resistance to ddI [13], but several studies have now reported that a single M184V mutation may not affect the clinical response to ddI [11]. However, most in vivo data have been collected from studies of the major viral population using direct sequencing.…”

Section: Discussionmentioning

confidence: 99%

“…The M184V mutation can also be selected in vitro by abacavir (ABC) [8] and didanosine (ddI) [9]. However, it has been reported that a single M184V mutation may not affect the clinical response to ABC [10] and ddI [11]. Hence, the resistance effect of the M184V mutation may be present only in the presence of additional mutations in the RT gene [12].…”

Section: Introductionmentioning

confidence: 99%

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Presence of M184I/V in minor HIV‐1 populations of patients with lamivudine and/or didanosine treatment failure

et al. 2007

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ObjectivesThe aim of the study was to investigate the presence of M184I/V in minor HIV-1 populations of patients who failed lamivudine (3TC) and/or didanosine (ddI) treatment. Materials and methodsFourteen 3TC-experienced patients who, after switching therapy to a ddI regimen, had a new failure without M184I/V in the major viral population were included in the study. Ninety plasma samples were analysed by direct sequencing and selective real-time polymerase chain reaction (SPCR), which detects GTG/GTA and ATA mutants down to 1 and 0.2% of the population, respectively. ResultsIn five samples, SPCR detected resistant virus when direct sequencing detected wild-type M184. In patients with mixed viral populations at sequencing, the median proportion of mutants detected by SPCR was 30%. SPCRGTG reactivity dominated, while SPCRATA reactivity only was uncommon. M184I/V disappeared in patients in whom 3TC was stopped but ddI continued. Ten patients with ddI failure had no M184I/V. ConclusionsMinor HIV-1 strains may harbour M184I/V in patients failing ddI therapy, despite direct sequencing showing wild-type virus. Although M184I/V may reduce the genetic barrier of ddI for mutations such as K65R and L74V, the lack of re-emergence of M184I/V in the minor quasispecies of most patients who failed ddI suggests that M184I/V was not a preferred route to ddI resistance in our patient population.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Presence of M184I/V in minor HIV‐1 populations of patients with lamivudine and/or didanosine treatment failure

et al. 2007

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“…ddC or ddI treatment (7,8,10,28), and the 184V mutation is associated with high-level resistance to 3TC and (Ϫ)-2Ј-deoxy-3Ј-thiacytidine (FTC) (1,25,28). The 65R mutation has also previously been reported to give low-level resistance to 3TC (11), as confirmed in this study, and to 9-(2-phosphonylmethoxyethyl)adenine (12). The fourth mutation, Y115 to F, has not been observed previously in resistance selection studies, although this residue has been shown by site-directed mutagenesis to be critical for enzyme activity (2,3,20).…”

Section: Discussionmentioning

confidence: 99%

Combination of mutations in human immunodeficiency virus type 1 reverse transcriptase required for resistance to the carbocyclic nucleoside 1592U89

Tisdale

Alnadaf

Cousens

1997

Antimicrob Agents Chemother

211

107

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The carbocyclic nucleoside 1592U89 is a selective inhibitor of the human immunodeficiency virus (HIV), targeting the reverse transcriptase (RT). In vitro selection studies were undertaken to generate resistant variants with both HIV type 1 (HIV-1) wild-type strain HIV-1 (HXB2) and 3-azido-3-deoxythymidine (AZT)resistant strain HIV-1 (RTMC) . At least two or three mutations in RT were required to produce a 10-fold reduction in susceptibility. The first RT mutation selected was at codon 184, methionine (M) to valine (V), for HIV-1 (HXB2) and HIV-1 (RTMC) , conferring two-and fivefold resistance, respectively. Two additional mutations were selected with HIV-1 (HXB2) , either leucine (L) 74 to V and lysine (K) 65 to arginine (R) (first-passage series) or L74 to V and tyrosine (Y) 115 to phenylalanine (F) (second-passage series). Cloned variants, obtained from the 1592U89 selection, were either double RT mutants 65R/184V and 74V/184V or triple RT mutant 74V/115Y/184V. Molecular clones were constructed with single, double, and triple combinations of these mutations for resistance analysis with different RT inhibitors. Each individual mutation conferred only low-level resistance (two-to fourfold) to 1592U89 in the HXB2 background. Double mutants containing the 184V mutation and triple mutants showed slightly greater levels of resistance to 1592U89 (7-to 11-fold). Some of the 1592U89-resistant variants were cross-resistant with 2,3-dideoxycytidine, 2,3-dideoxyinosine, and (؊)-2-deoxy-3-thiacytidine, but none were resistant to 2,3-didehydro-3-deoxythymidine or AZT.

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“…The cells were then washed extensively and maintained in tissue culture medium in either the absence or the presence of subinhibitory concentrations of 3TC, beginning with 0.01 M. The medium was changed twice weekly; each replacement contained an increased drug concentration, as follows: 0.01, 0.05, 0.2, 1, 2.5, 10, 25, 100, 250, 500, and 750 M. Culture fluids (0.5 ml) from each passage were used to infect fresh C8166 cells as described previously (7). Cultures were monitored for the presence of RT activity and the presence of a cytopathic effect as described previously (9). After 8 and 24 weeks (final 3TC concentration, 2.5 or 750 M), viral variants of pJ5 and pC8 contained either the M184I or M184V substitutions, respectively, and were capable of growth in the presence of greater than 500 and 2,000 M 3TC, i.e., more than 1,000-and 4,000-fold the usual inhibitory drug concentration, respectively ( Table 1).…”

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confidence: 99%

Mutations at codon 184 in simian immunodeficiency virus reverse transcriptase confer resistance to the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine

Cherry

Slater

Salomón

et al. 1997

Antimicrob Agents Chemother

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Variants of simian immunodeficiency virus (SIV) that display greater than 2,000-fold resistance to the (؊) enantiomer of 2,3-dideoxy-3-thiacytidine (3TC) were generated through in vitro passage and drug selection. The polymerase regions of several of these resistant viruses were sequenced and were found to share either of two codon alterations at site 184 in reverse transcriptase (ATG to ATA [methionine to isoleucine] and ATG to GTA [methionine to valine]). The biological relevance of these substitutions for 3TC was confirmed by site-directed mutagenesis with the SIVmac239 infectious recombinant clone of SIV.

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Novel mutation in the human immunodeficiency virus type 1 reverse transcriptase gene that encodes cross-resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine

Cited by 224 publications

References 37 publications

Presence of M184I/V in minor HIV‐1 populations of patients with lamivudine and/or didanosine treatment failure

Presence of M184I/V in minor HIV‐1 populations of patients with lamivudine and/or didanosine treatment failure

Combination of mutations in human immunodeficiency virus type 1 reverse transcriptase required for resistance to the carbocyclic nucleoside 1592U89

Mutations at codon 184 in simian immunodeficiency virus reverse transcriptase confer resistance to the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine

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