Multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 strains isolated from patients from different European countries

Schmit, Jean-Claude; Laethem, Kristel Van; Ruiz, Lı́dia; Hermans, Philippe; Sprecher, S; Sönnerborg, Anders; Leal, Manuel; Harrer, Thomas; Clotet, Bonaventura; Arendt, Vic; Lissén, E; Witvrouw, Myriam; Desmyter, Jan; Clercq, Erik De; Vandamme, Anne‐Mieke

doi:10.1097/00002030-199815000-00012

Cited by 82 publications

(62 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Those mutations that confer moderate (4-to Ͻ50-fold) levels of phenotypic resistance to 3TC reported previously always appeared in the context of a constellation of mutations that confer resistance to multiple nucleoside analogues or as a cross-resistance phenomenon that appears with the emergence of resistance to another nucleoside analogue. This has been the case for the nucleoside multidrug resistance complex of mutations Q151M, F77L, F116Y, A62V, and V75I, although the increase in the level of phenotypic resistance to 3TC in viruses that harbor those mutations is slight (9,20,24,25). In the case of the insertion mutations near position 69 of RT, a notable increase in the frequency of 3TC resistance has been reported together with an increased frequency of phenotypic resistance to other nucleosides (2, 17, 29).…”

mentioning

confidence: 98%

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

Hertogs¹,

Bloor²,

Vroey³

et al. 2000

Antimicrob Agents Chemother

107

View full text Add to dashboard Cite

We describe a new human immunodeficiency virus type 1 (HIV-1) mutational pattern associated with phenotypic resistance to lamivudine (3TC) in the absence of the characteristic replacement of methionine by valine at position 184 (M184V) of reverse transcriptase. Combined genotypic and phenotypic analyses of clinical isolates revealed the presence of moderate levels of phenotypic resistance (between 4-and 50-fold) to 3TC in a subset of isolates that did not harbor the M184V mutation. Mutational cluster analysis and comparison with the phenotypic data revealed a significant correlation between moderate phenotypic 3TC resistance and an increased incidence of replacement of glutamic acid by aspartic acid or alanine and of valine by isoleucine at residues 44 and 118 of reverse transcriptase, respectively. This occurred predominantly in those isolates harboring zidovudine resistance-associated mutations (41L, 215Y). The requirement of the combination of mutations 41L and 215Y with mutations 44D and 44A and/or 118I for phenotypic 3TC resistance was confirmed by site-directed mutagenesis experiments. These data support the assumption that HIV-1 may have access to several different genetic pathways to escape drug pressure or that the increase in the frequency of particular mutations may affect susceptibility to drugs that have never been part of a particular regimen.The emergence of drug-resistant human immunodeficiency virus type 1 (HIV-1) variants is almost always observed during the course of treatment of patients with antiretroviral drugs (3, 10, 14-16, 18, 21, 27 Strategies, abstr. 19, p. 15, 1998). The mutational profile of the resistant viruses generally is characteristic for the particular drug(s) taken. 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. Those mutations that confer moderate (4-to Ͻ50-fold) levels of phenotypic resistance to 3TC reported previously always appeared in the context of a constellation of mutations that confer resistance to multiple nucleoside analogues or as a cross-resistance phenomenon that appears with the emergence of resistance to another nucleoside analogue. This has been the case for the nucleoside multidrug resistance complex of mutations Q151M, F77L, F116Y, A62V, and V75I, although the increase in the level of phenotypic resistance to 3TC in viruses that harbor those mutations is slight (9,20,24,25). In the case of the insertion mutations near position 69 of RT, a notable increase in the frequency of 3TC resistance has been reported together with an increased frequency of phenotypic resistance to other nucleosides (2, 17, 29). The K65R mutation appears infrequently during the course of tr...

show abstract

mentioning

confidence: 98%

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

Hertogs¹,

Bloor²,

Vroey³

et al. 2000

Antimicrob Agents Chemother

107

View full text Add to dashboard Cite

show abstract

“…Despite the long experience with d4T, both the genotypic and phenotypic correlates of resistance to d4T and their relationship to treatment failure remain poorly understood. Mutations conferring multi-nucleoside analog resistance, including the Q151M mutation and amino acid insertions at position 69 of the RT, are found in d4T-treated patients (32,38,46). However, these mutations are only seen in a small proportion of clinical isolates (20,21).…”

mentioning

confidence: 99%

A Novel Genetic Pathway of Human Immunodeficiency Virus Type 1 Resistance to Stavudine Mediated by the K65R Mutation

Garcı́a-Lerma

MacInnes

Bennett

et al. 2003

J Virol

View full text Add to dashboard Cite

Stavudine (d4T) and zidovudine (AZT) are thymidine analogs widely used in the treatment of human immunodeficiency virus type 1 (HIV-1)-infected persons. Resistance to d4T is not fully understood, although the selection of AZT resistance mutations in patients treated with d4T suggests that both drugs have similar pathways of resistance. Through the analysis of genotypic changes in nine recombinant viruses cultured with d4T, we identified a new pathway for d4T resistance mediated by K65R, a mutation not selected by AZT. Passaged viruses were derived from treatment-naïve persons or HIV-1 HXB2 and had wild-type reverse transcriptase (RT) or T215C/D mutations. K65R was selected in seven viruses and was associated with a high level of enzymatic resistance to d4T-triphosphate (median, 16-fold; range, 5-to 48-fold). The role of K65R in d4T resistance was confirmed in site-directed mutants generated in three different RT backgrounds. Phenotypic assays based on recombinant single-cycle replication or a whole-virus multiple replication cycle were unable to detect d4T resistance in d4T-selected mutants with K65R but detected cross-resistance to other nucleoside RT inhibitors. Four of the six viruses that had 215C/D mutations at baseline acquired the 215Y mutation alone or in association with K65R. Mutants having K65R and T215Y replicated less efficiently than viruses that had T215Y only, suggesting that selection of T215Y in patients treated with d4T may be favored. Our results demonstrate that K65R plays a role in d4T resistance and indicate that resistance pathways for d4T and AZT may not be identical. Biochemical analysis and improved replication assays are both required for a full phenotypic characterization of resistance to d4T. These findings highlight the complexity of the genetic pathways of d4T resistance and its phenotypic expression.

show abstract

“…This insertion mutation is often accompanied by mutations at sites M41L, A62V, D67N, K70R, L210W, T215Y/F, K219Q/E (Winters et al 1998). The multi-NRTI resistance related to the 151-complex is observed at codons A62V, V75I, F77L, F116Y, and Q151M (Schmit et al 1998). Multi-NNRTI resistance is caused by accumulation of mutations at codons L100I, V106A, Y181C/I, G190S/A, M230L or by mutations occurring specifically at codons K103N or Y188L that can, each by itself substantially reduce the clinical utility of all currently approved drugs (Schmit et al 1996).…”

mentioning

confidence: 99%

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

Simonetti

Schatzmayr

Simonetti

2003

Mem. Inst. Oswaldo Cruz

View full text Add to dashboard Cite

show abstract

Multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 strains isolated from patients from different European countries

Abstract: MddNR resistant HIV-1 can be found in European patients. MddNR is characterized by a specific set of drug resistance mutations, cross-resistance to most ddN analogues and a fast clinical progression. MddNR can be associated with protease inhibitor or NNRTI resistance.

Cited by 82 publications

References 20 publications

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

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

A Novel Genetic Pathway of Human Immunodeficiency Virus Type 1 Resistance to Stavudine Mediated by the K65R Mutation

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

Contact Info

Product

Resources

About