Emergence of zidovudine and multidrug-resistance mutations in the HIV-1 reverse transcriptase gene in therapy-naive patients receiving stavudine plus didanosine combination therapy

Pellegrin, Isabelle; Izopet, Jacques; Reynes, Jacques; Denayrolles, Muriel; Montès, Brigitte; Pellegrin, Jean‐Luc; Massip, Patrice; Puel, J

doi:10.1097/00002030-199909100-00014

Cited by 102 publications

(72 citation statements)

References 9 publications

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“…The reduced fitness in this virus might be related to changes in processivity and fidelity of RT conferred by K65R (1,41). A lower fitness of HIV-1 K65R/T215Y compared to HIV-1 T215Y might favor reversion of K65R, and might explain the frequent observation of T215Y but not K65R in patients treated with d4T (5,20,21,30). However, our data raise questions on whether an increased prevalence of K65R will be seen in the future in patients failing regimens containing d4T and other K65R-selecting drugs like abacavir or tenofovir.…”

Section: Discussionmentioning

confidence: 94%

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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

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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.

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Section: Discussionmentioning

confidence: 94%

“…These mutations can be selected in AZT-naïve patients who are treated with d4T (5,21,22,30,36,37). The presence of AZT mutations has also been shown to reduce the virologic benefit derived from d4T treatment (42).…”

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

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“…Despite the extensively reported evidence of cross-resistance between AZT and d4T in clinical settings (65)(66)(67), the relatively high dNTP levels could explain the large differences between AZT and d4T susceptibilities obtained in phenotypic assays (65,68,69). For example, M41L/L210W/ T215Y confers Ͼ100-fold increased resistance to AZT in phenotypic assays but only a 2.1-fold increase in the IC 50 for d4T relative to the wildtype HIV-1 (70).…”

Section: Discussionmentioning

confidence: 99%

Thymidine Analogue Resistance Suppression by V75I of HIV-1 Reverse Transcriptase

Matamoros

Nevot

Martı́nez

et al. 2009

Journal of Biological Chemistry

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Val75 of HIV-1 reverse transcriptase (RT) plays a role in positioning the template nucleotide ؉1 during the formation of the ternary complex. Mutations, such as V75M and V75A, emerge in patients infected with HIV-1 group M subtype B and group O variants, after failing treatment with stavudine (d4T) and other nucleoside RT inhibitors. V75I is an accessory mutation of the Q151M multidrug resistance complex of HIV-1 RT and is rarely associated with thymidine analogue resistance mutations (TAMs). In vitro, it confers resistance to acyclovir. TAMs confer resistance to zidovudine (AZT) and d4T by increasing the rate of ATP-mediated excision of the terminal nucleotide monophosphate (primer unblocking). In a wild-type HIV-1 group O RT sequence context, V75A and V75M conferred increased excision activity on d4T-terminated primers, in the presence of PP i . In contrast, V75I decreased the PP i -mediated unblocking efficiency on AZT and d4T-terminated primers, in different sequence contexts (i.e. wild-type group M subtype B or group O RTs). Interestingly, in the sequence context of an excision-proficient RT (i.e. M41L/A62V/T69SSS/K70R/ T215Y), the introduction of V75I led to a significant decrease of its ATP-dependent excision activity on AZT-, d4T-, and acyclovir-terminated primers. The excision rate of d4T-monophosphate in the presence of ATP (3.2 mM) was about 10 times higher for M41L/A62V/T69SSS/K70R/T215Y than for the mutant M41L/A62V/T69SSS/K70R/V75I/T215Y RT. The antagonistic effect of V75I with TAMs was further demonstrated in phenotypic assays. Recombinant HIV-1 containing the M41L/A62V/ T69SSS/K70R/V75I/T215Y RT showed 18.3-and 1.5-fold increased susceptibility to AZT and d4T, respectively, in comparison with virus containing the M41L/A62V/T69SSS/K70R/ T215Y RT.

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“…Nevertheless, a clearcut correlation between zidovudine resistance and treatment failure was not demonstrated in a subgroup of patients enrolled in the Delta trial (8). Mutations associated with resistance to zidovudine could be selected also during treatment with either didanosine (9), orstavudine (10,11), or both (12,13). However, a relevant decrease in didanosine or stavudine susceptibility was not observed in the presence of these substitutions (13).…”

mentioning

confidence: 99%

“…Finally, it must be outlined that during combination therapies multidrug-resistant isolates or previously unreported mutations can arise. For instance, a virus with five previously unidentified mutations (62V + 751 + 77L + 116Y + 151M) that was resistant to zidovudine, didanosine, zalcitabine and stavudine, and partially to lamivudine, has been isolated from patients receiving zidovudine plus didanosine (26) or didanosine plus stavudine (12,13).…”

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confidence: 99%

Reverse Transcriptase Mutations in HIV-1 Infected Patients Treated with Two Nucleoside Analogues: The Smart Study

Gianotti

Setti

Manconi

et al. 2002

Int J Immunopathol Pharmacol

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Resistance to nucleoside reverse transcriptase inhibitors (NRTIs) was studied in 527 HIV-1-infected patients, 342 responder and 185 non-responder to two NRTIs. Responders were followed for one year to assess the incidence of clinical failure. The prevalence of the 215Y/F substitution was higher among non-responder, compared to responder patients (33.7% vs. 17%, P = 0.0005), whereas the prevalence of the 184V and of the 70R mutations was comparable between these two groups. The 74V substitution was never observed and the 75T mutation was detected in only two subjects non-responder to a stavudine including regimen. Reduced susceptibility to didanosine or stavudine was infrequent. Reduced susceptibility to zidovudine was observed in 25% of individuals failing a zidovudine including regimen, whereas reduced susceptibility to lamivudine was detected in all subjects failing a lamivudine including regimen. In the prospective analysis, patients with undetectable viral load at enrollment had a lower incidence of failure rate over one year compared to those with detectable HIV-RNA at entry (P < 0.0001). A detectable viral load at enrollment was the only independent variable that predicted clinical failure over one year (P < 0.0001).

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Emergence of zidovudine and multidrug-resistance mutations in the HIV-1 reverse transcriptase gene in therapy-naive patients receiving stavudine plus didanosine combination therapy

Cited by 102 publications

References 9 publications

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

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

Thymidine Analogue Resistance Suppression by V75I of HIV-1 Reverse Transcriptase

Reverse Transcriptase Mutations in HIV-1 Infected Patients Treated with Two Nucleoside Analogues: The Smart Study

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