Phenotypic and genotypic resistance patterns of HIV-1 isolates derived from individuals treated with didanosine and stavudine

Coakley, Eoin; Gillis, Jacqueline

doi:10.1097/00002030-200001280-00002

Cited by 122 publications

(102 citation statements)

References 15 publications

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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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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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“…Antiretroviral therapy with thymidine nucleoside analogs such as AZT or d4T selects for several mutations (generally referred to as thymidine analog mutations or TAMs) in the RT gene that confer high-level resistance to AZT, and moderate levels of resistance to d4T (27)(28)(29). It is increasingly evident that TAMs are associated with varying degrees of cross-resistance to other "non-thymidine" NRTI including abacavir, ddI, ddC, and tenofovir (30 -33).…”

Section: Discussionmentioning

confidence: 99%

The 3′-Azido Group Is Not the Primary Determinant of 3′-Azido-3′-deoxythymidine (AZT) Responsible for the Excision Phenotype of AZT-resistant HIV-1

Sluis‐Cremer

Arion

Parikh

et al. 2005

Journal of Biological Chemistry

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The mechanism of human immunodeficiency virus (HIV) 1 resistance to 3-azido-3-deoxythymidine (AZT) involves reverse transcriptase (RT)-catalyzed phosphorolytic excision of the chain-terminating AZT-5-monophosphate (AZTMP). Primers terminated with AZTMP are generally better substrates for this reaction than those terminated with 2,3-dideoxynucleoside-5-monophosphate (2,3-ddNMP) analogs that lack a 3-azido moiety. This led to the hypothesis that the 3-azido group is a major structural determinant for maintaining the primer terminus in the appropriate site for phosphorolytic excision of AZTMP by AZT-resistant (AZT R ) RT. To test this hypothesis, we evaluated the incorporation, phosphorolytic excision, and antiviral activity of a panel of 3-azido-2,3-ddN including 3-azido-2,3-ddA (AZddA), 3-azido-2,3-ddC (AZddC), 3-azido-2,3-ddG (AZddG), AZT, and 3-azido-2,3-ddU (AZddU). The results indicate that mutations correlated with resistance to AZT (D67N/K70R/T215F/K219Q) confer resistance to the 3-azidopyrimidine nucleosides (AZddC, AZT, and AZddU) but not to the 3-azidopurine nucleosides (AZddA and AZddG). The data suggest that the presence of a 3-azido group on the 3-terminal nucleotide of the primer does not confer increased phosphorolytic excision by AZT R RT for all 3-azido-ddNMP analogs. Thus, the 3-azido group cannot be the only structural determinant important for the enhanced phosphorolytic excision of AZTMP associated with HIV resistance to AZT. Other structural components, such as the base, must play a role in defining the specificity of the excision phenotype arising from AZT resistance mutations. The replication of human immunodeficiency virus (HIV)1 1 is dependent on the enzymatic activities of reverse transcriptase (RT), an RNA-and DNA-dependent DNA polymerase encoded by the viral pol gene. RT synthesizes the double-stranded proviral DNA precursor from the viral (ϩ) RNA genome (1). Because of its essential role in HIV-1 replication, RT is a major target for antiretroviral drug development and two structurally dissimilar classes of RT inhibitors, termed nucleoside RT inhibitors (NRTI) and nonnucleoside RT inhibitors, are routinely used for the clinical treatment of HIV-1-infected individuals (2). NRTI are 2Ј-deoxyribonucleoside analogs that usually lack a 3Ј-OH group on the ribose moiety. After intracellular conversion to the active 5Ј-triphosphate form, NRTI-TP inhibit DNA synthesis by competing with the natural nucleotides both for recognition by RT as a substrate and by incorporation into the nascent viral DNA chain (3). Incorporation of an NRTI into the nascent viral DNA chain by RT results in termination of DNA synthesis.As is the case with all antiretroviral agents, the emergence of drug-resistant HIV-1 variants limits the efficacy of NRTI. Most NRTI-resistant viruses isolated from patients treated with nucleoside analogs have mutations in the pol gene (4). To date, two major phenotypic mechanisms have been proposed to account for HIV-1 resistance to NRTIs (5, 6). One mechanism is NRTI discrimination in...

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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).…”

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confidence: 99%

“…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). High level resistance to lamivudine occurs quickly in individuals treated with this drug and without a complete suppression of viral replication, and is associated with the appearance of the 184V mutation (14).…”

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confidence: 99%

“…(10) found that variants carrying this mutation had IC50 levels corresponding to a wild-type phenotype, whereas two further patients in this study harbored virus strains showing an elevated stavudine IC50, but not bearing the 75T mutation. Furthermore, a correlation between the 75T mutation and phenotypic resistance to stavudine has not been demonstrated in patients treated with didanosine plus stavudine (13) and in larger cohorts (22). Finally, it must be outlined that during combination therapies multidrug-resistant isolates or previously unreported mutations can arise.…”

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confidence: 99%

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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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Phenotypic and genotypic resistance patterns of HIV-1 isolates derived from individuals treated with didanosine and stavudine

Cited by 122 publications

References 15 publications

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

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

The 3′-Azido Group Is Not the Primary Determinant of 3′-Azido-3′-deoxythymidine (AZT) Responsible for the Excision Phenotype of AZT-resistant HIV-1

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

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