Genotypic and Phenotypic Resistance Patterns of Human Immunodeficiency Virus Type 1 Variants with Insertions or Deletions in the Reverse Transcriptase (RT): Multicenter Study of Patients Treated with RT Inhibitors

Masquelier, Bernard; Race, Esther; Tamalet, Catherine; Descamps, Diane; Izopet, Jacques; Buffet-Janvresse, C; Ruffault, Annick; Mohammed, Ali Si; Cottalorda, J.; Schmuck, Anne; Cálvez, Vincent; Dam, Elisabeth; Fleury, Hervé; Brun‐Vézinet, Françoise

doi:10.1128/aac.45.6.1836-1842.2001

Cited by 60 publications

(79 citation statements)

References 27 publications

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“…Hydrogen bonds between the side chains of Lys-65 and Arg-72 and the triphosphate moiety of the incoming dNTP are required for the stabilization of the dNTP/Mg 2ϩ complex within the nucleotide binding site of the RT (8). Amino acid sequences around the ␤3-␤4 region of the RT show remarkable variability, with ⌬69/ ⌬70 deletions appearing frequently in combination with the Q151M complex (21,23,40,41), and ⌬67 in isolates containing TAMs (22,26,40). We found that more than 90% of the HIV-1 pol sequences bearing a deletion at codon 67 contained additional mutations at neighboring residues (usually T69G and K70R).…”

Section: Discussionmentioning

confidence: 99%

“…Loop of the RT-The prevalence of deletions in the RT fingers subdomain has been estimated to be less than 0.2% in HIVinfected patients, treated with nucleoside inhibitors (21,22). After searching the Stanford HIV Drug Resistance database, we identified 68 RT sequences containing three-nucleotide deletions in the ␤3-␤4 hairpin loop.…”

Section: Mutations Associated With Deletions In the ␤3-␤4 Hairpinmentioning

confidence: 99%

“…The prevalence of ␤3-␤4 hairpin loop deletions has been estimated to be less than 0.2% among patients failing antiretroviral treatment including NRTIs (21,22). These deletions may appear together with mutations of the Q151M complex or with TAMs.…”

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confidence: 99%

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Thymidine Analogue Excision and Discrimination Modulated by Mutational Complexes Including Single Amino Acid Deletions of Asp-67 or Thr-69 in HIV-1 Reverse Transcriptase

Kisic

Matamoros

Nevot

et al. 2011

Journal of Biological Chemistry

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Single amino acid deletions in the ␤3-␤4 hairpin loop of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have been identified in heavily treated patients. The deletion of Asp-67 together with mutations T69G and K70R (⌬67 complex) are usually associated with thymidine analog resistance mutations (TAMs) (e.g. M41L, T215Y, etc.) while the deletion of Thr-69 (⌬69) is rarely found in isolates containing TAMs. Here, we show that the complex ⌬67/T69G/K70R enhances ATP-dependent phosphorolytic activity on primers terminated with 3-azido-3-deoxythymidine (AZT) or 2,3-didehydro-2,3-dideoxythymidine (d4T) both in the presence or absence of TAMs (i.e. M41L/T215Y), while ⌬69 (or the complex S68G/⌬69/K70G) antagonize the effects of TAMs in ATP-mediated excision. These effects are consistent with AZT susceptibility data obtained with recombinant HIV-1 bearing the relevant RTs. Molecular dynamics studies based on models of wild-type HIV-1 RT and mutant ⌬69, ⌬67/T69G/K70R, and D67N/K70R RTs support a relevant role for Lys/Arg-70 in the excision reaction. In ⌬69 RT, the side chain of Lys-70 locates away from the putative pyrophosphate binding site. Therefore, its participation in interactions required for the excision reaction is unlikely. Our theoretical studies also suggest a role for Lys-219 in thymidine analog excision/discrimination. However, pre-steady-state kinetics revealed only minor differences in selectivity of AZTtriphosphate versus dTTP between deletion-containing RTs and their homologous enzymes having the K219E mutation. K219E reduced both ATP-and pyrophosphate-mediated excision of primers terminated with thymidine analogues, only when introduced in RTs bearing ⌬69 or S68G/⌬69/K70G, providing further biochemical evidence that explains the lack of association of ⌬69 and TAMs in HIV-1 isolates.

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Section: Discussionmentioning

confidence: 99%

Section: Mutations Associated With Deletions In the ␤3-␤4 Hairpinmentioning

confidence: 99%

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Thymidine Analogue Excision and Discrimination Modulated by Mutational Complexes Including Single Amino Acid Deletions of Asp-67 or Thr-69 in HIV-1 Reverse Transcriptase

Kisic

Matamoros

Nevot

et al. 2011

Journal of Biological Chemistry

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“…Although with a relatively low prevalence (1 to 3%), several studies have identified heavily treated patients carrying HIV-1 isolates with the MNR 69 insertion complex (1,2,6,10,11,19,24,31,34,(37)(38)(39)(40)41). Viral isolates harboring these mutations often show moderate to high-level resistance to all NRTI (11, 19, 23-25, 34, 37, 39, 41).…”

mentioning

confidence: 99%

Insertions in the Reverse Transcriptase Increase both Drug Resistance and Viral Fitness in a Human Immunodeficiency Virus Type 1 Isolate Harboring the Multi-Nucleoside Reverse Transcriptase Inhibitor Resistance 69 Insertion Complex Mutation

Quiñones‐Mateu

Tadele

Parera

et al. 2002

J Virol

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Recent studies have shown that the accumulation of multiple mutations associated with nucleoside reverse transcriptase inhibitor (NRTI) resistance may be grouped as multi-NRTI resistance (MNR) complexes. In this study, we have examined the viral fitness of recombinant viruses carrying the reverse transcriptase (RT) of a human immunodeficiency virus type 1 (HIV-1) primary isolate harboring mutations comprising the MNR 69 insertion complex. Different RT mutants were prepared in the sequence context of either the wild-type RT sequence of the HIV-1 BH10 isolate or the sequence found in a clinical HIV-1 isolate with the MNR 69 insertion mutation. As expected, in the presence of zidovudine, recombinant viruses harboring the MNR RT from the patient were more fit than wild-type viruses. However, in the absence of drug, the virus with the RT from the original clinical isolate (SS) was more fit than (i) the wild-type virus with an engineered serine insertion between residues 69 and 70 (T69SSS) and (ii) the recombinant virus with the MNR RT where the insertion was removed (2S0S). These results suggest that RT insertions, in the right sequence context (i.e., additional mutations contained in the MNR 69 insertion complex), enhance NRTI resistance and may improve viral fitness. Thus, comparing complex mutation patterns with viral fitness may help to elucidate the role of uncharacterized drug resistance mutations in antiretroviral treatment failure.

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“…Occasionally, amino acid insertions instead of substitutions are selected during antiretroviral therapy. Insertion mutations are not unusual in HIV reverse transcriptase (RT) isolated from patients treated by RT inhibitors (24,42). Amino acid insertions in the PR coding region (1 to 6 amino acids) have been recently detected at various sites in the viral PR sequence, e.g., in regions between codons 17 to 18, 22 to 25, 31 to 32, 35 to 38, 70 to 71, and 95 to 96 (43).…”

mentioning

confidence: 99%

Ninety-Nine Is Not Enough: Molecular Characterization of Inhibitor-Resistant Human Immunodeficiency Virus Type 1 Protease Mutants with Insertions in the Flap Region

Kožíšek

Šašková

Řezáčová

et al. 2008

J Virol

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Genotypic and Phenotypic Resistance Patterns of Human Immunodeficiency Virus Type 1 Variants with Insertions or Deletions in the Reverse Transcriptase (RT): Multicenter Study of Patients Treated with RT Inhibitors

Cited by 60 publications

References 27 publications

Thymidine Analogue Excision and Discrimination Modulated by Mutational Complexes Including Single Amino Acid Deletions of Asp-67 or Thr-69 in HIV-1 Reverse Transcriptase

Thymidine Analogue Excision and Discrimination Modulated by Mutational Complexes Including Single Amino Acid Deletions of Asp-67 or Thr-69 in HIV-1 Reverse Transcriptase

Insertions in the Reverse Transcriptase Increase both Drug Resistance and Viral Fitness in a Human Immunodeficiency Virus Type 1 Isolate Harboring the Multi-Nucleoside Reverse Transcriptase Inhibitor Resistance 69 Insertion Complex Mutation

Ninety-Nine Is Not Enough: Molecular Characterization of Inhibitor-Resistant Human Immunodeficiency Virus Type 1 Protease Mutants with Insertions in the Flap Region

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