Prevalence and Genetic Heterogeneity of the Reverse Transcriptase T69S-S-X Insertion in Pretreated HIV-Infected Patients

Briones, Carlos; Más, Antonio; Pérez‐Olmeda, Mayte; Altisent, Carmen; Domingo, Esteban; Soriano, Vincent

doi:10.1159/000050068

Cited by 8 publications

(6 citation statements)

References 11 publications

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“…Taken together, these results lead to the prediction that the 69S-SS mutations may be replaced by 69S-SG or other amino acid insertions over time due to selective pressure. The predicted evolution has, in fact, been reported for several HIV-1-infected individuals (6,14,31). Our results reinforce the importance of ATP-dependent removal of chain terminators in resistance to nucleoside analogues.…”

supporting

confidence: 87%

Effects of Dipeptide Insertions between Codons 69 and 70 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase on Primer Unblocking, Deoxynucleoside Triphosphate Inhibition, and DNA Chain Elongation

Meyer

Lennerstrand

Matsuura

et al. 2003

J Virol

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Finger insertion mutations of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) (T69S mutations followed by various dipeptide insertions) have a multinucleoside resistance phenotype that can be explained by decreased sensitivity to deoxynucleoside triphosphate (dNTP) inhibition of the nucleotidedependent unblocking activity of RT. We show that RTs with SG or AG (but not SS) insertions have three-to fourfold-increased unblocking activity and that all three finger insertion mutations have threefold-decreased sensitivity to dNTP inhibition. The additional presence of M41L and T215Y mutations increased unblocking activity for all three insertions, greatly reduced the sensitivity to dNTP inhibition, and resulted in defects in in vitro DNA chain elongation. The DNA chain elongation defects were partially repaired by additional mutations at positions 210, 211, and 214. These results suggest that structural communication between the regions of RT defined by these mutations plays a role in the multinucleoside resistance phenotype.Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is responsible for replication of the HIV-1 genome and is therefore an important target for antiretroviral therapy. Many inhibitors of HIV-1 RT are nucleoside analogues that are converted to their active triphosphate forms by host cell kinases and are incorporated into the viral genome by HIV-1 RT. Because nucleoside analogues lack a 3Ј-OH group, their incorporation prevents further extension of the DNA chain. HIV-1 RT becomes resistant to nucleoside analogues primarily through two mechanisms (8, 12): (i) increased discrimination against the compounds (9, 13, 35) leading to decreased incorporation and less chain termination and (ii) increased ability to remove chain terminators from blocked DNA chains, allowing DNA synthesis to resume (1,3,19,20,22,26). The removal occurs through excision of the 3Ј-terminal nucleotide by transfer to one of several potential acceptor substrates, including pyrophosphate (PP i ) or ATP, generating the triphosphate form of the chain terminator or a dinucleoside polyphosphate, respectively. Most zidovudine (AZT) resistance mutations, including M41L, D67N, K70R, T215F/Y, and K219Q (29), confer increased removal, compared to wildtype (WT) RT (3,19,22,25,26). The effect of these mutations is greatest when a nucleoside triphosphate, such as ATP, is used as the acceptor substrate, whereas there is little if any effect of AZT resistance mutations on removal when a nucleoside diphosphate or PP i is used as the substrate (3,16,20,22,25).The efficiency of the removal reaction under physiological conditions will depend on the rate of the reaction and the ability of deoxynucleoside triphosphates (dNTPs) to inhibit it. HIV-1 RT bound to a chain-terminated primer-template will still bind the dNTP complementary to the next nucleotide on the template strand (34) to form a stable complex. Since chemical bond formation is prevented due to lack of a 3Ј-OH, this complex has been named a dead-end...

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supporting

confidence: 87%

Effects of Dipeptide Insertions between Codons 69 and 70 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase on Primer Unblocking, Deoxynucleoside Triphosphate Inhibition, and DNA Chain Elongation

Meyer

Lennerstrand

Matsuura

et al. 2003

J Virol

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“…The lowest figures (< 1 %) were usually obtained with populations including all patients subjected to HIV protease and RT genotyping [48,[59][60][61][62]. When the study population was restricted to those patients who did not respond to the antiretroviral therapy, the prevalence of the dipeptide insertion increased to 1.9 -2.7% [53,54,63,64].…”

Section: Hiv-1 Rts With Insertions In the Fingers Subdomainmentioning

confidence: 99%

Insertions and Deletions in HIV-1 Reverse Transcriptase: Consequences for Drug Resistance and Viral Fitness

Menéndez‐Arias¹,

Matamoros²,

Cases-González

2006

CPD

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Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is an important target of drugs fighting HIV infection. The introduction of potent antiretroviral therapies based on the use of RT inhibitors and/or protease inhibitors has been an important achievement towards the control of AIDS. However, the development of drug resistance constitutes a major hurdle towards long-term efficacy of those therapies. With the increasing complexity of the antiretroviral regimens, novel mutational patterns conferring high-level resistance to nucleoside and nonnucleoside RT inhibitors have been identified in viral isolates. Among them, insertions and deletions in the beta3-beta4 hairpin-loop-coding region of HIV-1 RT have been identified in heavily-treated patients. Insertions of one, two or several residues appear to have a significant impact on nucleoside analogue resistance. The frequently found combination of a dipeptide insertion and thymidine analogue resistance mutations (i.e. T215Y) in the viral RT confers an ATP-dependent phosphorolytic activity that facilitates the removal of the inhibitor from primers terminated with zidovudine or stavudine. Furthermore, this mechanism appears to be relevant for resistance mediated by one amino acid-deletions appearing in combination with thymidine analogue resistance mutations. However, in other sequence contexts (i.e. in the presence of Q151M), the effects of the deletion are not fully understood. Drugs targeting the excision repair mechanism could be an important aid in the fight against multinucleoside-resistant HIV isolates bearing complex mutational patterns in their RT-coding region.

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“…Underlined amino acid residues are those characteristic of the Q151M multinucleoside analogue resistance complex. hairpin loop insertions has been estimated to be around 0.5-2.7%, [23][24][25][26][27] but deletions are less frequently observed, with a prevalence of b 0.2% of HIV-infected patients treated with nucleoside RT inhibitors. 28 A frequent deletion found in viral isolates from treated patients involves the loss of codon 67 in the RT-coding sequence, usually associated with amino acid substitutions T69G and K70R, as well as with one to three thymidine analogue resistance mutations.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Basis of Zidovudine Hypersusceptibility and Lamivudine Resistance Conferred by the Deletion of Codon 69 in the HIV-1 Reverse Transcriptase Coding Region

Kisic

Mendieta

Puertas

et al. 2008

Journal of Molecular Biology

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Prevalence and Genetic Heterogeneity of the Reverse Transcriptase T69S-S-X Insertion in Pretreated HIV-Infected Patients

Cited by 8 publications

References 11 publications

Effects of Dipeptide Insertions between Codons 69 and 70 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase on Primer Unblocking, Deoxynucleoside Triphosphate Inhibition, and DNA Chain Elongation

Effects of Dipeptide Insertions between Codons 69 and 70 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase on Primer Unblocking, Deoxynucleoside Triphosphate Inhibition, and DNA Chain Elongation

Insertions and Deletions in HIV-1 Reverse Transcriptase: Consequences for Drug Resistance and Viral Fitness

Mechanistic Basis of Zidovudine Hypersusceptibility and Lamivudine Resistance Conferred by the Deletion of Codon 69 in the HIV-1 Reverse Transcriptase Coding Region

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