Phenotypic analysis of HIV-1 E157Q integrase polymorphism and impact on virological outcome in patients initiating an integrase inhibitor-based regimen

Charpentier, Charlotte; Malet, Isabelle; André-Garnier, Élisabeth; Storto, Alexandre; Bocket, Laurence; Amiel, Corinne; Morand‐Joubert, Laurence; Tumiotto, Camille; Nguyen, Thuy; Maillard, Anne; Rodallec, Audrey; Leoz, Marie; Montès, Brigitte; Schneider, Véronique; Plantier, Jean‐Christophe; Dina, Julia; Pallier, C.; Mirand, Audrey; Roussel, Catherine; Signori-Schmück, Anne; Raymond, Stéphanie; Cálvez, Vincent; Delaugerre, Constance; Marcelin, Anne–Geneviève; Descamps, Diane

doi:10.1093/jac/dkx511

Cited by 40 publications

(25 citation statements)

References 11 publications

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“…Similarly, although L74M and E157Q individually have minimal effect on the susceptibility to INSTIs, a combination of L74M and E157Q with other INSTIs RAMs result in reduced susceptibility to INSTIs. In fact, patients harboring viruses with L74M [61] or E157Q [64] mutations in addition to other integrase RAMs showed reduced susceptibility to DTG.…”

Section: Discussionmentioning

confidence: 99%

“…In summary, the current study of integrase and nef viral sequences from 345 HIV-infected Cameroonians showed only 2 subjects with INSTIs major RAMs, but several subjects with INSTIs accessory RAMs and polymorphic mutations, including 10 subjects harboring viruses that simultaneously had two different INSTIs accessory RAMs. Individually, INSTIs accessory RAMs do not have major effects on susceptibility to INSTIs, but the simultaneous presence of several accessory mutations or their presence in combination with other mutations has been associated with reduced susceptibility to INSTIs, increased viral fitness and virologic failure [40,[60][61][62][63][64][65]. With the current worldwide push to expand the use of DTG/INSTIs-based ART, it is inevitable that some patients on these regimens could experience virologic failure at some point during the course of their treatment.…”

Section: Discussionmentioning

confidence: 99%

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Variability in HIV-1 Integrase Gene and 3′-Polypurine Tract Sequences in Cameroon Clinical Isolates, and Implications for Integrase Inhibitors Efficacy

Acharya

Tagny

Mbanya

et al. 2020

IJMS

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Integrase strand-transfer inhibitors (INSTIs) are now included in preferred first-line antiretroviral therapy (ART) for HIV-infected adults. Studies of Western clade-B HIV-1 show increased resistance to INSTIs following mutations in integrase and nef 3′polypurine tract (3′-PPT). With anticipated shifts in Africa (where 25.6-million HIV-infected people resides) to INSTIs-based ART, it is critical to monitor patients in African countries for resistance-associated mutations (RAMs) affecting INSTIs efficacy. We analyzed HIV-1 integrase and 3′-PPT sequences in 345 clinical samples from INSTIs-naïve HIV-infected Cameroonians for polymorphisms and RAMs that affect INSTIs. Phylogeny showed high genetic diversity, with the predominance of HIV-1 CRF02_AG. Major INSTIs RAMs T66A and N155K were found in two (0.6%) samples. Integrase polymorphic and accessory RAMs found included T97A, E157Q, A128T, M50I, S119R, L74M, L74I, S230N, and E138D (0.3′23.5% of samples). Ten (3.2%) samples had both I72V+L74M, L74M+T97A, or I72V+T97A mutations; thirty-one (9.8%) had 3′-PPT mutations. The low frequency of major INSTIs RAMs shows that INSTIs-based ART can be successfully used in Cameroon. Several samples had ≥1 INSTIs accessory RAMs known to reduce INSTIs efficacy; thus, INSTIs-based ART would require genetic surveillance. The 3′-PPT mutations could also affect INSTIs. For patients failing INSTIs-based ART with no INSTIs RAMs, monitoring 3′-PPT sequences could reveal treatment failure etiology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Variability in HIV-1 Integrase Gene and 3′-Polypurine Tract Sequences in Cameroon Clinical Isolates, and Implications for Integrase Inhibitors Efficacy

Acharya

Tagny

Mbanya

et al. 2020

IJMS

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“…Integrase E157Q substitution has been described as a polymorphism present in 2.4% of viral sequences obtained from cART-naïve patients in the ARCA Italian database and in 5.0% in the last French transmitted drug resistance survey study [ 3 , 24 ]. A recent study of the French ANRS AC11 virology network conducted on 8528 integrase sequences from INI-naïve patients showed that the overall prevalence of E157Q polymorphism was 2.7% and its distribution among HIV-1 subtypes was 1.7%, 5.6% and 2.2% in B, CRF02_AG and others non-B subtypes, respectively [ 25 ].…”

Section: E157q Integrase Mutationmentioning

confidence: 99%

“…These in vitro phenotypic data are in accordance with the recent findings of the Italian study using similar phenotypic assays [ 3 ]. However, we observed a slight increase of FC to EVG at 1.9 and 2.4 in the presence of E157Q in B and CRF02_AG contexts, respectively [ 25 ]. Thus, E157Q polymorphism does not seem to impact phenotypic susceptibility to RAL or DTG, in contrast a potential low-level resistance, especially in the context of CRF02_AG recombinant, was observed for EVG.…”

Section: E157q Integrase Mutationmentioning

confidence: 99%

Resistance to HIV Integrase Inhibitors: About R263K and E157Q Mutations

Charpentier

Descamps

2018

Viruses

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The use of integrase inhibitors (INI) is increasing in antiretroviral therapies (ART) and INI are not all equal regarding genetic barrier to resistance. The aim of this manuscript was to review main in vivo and in vitro knowledge about two particular integrase resistance-associated mutations: R263K and E157Q. The R263K mutation was the first mutation rarely found selected at time of virological failure in patients failing a first-line dolutegravir-based treatment. Further in vitro studies on R263K mutants showed a moderate increase in phenotypic resistance level and a drastic reduction in viral replicative capacity. No compensatory mutations were evidenced. The E157Q mutation is polymorphic, found between 1.7% and 5.6% of viral sequences issued from ART-naïve patients depending on the viral subtype; as well as acquired resistance emerging at failure of a raltegravir-based regimen in two case reports. We reported data on phenotypic resistance level of E157Q mutants and virological response of patients harboring a E157Q virus initiating an INI-based regimen, showing that dolutegravir might be the most recommended INI in such patients. These findings show that there is still a need for a better understanding of resistance mechanisms to INI and emphasized the importance of genotypic background in viral evolution under drug pressure.

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“…11 E157Q, which was detected in 3/158 (1.8%) patients in our study, has been reported to have no impact on phenotypic susceptibility to dolutegravir when expressed alone. 12 However, when E157Q is expressed in combination with R263K, it has been reported to increase dolutegravir resistance mediated by R263K. 13 The importance of naturally occurring polymorphisms at codons 97 and 157 in the subsequent development of resistance to dolutegravir in Tanzanian settings should therefore be investigated with strategic longitudinal studies.…”

mentioning

confidence: 99%

Circulating HIV-1 Integrase Genotypes in Tanzania: Implication on the Introduction of Integrase Inhibitors-Based Antiretroviral Therapy Regimen

Masoud

Kamori

Barabona

et al. 2020

AIDS Research and Human Retroviruses

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Tanzania has recently adapted World Health Organization antiretroviral guidelines that include integrase strand transfer inhibitors (INSTIs) in the first-line regimen. However, there is lack of evidence on integrase (IN) gene polymorphisms in viral strains circulating in Tanzania. In this study, we characterize IN gene polymorphisms in viral strains circulating in Dar es Salaam, Tanzania, before introduction of INSTIs. Plasma viral RNAs were prepared from 158 HIV-1-infected subjects, including 111 treated, but viremic (INSTI-naïve), subjects. A part of the pol gene encompassing the IN-coding region was amplified and directly sequenced by the Sanger sequencing method. Subtype analysis revealed that subtypes A1, C, and D and intersubtype recombinants were 42%, 38%, 11%, and 9%, respectively. Although multiple subtypes cocirculate, the IN gene exhibited a relatively conserved amino acid sequence pattern with an average Shannon entropy score of 0.16. No major INSTI resistance mutations were found; however, accessory resistance mutations at positions T97A, E157Q, G163E/K, and 128A/T were detected in 5% of subjects.

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Phenotypic analysis of HIV-1 E157Q integrase polymorphism and impact on virological outcome in patients initiating an integrase inhibitor-based regimen

Cited by 40 publications

References 11 publications

Variability in HIV-1 Integrase Gene and 3′-Polypurine Tract Sequences in Cameroon Clinical Isolates, and Implications for Integrase Inhibitors Efficacy

Variability in HIV-1 Integrase Gene and 3′-Polypurine Tract Sequences in Cameroon Clinical Isolates, and Implications for Integrase Inhibitors Efficacy

Resistance to HIV Integrase Inhibitors: About R263K and E157Q Mutations

Circulating HIV-1 Integrase Genotypes in Tanzania: Implication on the Introduction of Integrase Inhibitors-Based Antiretroviral Therapy Regimen

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