Evidence map›Paper›PMID 34894227›Full record

ArticleThe Journal of antimicrobial chemotherapy2022

Specific mutations in the HIV-1 G-tract of the 3'-polypurine tract cause resistance to integrase strand transfer inhibitors.

Atsuko Hachiya, Mai Kubota, Urara Shigemi, Hirotaka Ode, Yoshiyuki Yokomaku, Karen A Kirby, Stefan G Sarafianos, Yasumasa Iwatani

Open access · greenAbstract read
In one paragraph

Article in The Journal of antimicrobial chemotherapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
0.5field-weighted citation impact, top 31% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

12 citing papers in PubMed, 12 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 3 institutions in 2 countries.

Atsuko HachiyaClinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan.
Mai KubotaClinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan.
Urara ShigemiClinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan.
Hirotaka OdeClinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan.
Yoshiyuki YokomakuClinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan.
Karen A KirbyLaboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
Stefan G SarafianosLaboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
Yasumasa IwataniClinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan.
Nagoya Medical Center · JPNational Hospital Organization · JPChildren's Healthcare of Atlanta · US

Funding

Novel mechanism of integrase (IN) resistance to Dolutegravir through epistatic interactions between IN and the nucleocapsid and polypurine tract regions of HIV-1R01AI146017 · NIAID · EMORY UNIVERSITY · PI HACHIYA, ATSUKO, LYUMKIS, DMITRY · 2019 to 2023
$2.6M
NIAID NIH HHS R01 AI146017NIH HHS R01 AI146017 to S.G.S. and A.H.
6 · The paper itself

Abstract

backgroundIn vitro selection experiments identified viruses resistant to integrase strand transfer inhibitors (INSTIs) carrying mutations in the G-tract (six guanosines) of the 3'-polypurine tract (3'-PPT). A clinical study also reported that mutations in the 3'-PPT were observed in a patient receiving dolutegravir monotherapy. However, recombinant viruses with the 3'-PPT mutations that were found in the clinical study were recently shown to be susceptible to INSTIs.

objectivesTo identify the specific mutation(s) in the G-tract of the 3'-PPT for acquiring INSTI resistance, we constructed infectious clones bearing single or multiple mutations and systematically characterized the susceptibility of these clones to both first- and second-generation INSTIs.

methodsThe infectious clones were tested for their infectivity and susceptibility to INSTIs in a single-cycle assay using TZM-bl cells.

resultsA single mutation of thymidine (T) at the fifth position (GGG GTG) in the G-tract of the 3'-PPT had no effect on INSTI resistance. A double mutation, cytidine (C) or 'T' at the second position and 'T' at the fifth position (GCG GTG and GTG GTG), increased resistance to INSTIs, with the appearance of a plateau in the maximal percentage inhibition (MPI) of the dose-response curves, consistent with a non-competitive mechanism of inhibition.

conclusionsMutations at the second and fifth positions in the G-tract of the 3'-PPT may result in complex resistance mechanism(s), rather than simply affecting INSTI binding at the IN active site.

Indexed as

HIV-1HIV InfectionsHIV IntegraseHIV Integrase InhibitorsDrug Resistance, ViralHumansMutationHIV IntegraseHIV Integrase Inhibitors

Identifiers

PMID34894227
PMCPMC8865006
OpenAlexW4200590455

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.