Insertion as a Resistance Mechanism Against Integrase Inhibitors in Several Retroviruses

Pham, Hanh Thi; Hassounah, Said; Keele, Brandon F.; Rompay, Koen K. A. Van; Mésplède, Thibault

doi:10.1093/cid/ciz136

Clinical Infectious Diseases

2019

DOI: 10.1093/cid/ciz136

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Insertion as a Resistance Mechanism Against Integrase Inhibitors in Several Retroviruses

Hanh Thi Pham

Said Hassounah

Brandon F. Keele

et al.

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Cited by 4 publications

References 6 publications

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Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication

Wißing,

Meister,

Nocke

et al. 2024

Nat Commun

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Hepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans. Recent data suggest that HEV has a very heterogeneous hypervariable region (HVR), which can tolerate major genomic rearrangements. In this study, we identify insertions of previously undescribed sequence snippets in serum samples of a ribavirin treatment failure patient. These insertions increase viral replication while not affecting sensitivity towards ribavirin in a subgenomic replicon assay. All insertions contain a predicted nuclear localization sequence and alanine scanning mutagenesis of lysine residues in the HVR influences viral replication. Sequential replacement of lysine residues additionally alters intracellular localization in a fluorescence dye-coupled construct. Furthermore, distinct sequence patterns outside the HVR are identified as viral determinants that recapitulate the enhancing effect. In conclusion, patient-derived insertions can increase HEV replication and synergistically acting viral determinants in and outside the HVR are described. These results will help to understand the underlying principles of viral adaptation by viral- and host-sequence snatching during the clinical course of infection.

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Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication

Wißing,

Meister,

Nocke

et al. 2024

Nat Commun

View full text Add to dashboard Cite

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HIV-1 Integrase T218I/S Polymorphisms Do Not Reduce HIV-1 Integrase Inhibitors’ Phenotypic Susceptibility

Rodríguez-López,

López,

Rodríguez

et al. 2024

AIDS Research and Human Retroviruses

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In vitro analysis of the replicative capacity and phenotypic susceptibility to integrase inhibitors of HIV-2 mutants with integrase insertions

Hingrat

Collin

Damond

et al. 2021

Journal of Antimicrobial Chemotherapy

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Background HIV-2 resistance to integrase strand-transfer inhibitors (INSTIs) is characterized by two main pathways: (i) mutations at codons 143, 148 and155; and (ii) amino acid insertion after integrase codon 231 (231ins). Objectives To complete INSTI resistance data on HIV-2 by determining the viral replicative capacity and INSTI phenotypic susceptibility of integrase mutants obtained through site-directed mutagenesis. Methods Site-directed mutants (SDMs) were constructed and viral stocks produced. Viral replicative capacity was assessed by measuring HIV-2 viral load at days 3, 7 and 14. In vitro phenotypic susceptibility was measured using the ANRS PBMC assay. Results Viruses bearing 231ins did not present impaired replicative capacity, except the 231ins GIRGK mutant. A 231ins GK SDM was resistant to raltegravir and cabotegravir, but remained susceptible to dolutegravir and bictegravir. SDMs harbouring a 5 amino acid insertion (GYKGK or SREGK) were both resistant to all INSTIs. The SDM with T97A+N155H, with or without E92Q, was resistant to all INSTIs, except bictegravir. Conclusions These first data on the newly described resistance pathway 231ins, using site-directed mutagenesis, showed no measurable impact on viral fitness and confirmed the decreased susceptibility to a first-generation INSTI (raltegravir) and cabotegravir. Resistance to second-generation INSTIs (dolutegravir and bictegravir) occurred for mutants with a 5 amino acid 231ins.

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Insertion as a Resistance Mechanism Against Integrase Inhibitors in Several Retroviruses

Cited by 4 publications

References 6 publications

Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication

Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication

HIV-1 Integrase T218I/S Polymorphisms Do Not Reduce HIV-1 Integrase Inhibitors’ Phenotypic Susceptibility

In vitro analysis of the replicative capacity and phenotypic susceptibility to integrase inhibitors of HIV-2 mutants with integrase insertions

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