1. In vitro analysis of the replicative capacity and phenotypic susceptibility to integrase inhibitors of HIV-2 mutants with integrase insertions
- Author
-
Gilles Peytavin, Florence Damond, Sophie Matheron, A. Bachelard, Samuel Lebourgeois, Gilles Collin, Charlotte Charpentier, Jade Ghosn, Quentin Le Hingrat, Diane Descamps, and Valentine Marie Ferré
- Subjects
Microbiology (medical) ,Pyridones ,Mutagenesis (molecular biology technique) ,Integrase inhibitor ,HIV Infections ,HIV Integrase ,Biology ,chemistry.chemical_compound ,Cabotegravir ,Raltegravir Potassium ,Drug Resistance, Viral ,medicine ,Humans ,Pharmacology (medical) ,HIV Integrase Inhibitors ,Pharmacology ,Bictegravir ,Raltegravir ,Virology ,Integrase ,Infectious Diseases ,chemistry ,HIV-2 ,Dolutegravir ,HIV-1 ,Leukocytes, Mononuclear ,biology.protein ,Heterocyclic Compounds, 3-Ring ,Viral load ,medicine.drug - Abstract
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.
- Published
- 2021