HIV-1 subtype F integrase polymorphisms external to the catalytic core domain contribute to severe loss of replication capacity in context of the integrase inhibitor resistance mutation Q148H.
J Antimicrob Chemother
; 77(10): 2793-2802, 2022 09 30.
Article
in En
| MEDLINE
| ID: mdl-35897124
ABSTRACT
BACKGROUND:
In prior studies, HIV-1 BF recombinants with subtype F integrases failed to develop resistance to raltegravir through the Q148H mutational pathway. We aimed to determine the role of subtype-specific polymorphisms in integrase on drug susceptibility, viral replication and integration.METHODS:
Integrase sequences were retrieved from the Los Alamos Database or obtained from the Garrahan HIV cohort. HIV-1 infectious molecular clones with or without Q148H (+âG140S) resistance mutations were constructed using integrases of subtype B (NL4-3) or F1(BF) ARMA159 and URTR23. Integrase chimeras were generated by reciprocal exchanges of a 200â bp fragment spanning amino acids 85-150 of the catalytic core domain (CCD) of NL4-3-Q148H and either ARMA159-Q148H or URTR23-Q148H. Viral infections were quantified by p24 ELISA and Alu-gag integration PCR assay.RESULTS:
At least 18 different polymorphisms distinguish subtype B from F1(BF) recombinant integrases. In phenotypic experiments, p24 at Day 15 post-infection was high (105-106â pg/mL) for WT and NL4-3-Q148H; by contrast, it was low (102-104â pg/mL) for both F1(BF)-Q148Hâ+âG140S viruses, and undetectable for the Q148H mutants. Compared with WT viruses, integrated DNA was reduced by 5-fold for NL4-3-Q148H (Pâ=â0.05), 9-fold for URTR23-Q148H (Pâ=â0.01) and 16000-fold for ARMA159-Q148H (Pâ=â0.01). Reciprocal exchange between B and F1(BF) of an integrase CCD region failed to rescue the replicative defect of F1(BF) integrase mutants.CONCLUSIONS:
The functional impairment of Q148H in the context of subtype F integrases from BF recombinants explains the lack of selection of this pathway in vivo. Non-B polymorphisms external to the integrase CCD may influence the pathway to integrase strand transfer inhibitor resistance.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
HIV Infections
/
HIV-1
/
HIV Integrase Inhibitors
/
HIV Integrase
Limits:
Humans
Language:
En
Journal:
J Antimicrob Chemother
Year:
2022
Document type:
Article
Affiliation country:
Argentina