Interaction Analysis of Statistically Enriched Mutations Identified in Cameroon Recombinant Subtype CRF02_AG that can Influence the Development of Dolutegravir Drug Resistance Mutations

Résumé

Abstract Background The Integrase (IN) strand transfer inhibitor (INSTI), Dolutegravir (DTG), has been given the green light to form part of first-line combination antiretroviral therapy (cART) by the World Health Organization (WHO). DTG is clinically effective against all HIV-1 isolates previously showing resistance to INSTIs.Methods We evaluated the HIV-1 CRF02_AG IN gene sequences from Cameroon for the presence of resistance-associated mutations (RAMs) against INSTIs and naturally occurring polymorphisms (NOPs), using study sequences (n=20) and (n=278) sequences data derived from HIV Los Alamos National Library (LANL) database. The possible impact of NOPs on protein structure caused by HIV-1 CRF02_AG variations was addressed within the context of a 3D model of the HIV-1 IN complex. Results We observed 12.8% (37/287) sequences to contain RAMs, with only 1.0% (3/287) of the sequences having major INSTI RAMs: T66A, Q148H, R263K and N155H. Of these,11.8% (34/287) of the sequences contained five different IN accessory mutations; namely Q95K, T97A, G149A, E157Q and D232N. NOP rates equal or above 50% were found for 66% of central core domain (CCD) positions, 44% C-terminal domain (CTD) positions and 35% of the N-terminal domain (NTD) positions.Conclusions Our analysis indicated that all mutations that resulted in a change in the number of interactions encompassing residues were found within the stable alpha-helix secondary structure element and not in close proximity to the drug active site. Our findings highlight the structural basis for HIV-1 IN interactions and that INSTIs will remain effective against CRF02_AG.

Citer ce document

Accès au document

Ce document est hébergé sur son dépôt institutionnel d'origine.

Auteur(s)

Statistiques

Consultations : 1

Téléchargements : 0