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

Abstract

<jats:title>Abstract</jats:title> <jats:p><jats:bold>Background </jats:bold>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.<jats:bold>Methods </jats:bold>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. <jats:bold>Results </jats:bold>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.<jats:bold>Conclusions </jats:bold>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.</jats:p>