Interaction analysis of statistically enriched mutations identified in Cameroon recombinant subtype CRF02_AG that can influence the development of Dolutegravir drug resistance mutations
Date
2021-04-23
Journal Title
Journal ISSN
Volume Title
Publisher
BMC (part of Springer Nature)
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
containing regimens have shown a high genetic barrier against HIV-1 isolates carrying specific resistance mutations
when compared with other class of regimens.
Methods: We evaluated the HIV-1 CRF02_AG IN gene sequences from Cameroon for the presence of resistanceassociated
mutations (RAMs) against INSTIs and naturally occurring polymorphisms (NOPs), using study sequences
(n = 20) and (n = 287) sequences data derived from HIV Los Alamos National Laboratory 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 and interaction analysis was performed using PyMol to validate DTG binding to
the Wild type and seven mutant structures.
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. NOPs occurred at a frequency of
66% on the central core domain (CCD) position, 44% on the C-terminal domain (CTD) position and 35% of the Nterminal
domain (NTD) position. The interaction analysis revealed that DTG bound to DNA, 2MG ions and DDE
motif residues for T66A, T97A, Q148H, N155H and R263K comparable to the WT structure. Except for accessory
mutant structure E157Q, only one MG contact was made with DTG, while DTG had no MG ion contacts and no
DDE motif residue contacts for structure D232N.
Conclusions: Our analysis indicated that all RAM’s that resulted in a change in the number of interactions with
encompassing residues does not affect DTG binding, while accessory mutations E157Q and D232N could affect
DTG binding leading to possible DTG resistance. However, further experimental validation is required to validate the
in silico findings of our study.
Description
CITATION: Mikasi, S. G., et al. 2021. Interaction analysis of statistically enriched mutations identified in Cameroon recombinant subtype CRF02_AG that can influence the development of Dolutegravir drug resistance mutations. BMC Infectious Diseases, 21:379, doi:10.1186/s12879-021-06059-x.
The original publication is available at https://bmcinfectdis.biomedcentral.com
The original publication is available at https://bmcinfectdis.biomedcentral.com
Keywords
Inhibitors, Strand transfer inhibitor, Dolutegravir, Drug resistance -- Mutation (Biology), Recombinant protease inhibitors
Citation
Mikasi, S. G., et al. 2021. Interaction analysis of statistically enriched mutations identified in Cameroon recombinant subtype CRF02_AG that can influence the development of Dolutegravir drug resistance mutations. BMC Infectious Diseases, 21:379, doi:10.1186/s12879-021-06059-x