South African Medical Research Council (SAMRC) Repository
Not a member yet
1675 research outputs found
Sort by
Interaction analysis of statistically enriched mutations identified in Cameroon recombinant subtype CRF02_AG that can influence the development of Dolutegravir drug resistance mutations
No full textBackground: 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 resistance-associated 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 N-terminal 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.The study was supported by the National Research Foundation (NRF) of
South Africa, Poliomyelitis Research Foundation (PRF) of South Africa, Harry
Crossley Foundation, South African Research Chairs Initiative of the
Department of Science, Technology (DST). South African Medical Research
Council (SAMRC) and The Higher Education Department, next Generation of
Academic Programme (nGAP), provided support for this study in the form of
full time academic positions and salaries to R. Cloete and GBJ. Mr. Darren
Isaacs and Miss Rumbidzai Chitongo were funded by the South African
Research Chairs Initiative of the Department of Science and Innovation (DSI)
and National Research Foundation (NRF) of South Africa, award number UID
64751. The Funders had no role in the design of the study and collection,
analysis, and interpretation of data and in writing the manuscript
Inhaled corticosteroids in ambulatory and hospitalised patients with COVID-19, not requiring oxygen therapy
No full text"Progress in Vaccine development In Africa”
No full textInternational Society of Pharmacoepidemiology African virtual conference
Report on weekly deaths in South Africa: Week 30
No full textThis report provides estimates of the weekly number of deaths of person 1+ years in South Africa for epidemiological Week 30 of 2021, covering the period 25 – 31 Jul 2021
Report on weekly deaths in South Africa: Weeks 13 and 14
No full textThis report provides estimates of the weekly number of deaths of person 1+ years in South Africa for epidemiological Weeks 13 and 14 of 2021, covering the period 28 Mar – 3 April 2021 and 4 – 10 April 2021 respectively
Report on weekly deaths in South Africa: Week 35
No full textThis report provides estimates of the weekly number of deaths of all persons in South Africa for epidemiological Week 35 of 2021, covering the period 29 Aug – 4 Sep 2021
Report on weekly deaths in South Africa: Week 45
No full textThis report provides estimates of the weekly number of deaths of all persons in South Africa for epidemiological Week 45 of 2021, covering the period 7 - 13 November 2021