Dr. Ruben Cloete and his research group, together with researchers at the University of Stellenbosch, have recently published two papers. The first paper details their analysis work on drug resistance in HIV-1 integrase, and the second on identifying plausible candidate genes for Parkinson’s disease. A brief summary follows below.
Drug resistance analysis in HIV-1 Integrase:
One study in partnership with our Stellenbosch University collaborators showed that known resistance mutation G140S could have an effect on the novel Dolutegravir (DTG) binding efficacy currently being rolled out in South Africa. This study shows the importance of screening for known resistance mutations before the administering of standard HIV antiretroviral therapy within the South African population which may be ineffective due to the acquisition of specific mutations [1]. Another recent article published by our group investigated the impact caused by statistically enriched naturally occurring polymorphisms found in the Cameroon CRF02_AG subtype on the three-dimensional (3D) protein structure of the HIV-1CRF02-DNA-MG-DTG Integrase complex. This study indicated that all known resistance associated mutations do not affect DTG drug binding, while accessory mutations E157Q and D232N could affect DTG binding leading to possible DTG resistance [2]. Further experimental validation is required to determine no loss in viral integration using viral integration assays.
Chitongo R, Obasa AE, Mikasi SG, Jacobs GB, Cloete R. Molecular dynamic simulations to investigate the structural impact of known drug resistance mutations on HIV-1C Integrase-Dolutegravir binding. PloS one. 2020;15(5):e0223464.
Mikasi SG, Isaacs D, Chitongo R, Ikomey GM, Jacobs GB, Cloete R. 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. 2021;21(1):1–12.
Candidate gene prioritization for Parkinson’s disease
Another article published by our group in partnership with collaborators from Stellenbosch University successfully prioritized a sequence variant in one gene from South African Parkinson’s disease (PD) patient using computational methods [3]. Neurexin 2 (NRNX2) was found to satisfy the prioritization criteria as being a plausible candidate gene possibly associated with PD [3]. Ongoing experimental work identified altered protein expression of the mutant NRNX2 affecting neuronal cell viability due to toxicity. These results provide strong support for the role of this variant gene in Parkinson’s disease.
Sebate B, Cuttler K, Cloete R, Britz M, Christoffels A, Williams M, et al. Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools. PloS one. 2021;16(3):e0249324.