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Viruses 2017, 9(11), 330; https://doi.org/10.3390/v9110330

Characterization of Nucleoside Reverse Transcriptase Inhibitor-Associated Mutations in the RNase H Region of HIV-1 Subtype C Infected Individuals

1
HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Private Bag X7, Congella, Durban 4013, South Africa
2
Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Private Bag X7, Congella, Durban 4013, South Africa
3
Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven–University of Leuven, 3000 Leuven, Belgium
4
Artificial Intelligence Lab, Department of Computer Science, Vrije Universiteit Brussel, Brussels, 1050 Elsene, Belgium
5
Division of Infectious Disease, Emory University School of Medicine, Atlanta, GA 30322, USA
6
Infectious Diseases Unit, Nelson Mandela School of Medicine, University of KwaZulu-Natal, Private Bag X7, Congella, Durban 4013, South Africa
7
Africa Health Research Institute, University of KwaZulu-Natal, Private Bag X7, Congella, Durban 4013, South Africa
8
Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA 01239, USA
9
Max Planck Institute for Infection Biology, Chariteplatz, D-10117 Berlin, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 26 September 2017 / Revised: 2 November 2017 / Accepted: 4 November 2017 / Published: 8 November 2017
(This article belongs to the Section Antivirals & Vaccines)
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Abstract

The South African national treatment programme includes nucleoside reverse transcriptase inhibitors (NRTIs) in both first and second line highly active antiretroviral therapy regimens. Mutations in the RNase H domain have been associated with resistance to NRTIs but primarily in HIV-1 subtype B studies. Here, we investigated the prevalence and association of RNase H mutations with NRTI resistance in sequences from HIV-1 subtype C infected individuals. RNase H sequences from 112 NRTI treated but virologically failing individuals and 28 antiretroviral therapy (ART)-naive individuals were generated and analysed. In addition, sequences from 359 subtype C ART-naive sequences were downloaded from Los Alamos database to give a total of 387 sequences from ART-naive individuals for the analysis. Fisher’s exact test was used to identify mutations and Bayesian network learning was applied to identify novel NRTI resistance mutation pathways in RNase H domain. The mutations A435L, S468A, T470S, L484I, A508S, Q509L, L517I, Q524E and E529D were more prevalent in sequences from treatment-experienced compared to antiretroviral treatment naive individuals, however, only the E529D mutation remained significant after correction for multiple comparison. Our findings suggest a potential interaction between E529D and NRTI-treatment; however, site-directed mutagenesis is needed to understand the impact of this RNase H mutation. View Full-Text
Keywords: HIV-1; RNase H; resistance; mutations; NRTIs HIV-1; RNase H; resistance; mutations; NRTIs
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Ngcapu, S.; Theys, K.; Libin, P.; Marconi, V.C.; Sunpath, H.; Ndung’u, T.; Gordon, M.L. Characterization of Nucleoside Reverse Transcriptase Inhibitor-Associated Mutations in the RNase H Region of HIV-1 Subtype C Infected Individuals. Viruses 2017, 9, 330.

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