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Front. Microbiol. | doi: 10.3389/fmicb.2019.01981

Raltegravir-induced adaptations of the HIV-1 integrase: analysis of structure, variability, and mutation co-occurrence

  • 1Laboratory for Functional Genomics and Bioinformatics - Instituto Oswaldo Cruz, Oswaldo Cruz Foundation (Fiocruz), Brazil
  • 2Scientific Computing Program, Oswaldo Cruz Foundation (Fiocruz), Brazil

The human immunodeficiency virus type 1 (HIV-1) has several proteins of therapeutic importance, many of which are currently used as drug targets in antiretroviral therapy. Among these proteins is the Integrase, which is responsible for the integration of the viral DNA into the host genome - a crucial step for HIV-1 replication. Given the importance of this protein in the replication process, three integrase inhibitors are currently used as an option for antiretroviral therapy: Raltegravir, Elvitegravir, and Dolutegravir. However, the crescent emergence of mutations that cause resistance to these drugs has become a worldwide health problem.
In this study, we compared the variability of each position of the HIV-1 integrase sequence in clinical isolates of Raltegravir-treated and drug-naïve patients by calculating their Shannon entropies. A co-occurrence network was created to explore how mutations co-occur in patients treated with Raltegravir. Then, by building tridimensional models of the HIV-1 integrase intasomes, we investigated the relationship between variability, architecture, and co-occurrence.
We observed that positions bearing major resistance pathways are highly conserved among non-treated patients and variable among the treated ones. The residues involved in the major resistance-related mutations could be identified in the same group when the positions were clustered according to their entropies. Analysis of the integrase architecture showed that the high-entropy residues S119, T124, and T125, are in contact with the host DNA, and their variations may have impacts in the protein-DNA recognition. The co-occurrence network revealed that the major resistance pathways N155H and Q148HR share more mutations with each other than with the Y143R pathway, this observation corroborates the fact that the N155H pathway is most commonly converted into Q148HRK than into Y143RC pathway in patients’ isolates. The network and the structure analysis also support the hypothesis that the resistance-related E138K mutation may be a mechanism to compensate for mutations in neighbor lysine residues to maintain DNA binding.
The present study reveals patterns by which the HIV-1 integrase adapts during Raltegravir therapy. This information can be useful to comprehend the impacts of the drug in the enzyme, as well as help planning new therapeutic approaches.

Keywords: HIV-1, integrase, Raltegravir, Resistance, entropy, Co-Occurrence, Mutation

Received: 11 Apr 2019; Accepted: 12 Aug 2019.

Edited by:

Jason Kindrachuk, University of Manitoba, Canada

Reviewed by:

Jan Weber, Institute of Organic Chemistry and Biochemistry (ASCR), Czechia
Krishan K. Pandey, Saint Louis University, United States  

Copyright: © 2019 Machado, Gomes and Guimarães. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mr. Lucas d. Machado, Oswaldo Cruz Foundation (Fiocruz), Laboratory for Functional Genomics and Bioinformatics - Instituto Oswaldo Cruz, Rio de Janeiro, 21040-900, Rio de Janeiro, Brazil,