Relationship between HIV integrase polymorphisms and integrase inhibitor susceptibility: An in silico analysis

Hotma Martogi Lorensi Hutapea,Yustinus Maladan,Widodo Widodo

doi:10.1016/j.heliyon.2018.e00956

Hotma Martogi Lorensi Hutapea, Yustinus Maladan + Show 1 more

Open Access

https://doi.org/10.1016/j.heliyon.2018.e00956

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Journal: Heliyon	Publication Date: Dec 1, 2018
Citations: 3	License type: cc-by

Affiliation: Ministry of Health, University of Brawijaya

Abstract

Integrase (IN) plays an essential role in HIV-1 replication, by mediating integration of the viral genome into the host cell genome. IN is a potential target of antiretroviral (ARV) therapeutic drugs such as ALLINI, Raltegravir (RAL), and Elvitegravir (EVG). The effect of IN polymorphisms on its structure and binding affinity to the integrase inhibitors (INIs) is not well understood. The goal of this study was to examine the effect of IN polymorphisms on its tertiary structure and binding affinities to INIs using computational approaches. HIV genomes were isolated from patient blood and the IN gene was sequenced to identify polymorphisms. Protein structures were derived using FoldX and the binding affinity of IN for ALLINI, RAL, and EVG was evaluated using a molecular docking method. The binding affinities of ALLINI and EVG for wild-type IN were lower as compared to an IN variant; in contrast, the binding affinity of RAL for the IN variant was lower as compared to wild-type IN. These results suggested that IN variant interacts with ALLINI and EVG more efficiently as compared to the wildtype, which may not cause resistent to the drugs. In vitro and in vivo studies should be done to validate the findings of this study.

Highlights

Human Immunodeficiency Virus type 1 (HIV-1) integrase (IN) is an enzyme responsible for the integration of the double-stranded DNA form of the HIV-1 genome into the genome of infected cells
Mutation of any of the residues in this motif diminishes all catalytic activity of the protein [1]
A blood from an HIV-1 infected patient without INI treatment was obtained from Biobank Management in the Institute of Health Research and Development Papua, Ministry of Health, Indonesia that served as the source for the RNA genome of HIV-1

Summary

Introduction

Human Immunodeficiency Virus type 1 (HIV-1) integrase (IN) is an enzyme responsible for the integration of the double-stranded DNA form of the HIV-1 genome into the genome of infected cells. HIV-1 replication is a multistep process, which includes: 1) assembly of a stable complex between IN and specific viral DNA sequences at the end of the HIV-1 Long Terminal Repeat (LTR), 2) cleavage of the viral CA dinucleotide (30 processing), 3) preintegration complex translocation, 4) strand transfer, and 5) DNA gap repair and ligation. Any of these steps can be considered as a potential target of inhibitory drugs [2]

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