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  • br Acknowledgments We would like to thank

    2022-05-17


    Acknowledgments We would like to thank Coordenação de Aperfeiçoamento de Pessoal do Ensino Superior (CAPES) and Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq) for the grants and scholarships provide to the authors of this work.
    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 Cap Firefly Luciferase into the genome of infected cells. IN is composed of a central core domain that contains a conserved domain, D-35-E motif. Mutation of any of the residues in this motif diminishes all catalytic activity of the protein [1]. Integration of a cDNA copy of the viral genome into the infected cell's genome is an obligatory step in the replication of all retroviruses. 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 (3′ 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]. IN inhibitors (INIs) block IN activity, which prevents integration of the viral double-stranded DNA into the host cell's genomic DNA. Raltegravir (RAL) was the first INI approved for clinical use in both treatment-naive and treatment-experienced patients [3]. RAL is also useful for treating patients, which are infected by antiretroviral-resistant HIV-1 strain [4]. Elvitegravir (EVG) is another ARV that was approved by the FDA for clinical treatment of patients. Both RAL and EVG inhibit IN activity by forming a complex with viral DNA, which hinders the process of viral genome integration [5]. Another type of INI is the Allosteric Integrase Inhibitor (ALLINI) class that works by inhibiting binding interactions between IN and Lens Epithelium Derived Growth Factor (LEDGF/p75), which reduces IN catalytic activity [6]. ALLINIs (also referred to as LEDGINs, noncatalytic site integrase inhibitors (NCINIs), or multimodal inhibitors) are highly active against HIV replication in cell culture [7]. HIV-1 is characterized by extensive genetic heterogeneity resulting from the absence of reverse transcriptase (RT) proofreading activity, which leads to high genetic variability and rapid evolution of HIV-1. Genetic heterogeneity originates from the high mutation rate of RT [8]. Genetic mutations ultimately lead to drug resistance, yet little is known about IN polymorphisms, whereas a study on polymorphisms of HIV-1 RT and Protease has been conducted [9]. In this study, polymorphisms of HIV IN (i.e., IN variants) from one viral isolate were analyzed in silico.
    Methods
    Results and discussion The IN gene sequence corresponding to the Jayapura isolate (CRF01_AE) was aligned to the wild-type reference sequence (GenBank accession number K03455; reference strain HXB2). The alignment revealed several polymorphisms in the IN gene of CRF01_AE (Fig. 1A). Based on the Stanford HIVdb mutation interpretation database, the following polymorphisms were identified: I72V, T112V, T124A, T125A, G134N, I135V, K136Q and M154I (Fig. 1B). EVG-resistance related polymorphisms Q148H and N155H [15] were not observed in the CRF01_AE. The three-dimensional structure of the variant IN protein, derived using FoldX software, revealed that the alteration was caused by amino acid changes [10]. Structural modeling revealed that wild-type IN contains a longer helix domain as compared to the variant IN (Fig. 2). Minimal, if any, differences of protein stability were detected between the wild-type and variant IN (Table 1). Amino acid polymorphisms in the variant IN were predicted to slightly alter the structure, stability, and hydrophobicity of the protein, which changed the binding properties of the INIs (Fig. 3). The interaction of INIs with IN was mediated via hydrogen bonding, carbon-hydrogen bonding, unfavorable negative-negative, pi-anion, pi-donor hydrogen bonding, pi-sigma, alkyl, and pi-alkyl (Figs. 3 and 4). The variant IN may have a stronger binding affinity for ALLINIs and EVG, but not for RAL. However, changes in binding affinities were only minimally altered, although the binding affinity of ALLINI and EVG for the variant IN appeared to be stronger as compared to wild-type IN (Table 2).