Human Immunodeficiency Virus Gag and protease: partners in resistance

Department of Virology, Medical Microbiology, University Medical Center Utrecht, HP G04,614, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands.
Retrovirology (Impact Factor: 4.19). 08/2012; 9(1):63. DOI: 10.1186/1742-4690-9-63
Source: PubMed


Human Immunodeficiency Virus (HIV) maturation plays an essential role in the viral life cycle by enabling the generation of mature infectious virus particles through proteolytic processing of the viral Gag and GagPol precursor proteins. An impaired polyprotein processing results in the production of non-infectious virus particles. Consequently, particle maturation is an excellent drug target as exemplified by inhibitors specifically targeting the viral protease (protease inhibitors; PIs) and the experimental class of maturation inhibitors that target the precursor Gag and GagPol polyproteins. Considering the different target sites of the two drug classes, direct cross-resistance may seem unlikely. However, coevolution of protease and its substrate Gag during PI exposure has been observed both in vivo and in vitro. This review addresses in detail all mutations in Gag that are selected under PI pressure. We evaluate how polymorphisms and mutations in Gag affect PI therapy, an aspect of PI resistance that is currently not included in standard genotypic PI resistance testing. In addition, we consider the consequences of Gag mutations for the development and positioning of future maturation inhibitors.

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Available from: Annemarie M.J. Wensing
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    • "It is well documented that drug resistance exerted by mutations occur in active site or residues placing near binding site. Nevertheless these mutations lower enzyme affinity for inhibitors but they did not attenuate enzyme affinity for its natural substrates (Fun et al., 2012, Kolli et al., 2006, Prabu-Jeyabalan et al., 2006, Nalam et al., 2010). It should be noted that In vitro studies as site directed mutagenesis confirmed that the major or drug resistant mutations for HIV-1 protease are as follow: D30N, V32I, M46L, M46I, I47V, I47A, G48V, I50L, I50V, I54M, Q58E, T74P, L76V, V82A, V82F, V82T, V82S, V82L, N83D, I84V, N88S (Johnson et al., 2010). "
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    ABSTRACT: Background: HIV-1 protease plays a critical role in HIV life cycle, thus it has been targeted to design and synthesize drugs against HIV infections. So far 9 of the HIV-1 protease inhibitors have been supplied to use as HIV drugs. One the most important barriers on the effectiveness of these drugs is viral resistance that caused by high rate of HIV-1 protease mutations. Investigation of resistance mutations can provide ways to make better inhibitors. Objectives: in this study we are going to study the effect of resistance mutations on HIV-1 protease structure. By analyzing the mutations we hope to suggest new ideas for drug design with more effective actions. Method: all available structures for HIV-1 protease were downloaded from PDB bank and classified by their inhibitor constituent and the mutations they contain. Then the mutant structures were compared with wild types, in terms of RMSD and RMSF parameters to find out their effects on enzyme structure. Result: Our results show that resistance mutations mostly occur in regions of protein sequence with high RMSF, called briefly protein hot points. Our findings also indicate that RMSF changes for protein side chains are more than that for alpha carbons. The RMSD difference between mutant and wild type structures caused by resistance mutations is shown to be pretty low. Conclusion: Based on our study, resistance mutations mostly occur in flexible areas of protein to affect enzymatic parameters such as K cat and substrate specificity more effectively. Also our data convey that resistance mutations altered protein tertiary structure much more than secondary structure for HIV-1 protease. Nevertheless RMSD trend for all resistant mutants did not show huge deviation from native structure, and this is why virus remains active. Key words: AIDS, HIV-1 protease, inhibitor, resistance mutations, molecular dynamic
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    • "One of the therapeutic approaches has been inhibition of the virally encoded enzymatic proteins necessary for viral replication and maturation. Human Immunodeficiency Virus Type 1 Protease (HIV-1 PR) is one of the vital enzymes of HIV-1 retrovirus, which cleaves viral gag and pol polyproteins and releases structural and enzymatic proteins for its maturation and proliferation inside infected host (Fun et al., 2012). The inhibition of HIV PR activity can lead to disruption of the viral protein maturation and replication, thus making HIV protease a potential target for AIDS therapy (Heal et al., 2012). "
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    ABSTRACT: HIV-1 protease (HIV-1 PR) enzyme is essential for the accurate assembly and maturation of infectious HIV retroviruses. The significant role of HIV-1 protease in viral replication has made it a potential drug target. In recent past, phytochemical gallic acid derivatives have been screened for protease inhibitor activity. The present work aims to design and evaluate potential gallic acid (GA)-based HIV-1 PR phyto-inhibitors by docking approach. The ligands were prepared by ChemDraw and the docking was performed in HEX software. In this present study, one of the GA analogues (GA5) emerged as a potent drug candidate for HIV-1 PR inhibition and showed comparable docking results with an anti-HIV pro-drug, fosamprenavir. The GA5 derivative provided a lead for designing more effective HIV-1 PR inhibitor.
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    • "More detailed structural analyses of virus mutants indicated that not the presence of the spacer peptide itself, but possibly the proper kinetics of cleavages in this region is relevant (de Marco et al., 2012). This interpretation is in agreement with the observation that mutations in the NC-SP2 region are characteristically observed as tertiary resistance mutations restoring fitness to HIV-1 variants carrying resistance mutations in PR, which affect the catalytic activity of the enzyme (reviewed in (Clavel and Mammano, 2010; Fun et al., 2012)). Furthermore, NC-SP2-p6, NC-SP2 and NC display different abilities to condense nucleic acid ((Mirambeau et al., 2010) and references therein) suggesting that successive processing steps in this region regulate the dynamics of nucleocapsid core formation. "
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    ABSTRACT: Proteolytic processing of viral polyproteins is essential for retrovirus infectivity. Retroviral proteases (PR) become activated during or after assembly of the immature, non-infectious virion. They cleave viral polyproteins at specific sites, inducing major structural rearrangements termed maturation. Maturation converts retroviral enzymes into their functional form, transforms the immature shell into a metastable state primed for early replication events, and enhances viral entry competence. Not only cleavage at all PR recognition sites, but also an ordered sequence of cleavages is crucial. Proteolysis is tightly regulated, but the triggering mechanisms and kinetics and pathway of morphological transitions remain enigmatic. Here, we outline PR structures and substrate specificities focusing on HIV PR as a therapeutic target. We discuss design and clinical success of HIV PR inhibitors, as well as resistance development towards these drugs. Finally, we summarize data elucidating the role of proteolysis in maturation and highlight unsolved questions regarding retroviral maturation. Copyright © 2015 Elsevier Inc. All rights reserved.
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