Existing users Log In New users Sign up


The role of mutantion in HIV-1 protease flap dynamics

DISCOVERIES (ISSN 2359-7232), 2014, Oct-Dec

CITATION: 
Chordia P, Dewdney TG, Keusch B, Kuiper BD, Ross K, Kovari IA, MacArthur R, Salimnia H, Kovari LCThe role of mutations at codons 32, 47, 54, and 90 in HIV-1 protease flap dynamics. Discoveries 2014, Oct-Dec; 2(4): e27. DOI: 10.15190/d.2014.19

Submitted: July 31, 2014; Revised: December 22, 2014; AcceptedDecember 28, 2014Published: December 31, 2014;

GO BACK to 2014, October-December issue 
GO BACK to DISCOVERIES

The role of mutations at codons 32, 47, 54, and 90 in HIV-1 protease flap dynamics

(1,2,#), (1,#) (1) (1), (1), (1), (2), (3), (1,*)


(1) “Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA;
(2) Department of Infectious Diseases, Wayne State University School of Medicine, Detroit, Michigan, USA;
(3) Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, USA; 

# These authors contributed equally to this work;

*Correspondence to: Ladislau C. Kovari, PhD,  Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA 540 E. Canfield Street, Detroit, MI 48201, USA.  E-mail: kovari@med.wayne.edu;

Abstract

Treatment of Human Immunodeficiency Virus remains challenging due to the emergence of drug resistant strains under the selective pressure produced by standard anti-retroviral therapy. To explore the structural mechanisms of drug resistance, we performed 40 ns molecular dynamics simulations on three multi-drug resistant HIV-1 protease clinical isolates from patients attending an infectious diseases clinic in Detroit, MI. We identify a novel structural role for the I47V, V32I, I54M and L90M major resistance mutations in flap opening and closure of MDR-PR isolates. Our studies suggest I47V is involved in flap opening and the interaction between I47V and V32I tethers the flaps to the active site. Also, I54M and L90M may be responsible for asymmetric movement of the protease flaps. These findings can be utilized to improve drug design strategies against MDR HIV-1 PR variants.

Access full text of the manuscript here: 

References

1.  Wainberg MA, Gu Z, Gao Q, Arts E, Geleziunas R, Bour S, et al. Clinical correlates and molecular basis of HIV drug resistance. J Acquir Immune Defic Syndr. 1993;6 Suppl 1:S36–46. 

2. Smyth RP, Davenport MP, Mak J. The origin of genetic diversity in HIV-1. Virus Res. 2012 ;169(2):415–29. 

3. Tang MW, Shafer RW. HIV-1 antiretroviral resistance: scientific principles and clinical applications. Drugs. 2012;72(9):e1–25. 

4. Van Maarseveen N, Boucher C. Resistance to protease inhibitors. In: Geretti AM, editor. Antiretrovir Resist Clin Pract [Internet]. London: Mediscript; 2006 [cited 2013 Nov 7]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK2250/

5. McCoy C. Darunavir: a nonpeptidic antiretroviral protease inhibitor. Clin Ther. 2007;29(8):1559–76. 

6. Johnson VA, Calvez V, Gunthard HF, Paredes R, Pillay D, Shafer RW, et al. Update of the drug resistance mutations in HIV-1: March 2013. Top Antivir Med. 2013; 21(1):6–14. 

7. Wang Y, Liu Z, Brunzelle JS, Kovari IA, Dewdney TG, Reiter SJ, et al. The higher barrier of darunavir and tipranavir resistance for HIV-1 protease. Biochem Biophys Res Commun. 2011; 412(4):737–42. 

8. Berhan A, Berhan Y. Virologic response to tipranavir-ritonavir or darunavir-ritonavir based regimens in antiretroviral therapy experienced HIV-1 patients: a meta-analysis and meta-regression of randomized controlled clinical trials. PloS One. 2013;8(4):e60814. 

9. Harris M, Nosyk B, Harrigan R, Lima VD, Cohen C, Montaner J. Cost-Effectiveness of Antiretroviral Therapy for Multidrug-Resistant HIV: Past, Present, and Future. AIDS Res Treat. 2012;2012:595762. 

10. Rhee S-Y, Taylor J, Fessel WJ, Kaufman D, Towner W, Troia P, et al. HIV-1 protease mutations and protease inhibitor cross-resistance. Antimicrob Agents Chemother. 2010; 54(10):4253–61. 

11. Ceccherini-Silberstein F, Erba F, Gago F, Bertoli A, Forbici F, Bellocchi MC, et al. Identification of the minimal conserved structure of HIV-1 protease in the presence and absence of drug pressure. AIDS Lond Engl. 2004; 18(12):F11–19. 

12. Spagnuolo V, Gianotti N, Seminari E, Galli L, Fusetti G, Salpietro S, et al. Changes in darunavir/r resistance score after previous failure to tipranavir/r in HIV-1-infected multidrug-resistant patients. J Acquir Immune Defic Syndr 1999. 2009; 50(2):192–5. 

13. Lambert-Niclot S, Flandre P, Canestri A, Peytavin G, Blanc C, Agher R, et al. Factors associated with the selection of mutations conferring resistance to protease inhibitors (PIs) in PI-experienced patients displaying treatment failure on darunavir. Antimicrob Agents Chemother. 2008; 52(2):491–6. 

14. Wlodawer A, Erickson JW. Structure-based inhibitors of HIV-1 protease. Annu Rev Biochem. 1993; 62:543–85. 

15. Wlodawer A. Rational approach to AIDS drug design through structural biology. Annu Rev Med. 2002; 53:595–614. 

16. Liu Z, Yedidi RS, Wang Y, Dewdney TG, Reiter SJ, Brunzelle JS, et al. Crystallographic study of multi-drug resistant HIV-1 protease lopinavir complex: mechanism of drug recognition and resistance. Biochem Biophys Res Commun. 2013; 437(2):199–204. 

17. Liu Z, Wang Y, Brunzelle J, Kovari IA, Kovari LC. Nine crystal structures determine the substrate envelope of the MDR HIV-1 protease. Protein J. 2011; 30(3):173–83. 

18. Yedidi RS, Proteasa G, Martinez JL, Vickrey JF, Martin PD, Wawrzak Z, et al. Contribution of the 80s loop of HIV-1 protease to the multidrug-resistance mechanism: crystallographic study of MDR769 HIV-1 protease variants. Acta Crystallogr D Biol Crystallogr. 2011;67(Pt 6): 524–32. 

19. Van Houtte M, Picchio G, Van Der Borght K, Pattery T, Lecocq P, Bacheler LT. A comparison of HIV-1 drug susceptibility as provided by conventional phenotyping and by a phenotype prediction tool based on viral genotype. J Med Virol. 2009; 81(10):1702–9.

20. The PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LLC.

21. Rabi SA, Laird GM, Durand CM, Laskey S, Shan L, Bailey JR, et al. Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance. J Clin Invest. 2013; 123(9): 3848-3860.

22. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phys 1983; 79: 926.

23. Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, et al. Scalable molecular dynamics with NAMD. J Comput Chem. 2005; 26(16): 1781-1802.

24. Liu F, Kovalevsky AY, Tie Y, Ghosh AK, Harrison RW, Weber IT. Effect of flap mutations on structure of HIV-1 protease and inhibition by saquinavir and darunavir. J Mol Biol. 2008; 381: 102-115.

25. Muzammil S, Armstrong AA, Kang LW, Jakalian A, Bonneau PR, Schmeimer V et al. Unique thermodynamic response of tipranavir to human immunodeficiency virus type 1 protease drug resistance mutations. J Virol. 2007; 81: 5144-5154.

GO BACK to the 2014, October-December issue 
GO BACK to DISCOVERIES 
MEET OUR EDITORIAL BOARD 
SUBMIT A MANUSCRIPT

Email Email us at info@discoveriesjournals.org if you have any questions.

News & Events Latest news from Discoveries

  • 2018 | For Authors!

    PMC highlighted that a high proportion of authors of Discoveries articles are also members of our Editorial Board. As a result, from now on and for at least 1 year, we will only accept articles from authors that are NOT members of Discoveries' Editorial Board. All articles submitted by our members will be immediately rejected until further notice (one accepted article was already rejected). 

  • 2017-2018 | PubMed inclusion News!

    Discoveries successfully passed the Scientific Quality Review by NLM-NIH for PubMedCentral and PubMed indexing. This is the first and the most important step towards PubMedCentral and PubMed indexing! The second (last) step is the Technical Review.

  • April 2016 | Faster Peer-Review

    Starting on April 13th 2016, all articles selected for a peer-review will receive the post peer-review decision within 10 days. The initial pre-screening time will remain the same (48h from the submission of the manuscript). This decision will significantly accelerate the publication, with no effect on the quality of the peer-review process.

  • February 2016 | Manuscript submission

    Discoveries is commited to excellence, quality and high editorial standards. We are receiving an increasing number of manuscripts for which the identity of the authors/corresponding author can't be verified. Please NOTE that ALL these articles were and will be immediately REJECTED. Indicating an institutional email address is the easiest way to overcome this problem! Moreover, we do not accept any pressure on our editorial board to accept a manuscript. This results in a prompt rejection of the article.

    Editorial Policies
  • January 2016 | Main Objective

    After reaching all proposed milestones until now (including being indexed by Google Scholar in 2014), Discoveries' next Aim is PubMed indexing of all its articles (already published and upcoming). There will be no charge for the submission or publication of articles before Discoveries is indexed.

  • August 2015 | Discoveries - on PubMed

    We are happy to announce that our first Discoveries articles were included in PMC and PubMed. More articles (submitted by NIH funded authors) are now processed for being included.

    Discoveries articles now on PubMed
  • April 2015 | Special Issue

    DISCOVERIES published the SPECIAL ISSUE entitled "INFLAMMATION BETWEEN DEFENSE AND DISEASE: Impact on Tissue Repair and Chronic Sickness".

    Special Issue on "Inflammation"
  • 2015 | Ischemia Collection

    DISCOVERIES launched a call for papers for a Collection of Articles with focus on "ISCHEMIA". If you are interested to submit a manuscript, please contact us at info@discoveriesjournals.org

  • September 2014 | Special Issue

    DISCOVERIES just publish the SPECIAL ISSUE entitled "CELL SECRETION & MEMBRANE FUSION" in September 2014. Initially scheduled for publication between October 2014-March 2015, this issue was successfully published earlier than scheduled. 

    Special Issue
  • April 2014 | Indexed by Google Scholar

    All our published articles are now indexed by Google Scholar! First citations to Discoveries articles are included! Search for the article's title (recommended) or the authors:

    Google Scholar Search
  • 2014 | DISCOVERIES

    DOIs (Digital Object Identifiers) are now assigned to all our published manuscripts in Discoveries. DOI uniquely identifies an article and is provided by CrossRef.

    CrossRef
  • July 2013 | Manuscript Submission

    Submit your manuscript FREE, FAST and EASY ! (in less than 1 minute)! There are NO fees for the manuscript submission or publishing of the accepted manuscripts.
    read more

  • July 2013 | DISCOVERIES

    We are now ACCEPTING MANUSCRIPTS for publishing in DISCOVERIES. We aim publishing a small number of high impact experimental articles & reviews (around 40/year) to maintain a high impact factor. Domains of interest: all areas related to Medicine, Biology and Chemistry ...

    read more
Member Login
Free Registration Click here to sign up
Copyright © 2013 Applied Systems. All Rights Reserved.