The role of N-glycans of HIV-1 gp41 in virus infectivity and susceptibility to the suppressive effects of carbohydrate-binding agents.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read Online Read More Add to Saved list
  • Author(s): Mathys L;Mathys L; Balzarini J; Balzarini J
  • Source:
    Retrovirology [Retrovirology] 2014 Dec 11; Vol. 11, pp. 107. Date of Electronic Publication: 2014 Dec 11.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101216893 Publication Model: Electronic Cited Medium: Internet ISSN: 1742-4690 (Electronic) Linking ISSN: 17424690 NLM ISO Abbreviation: Retrovirology Subsets: MEDLINE
    • Publication Information:
      Original Publication: [London] : BioMed Central, c2004-
    • Subject Terms:
      Virus Assembly* ; Virus Internalization* ; Virus Replication*; HIV Envelope Protein gp41/*chemistry ; HIV-1/*physiology ; Lectins/*metabolism ; Polysaccharides/*analysis; Cells, Cultured ; HIV Envelope Protein gp41/genetics ; HIV Envelope Protein gp41/metabolism ; HIV-1/drug effects ; HIV-1/growth & development ; Humans ; Mutant Proteins/chemistry ; Mutant Proteins/genetics ; Mutant Proteins/metabolism ; Protein Binding
    • Abstract:
      Background: Carbohydrate-binding agents (CBAs) are potent antiretroviral compounds that target the N-glycans on the HIV-1 envelope glycoproteins. The development of phenotypic resistance to CBAs by the virus is accompanied by the deletion of multiple N-linked glycans of the surface envelope glycoprotein gp120. Recently, also an N-glycan on the transmembrane envelope glycoprotein gp41 was shown to be deleted during CBA resistance development.
      Results: We generated HIV-1 mutants lacking gp41 N-glycans and determined the influence of these glycan deletions on the viral phenotype (infectivity, CD4 binding, envelope glycoprotein incorporation in the viral particle and on the transfected cell, virus capture by DC-SIGN(+) cells and transmission of DC-SIGN-captured virions to CD4(+) T-lymphocytes) and on the phenotypic susceptibility of HIV-1 to a selection of CBAs. It was shown that some gp41 N-glycans are crucial for the infectivity of the virus. In particular, lack of an intact N616 glycosylation site was shown to result in the loss of viral infectivity of several (i.e. the X4-tropic IIIB and NL4.3 strains, and the X4/R5-tropic HE strain), but not all (i.e. the R5-tropic ADA strain) studied HIV-1 strains. In accordance, we found that the gp120 levels in the envelope of N616Q mutant gp41 strains NL4.3, IIIB and HE were severely decreased. In contrast, N616Q gp41 mutant HIV-1ADA contained gp120 levels similar to the gp120 levels in WT HIV-1ADA virus. Concomitantly deleting multiple gp41 N-glycans was often highly detrimental for viral infectivity. Using surface plasmon resonance technology we showed that CBAs have a pronounced affinity for both gp120 and gp41. However, the antiviral activity of CBAs is not dependent on the concomitant presence of all gp41 glycans. Single gp41 glycan deletions had no marked effects on CBA susceptibility, whereas some combinations of two to three gp41 glycan-deletions had a minor effect on CBA activity.
      Conclusions: We revealed the importance of some gp41 N-linked glycans, in particular the N616 glycan which was shown to be absolutely indispensable for the infectivity potential of several virus strains. In addition, we demonstrated that the deletion of up to three gp41 N-linked glycans only slightly affected CBA susceptibility.
    • References:
      PLoS One. 2014 Jun 26;9(6):e101181. (PMID: 24967714)
      Virology. 1998 Mar 15;242(2):338-45. (PMID: 9514971)
      J Gen Virol. 1994 Jun;75 ( Pt 6):1389-97. (PMID: 8207403)
      J Cell Biol. 1983 Aug;97(2):293-300. (PMID: 6350314)
      J Virol. 2007 Jan;81(1):362-73. (PMID: 17050611)
      J Virol. 1992 Mar;66(3):1799-803. (PMID: 1738209)
      Antimicrob Agents Chemother. 2010 Aug;54(8):3287-301. (PMID: 20498311)
      J Biol Chem. 2011 Dec 16;286(50):42900-10. (PMID: 22006924)
      Mol Biol Cell. 2008 Oct;19(10):4298-309. (PMID: 18653472)
      Retrovirology. 2013 Feb 06;10:14. (PMID: 23384254)
      Virology. 2012 Feb 5;423(1):97-106. (PMID: 22192629)
      Retrovirology. 2004 Mar 08;1:2. (PMID: 15169555)
      Antimicrob Agents Chemother. 2010 Apr;54(4):1425-35. (PMID: 20047920)
      Virology. 2007 Apr 10;360(2):294-304. (PMID: 17123566)
      Nat Rev Microbiol. 2007 Aug;5(8):583-97. (PMID: 17632570)
      J Virol. 2004 Oct;78(19):10617-27. (PMID: 15367629)
      J Acquir Immune Defic Syndr (1988). 1988;1(4):317-23. (PMID: 3265154)
      J Biol Chem. 2005 Dec 9;280(49):41005-14. (PMID: 16183648)
      Immunity. 2014 May 15;40(5):657-68. (PMID: 24768347)
      J Antimicrob Chemother. 2014 Mar;69(3):582-93. (PMID: 24144923)
      Virology. 2007 Nov 10;368(1):145-54. (PMID: 17658575)
      J Virol. 1999 Jul;73(7):5294-300. (PMID: 10364275)
      J Virol Methods. 2005 Jan;123(1):25-34. (PMID: 15582695)
      AIDS Res Hum Retroviruses. 1994 Apr;10(4):371-81. (PMID: 8068416)
      Cell. 2000 Mar 3;100(5):587-97. (PMID: 10721995)
      Mol Pharmacol. 2005 May;67(5):1556-65. (PMID: 15718224)
      J Virol. 1986 Jan;57(1):379-84. (PMID: 3001360)
      Virology. 1992 Mar;187(1):377-82. (PMID: 1736542)
      Nature. 2003 Mar 20;422(6929):307-12. (PMID: 12646921)
      J Virol. 1997 Oct;71(10):7719-27. (PMID: 9311856)
      J Virol Methods. 2006 Sep;136(1-2):102-17. (PMID: 16690137)
      Virology. 2008 Dec 5;382(1):10-9. (PMID: 18930512)
      PLoS One. 2011;6(8):e23521. (PMID: 21858152)
    • Accession Number:
      0 (HIV Envelope Protein gp41)
      0 (Lectins)
      0 (Mutant Proteins)
      0 (Polysaccharides)
      0 (gp41 protein, Human immunodeficiency virus 1)
    • Publication Date:
      Date Created: 20141216 Date Completed: 20151012 Latest Revision: 20240510
    • Publication Date:
      20240510
    • Accession Number:
      PMC4269863
    • Accession Number:
      10.1186/s12977-014-0107-7
    • Accession Number:
      25499264