Cryoelectron tomographic analysis of an HIV-neutralizing protein and its complex with native viral gp120 - PubMed

Affiliations

• PMID: 17599917
• DOI: 10.1074/jbc.M702025200

Free article

Cryoelectron tomographic analysis of an HIV-neutralizing protein and its complex with native viral gp120

Adam Bennett et al. J Biol Chem. 2007.

Free article

Abstract

Identifying structural determinants of human immunodeficiency virus (HIV) neutralization is an important component of rational drug and vaccine design. We used cryoelectron tomography and atomic force microscopy to characterize the structure of an extremely potent HIV-neutralizing protein, D1D2-Ig alpha tp (abbreviated as D1D2-IgP), a polyvalent antibody construct that presents dodecameric CD4 in place of the Fab regions. We show that D1D2-IgP has a novel structure, displaying greater flexibility of its antibody arms than the closely related IgM. Using simian immunodeficiency virus in complex with D1D2-IgP, we present unequivocal evidence that D1D2-IgP can cross-link surface spikes on the same virus and on neighboring viruses. The observed binding to the viral envelope spikes is the result of specific CD4-gp120 interaction, because binding was not observed with MICA-IgP, a construct that is identical to D1D2-IgP except that major histocompatibility complex Class I-related Chain A (MICA) replaces the CD4 moiety. CD4-mediated binding was also associated with a significantly elevated proportion of ruptured viruses. The ratio of inactivated to CD4-liganded gp120-gp41 spikes can be much greater than 1:1, because all gp120-gp41 spikes on the closely apposed surfaces of cross-linked viruses should be incapable of accessing the target cell surface and mediating entry, as a result of inter-virus spike cross-linking. These results implicate flexibility rather than steric bulk or polyvalence per se as a structural explanation for the extreme potency of D1D2-IgP and thus suggest polyvalence presented on a flexible scaffold as a key design criterion for small molecule HIV entry inhibitors.

Similar articles

• Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds.

  Madani N, Princiotto AM, Zhao C, Jahanbakhshsefidi F, Mertens M, Herschhorn A, Melillo B, Smith AB 3rd, Sodroski J. Madani N, et al. J Virol. 2017 Jan 18;91(3):e01880-16. doi: 10.1128/JVI.01880-16. Print 2017 Feb 1. J Virol. 2017. PMID: 27881646 Free PMC article.

• HIV-1 gp41 Residues Modulate CD4-Induced Conformational Changes in the Envelope Glycoprotein and Evolution of a Relaxed Conformation of gp120.

  Keller PW, Morrison O, Vassell R, Weiss CD. Keller PW, et al. J Virol. 2018 Jul 31;92(16):e00583-18. doi: 10.1128/JVI.00583-18. Print 2018 Aug 15. J Virol. 2018. PMID: 29875245 Free PMC article.

• Structure of Simian Immunodeficiency Virus Envelope Spikes Bound with CD4 and Monoclonal Antibody 36D5.

  Hu G, Liu J, Roux KH, Taylor KA. Hu G, et al. J Virol. 2017 Jul 27;91(16):e00134-17. doi: 10.1128/JVI.00134-17. Print 2017 Aug 15. J Virol. 2017. PMID: 28539445 Free PMC article.

• GP120: target for neutralizing HIV-1 antibodies.

  Pantophlet R, Burton DR. Pantophlet R, et al. Annu Rev Immunol. 2006;24:739-69. doi: 10.1146/annurev.immunol.24.021605.090557. Annu Rev Immunol. 2006. PMID: 16551265 Review.

• AIDS virus envelope spike structure.

  Roux KH, Taylor KA. Roux KH, et al. Curr Opin Struct Biol. 2007 Apr;17(2):244-52. doi: 10.1016/j.sbi.2007.03.008. Epub 2007 Mar 28. Curr Opin Struct Biol. 2007. PMID: 17395457 Review.

Cited by

• Mechanism of multivalent nanoparticle encounter with HIV-1 for potency enhancement of peptide triazole virus inactivation.

  Rosemary Bastian A, Nangarlia A, Bailey LD, Holmes A, Kalyana Sundaram RV, Ang C, Moreira DR, Freedman K, Duffy C, Contarino M, Abrams C, Root M, Chaiken I. Rosemary Bastian A, et al. J Biol Chem. 2015 Jan 2;290(1):529-43. doi: 10.1074/jbc.M114.608315. Epub 2014 Nov 4. J Biol Chem. 2015. PMID: 25371202 Free PMC article.

• Computational Inversion of Electron Tomography Images Using L²-Gradient Flows.

  Xu G, Li M, Gopinath A, Bajaj C. Xu G, et al. J Comput Math. 2011;29(5):501-525. doi: 10.4208/jcm.1103-m3261. J Comput Math. 2011. PMID: 25301977 Free PMC article.

• Estimating the stoichiometry of HIV neutralization.

  Magnus C, Regoes RR. Magnus C, et al. PLoS Comput Biol. 2010 Mar 19;6(3):e1000713. doi: 10.1371/journal.pcbi.1000713. PLoS Comput Biol. 2010. PMID: 20333245 Free PMC article.

• Patterns of conserved gp120 epitope presentation on attached HIV-1 virions.

  Mengistu M, Tang AH, Foulke JS Jr, Blanpied TA, Gonzalez MW, Spouge JL, Gallo RC, Lewis GK, DeVico AL. Mengistu M, et al. Proc Natl Acad Sci U S A. 2017 Nov 14;114(46):E9893-E9902. doi: 10.1073/pnas.1705074114. Epub 2017 Oct 30. Proc Natl Acad Sci U S A. 2017. PMID: 29087304 Free PMC article.

• The genotype of early-transmitting HIV gp120s promotes α (4) β(7)-reactivity, revealing α (4) β(7) +/CD4+ T cells as key targets in mucosal transmission.

  Nawaz F, Cicala C, Van Ryk D, Block KE, Jelicic K, McNally JP, Ogundare O, Pascuccio M, Patel N, Wei D, Fauci AS, Arthos J. Nawaz F, et al. PLoS Pathog. 2011 Feb;7(2):e1001301. doi: 10.1371/journal.ppat.1001301. Epub 2011 Feb 24. PLoS Pathog. 2011. PMID: 21383973 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Research Materials

  • NCI CPTC Antibody Characterization Program