This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Follis, K. E.
Right arrow Articles by Nunberg, J. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Follis, K. E.
Right arrow Articles by Nunberg, J. H.

 Previous Article  |  Next Article 

Journal of Virology, July 2002, p. 7356-7362, Vol. 76, No. 14
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.14.7356-7362.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Genetic Evidence that Interhelical Packing Interactions in the gp41 Core Are Critical for Transition of the Human Immunodeficiency Virus Type 1 Envelope Glycoprotein to the Fusion-Active State

Kathryn E. Follis,1 Scott J. Larson,1 Min Lu,2 and Jack H. Nunberg1*

Montana Biotechnology Center, The University of Montana, Missoula, Montana 59812,1 Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 100212

Received 13 February 2002/ Accepted 23 April 2002

The envelope glycoprotein complex (gp120-gp41) of human immunodeficiency virus type 1 (HIV-1) promotes the fusion of viral and cellular membranes through formation of the fusion-active six-helix bundle in the gp41 ectodomain. This gp41 core structure consists of three C-terminal helices packed in an antiparallel manner into hydrophobic grooves on the surface of the N-terminal trimeric coiled coil. Alanine mutations that destabilize the N- and C-terminal interhelical packing interactions also reduce viral infectivity. Here we show that viruses bearing these mutations exhibit a marked potentiation of inhibition by peptides that make up the gp41 core. By contrast, these viruses are unchanged in their sensitivities to soluble CD4, the CXCR4 coreceptor ligand SDF-1{alpha}, and human anti-HIV immunoglobulin, reagents that impact the initial, receptor-induced conformational changes in the envelope glycoprotein. Our results support the notion that these alanine mutations specifically affect the conformational transition to the fusion-active gp41 structure. The mutations also increase viral sensitivity to the gp41-directed monoclonal antibody 2F5, suggesting that this broadly neutralizing antibody may also interfere with this transition. The conformational activation of the HIV-1 envelope glycoprotein likely represents a viable target for vaccine and antiviral drug development.

* Corresponding author: Jack H. Nunberg, Montana Biotechnology Center, The University of Montana, Missoula, MT 59812. Phone: (406)243-6421. Fax: (406) 243-6425. E-mail: nunberg{at}selway.umt.edu.

Journal of Virology, July 2002, p. 7356-7362, Vol. 76, No. 14
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.14.7356-7362.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • He, Y., Liu, S., Li, J., Lu, H., Qi, Z., Liu, Z., Debnath, A. K., Jiang, S. (2008). Conserved Salt Bridge between the N- and C-Terminal Heptad Repeat Regions of the Human Immunodeficiency Virus Type 1 gp41 Core Structure Is Critical for Virus Entry and Inhibition. J. Virol. 82: 11129-11139 [Abstract] [Full Text]  
  • York, J., Dai, D., Amberg, S. M., Nunberg, J. H. (2008). pH-Induced Activation of Arenavirus Membrane Fusion Is Antagonized by Small-Molecule Inhibitors. J. Virol. 82: 10932-10939 [Abstract] [Full Text]  
  • He, Y., Cheng, J., Lu, H., Li, J., Hu, J., Qi, Z., Liu, Z., Jiang, S., Dai, Q. (2008). Potent HIV fusion inhibitors against Enfuvirtide-resistant HIV-1 strains. Proc. Natl. Acad. Sci. USA 105: 16332-16337 [Abstract] [Full Text]  
  • Zhang, M.-Y., Vu, B. K., Choudhary, A., Lu, H., Humbert, M., Ong, H., Alam, M., Ruprecht, R. M., Quinnan, G., Jiang, S., Montefiori, D. C., Mascola, J. R., Broder, C. C., Haynes, B. F., Dimitrov, D. S. (2008). Cross-Reactive Human Immunodeficiency Virus Type 1-Neutralizing Human Monoclonal Antibody That Recognizes a Novel Conformational Epitope on gp41 and Lacks Reactivity against Self-Antigens. J. Virol. 82: 6869-6879 [Abstract] [Full Text]  
  • He, Y., Cheng, J., Li, J., Qi, Z., Lu, H., Dong, M., Jiang, S., Dai, Q. (2008). Identification of a Critical Motif for the Human Immunodeficiency Virus Type 1 (HIV-1) gp41 Core Structure: Implications for Designing Novel Anti-HIV Fusion Inhibitors. J. Virol. 82: 6349-6358 [Abstract] [Full Text]  
  • Frey, G., Peng, H., Rits-Volloch, S., Morelli, M., Cheng, Y., Chen, B. (2008). A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodies. Proc. Natl. Acad. Sci. USA 105: 3739-3744 [Abstract] [Full Text]  
  • He, Y., Liu, S., Jing, W., Lu, H., Cai, D., Chin, D. J., Debnath, A. K., Kirchhoff, F., Jiang, S. (2007). Conserved Residue Lys574 in the Cavity of HIV-1 Gp41 Coiled-coil Domain Is Critical for Six-helix Bundle Stability and Virus Entry. J. Biol. Chem. 282: 25631-25639 [Abstract] [Full Text]  
  • Chinnadurai, R., Rajan, D., Munch, J., Kirchhoff, F. (2007). Human Immunodeficiency Virus Type 1 Variants Resistant to First- and Second-Version Fusion Inhibitors and Cytopathic in Ex Vivo Human Lymphoid Tissue. J. Virol. 81: 6563-6572 [Abstract] [Full Text]  
  • Steger, H. K., Root, M. J. (2006). Kinetic Dependence to HIV-1 Entry Inhibition. J. Biol. Chem. 281: 25813-25821 [Abstract] [Full Text]  
  • Doyle, J., Prussia, A., White, L. K., Sun, A., Liotta, D. C., Snyder, J. P., Compans, R. W., Plemper, R. K. (2006). Two Domains That Control Prefusion Stability and Transport Competence of the Measles Virus Fusion Protein. J. Virol. 80: 1524-1536 [Abstract] [Full Text]  
  • Kinomoto, M., Yokoyama, M., Sato, H., Kojima, A., Kurata, T., Ikuta, K., Sata, T., Tokunaga, K. (2005). Amino Acid 36 in the Human Immunodeficiency Virus Type 1 gp41 Ectodomain Controls Fusogenic Activity: Implications for the Molecular Mechanism of Viral Escape from a Fusion Inhibitor. J. Virol. 79: 5996-6004 [Abstract] [Full Text]  
  • Heap, C. J., Reading, S. A., Dimmock, N. J. (2005). An antibody specific for the C-terminal tail of the gp41 transmembrane protein of human immunodeficiency virus type 1 mediates post-attachment neutralization, probably through inhibition of virus-cell fusion. J. Gen. Virol. 86: 1499-1507 [Abstract] [Full Text]  
  • Desmezieres, E., Gupta, N., Vassell, R., He, Y., Peden, K., Sirota, L., Yang, Z., Wingfield, P., Weiss, C. D. (2005). Human Immunodeficiency Virus (HIV) gp41 Escape Mutants: Cross-Resistance to Peptide Inhibitors of HIV Fusion and Altered Receptor Activation of gp120. J. Virol. 79: 4774-4781 [Abstract] [Full Text]  
  • Pascual, R., Moreno, M. R., Villalain, J. (2005). A Peptide Pertaining to the Loop Segment of Human Immunodeficiency Virus gp41 Binds and Interacts with Model Biomembranes: Implications for the Fusion Mechanism. J. Virol. 79: 5142-5152 [Abstract] [Full Text]  
  • Lenz, O., Dittmar, M. T., Wagner, A., Ferko, B., Vorauer-Uhl, K., Stiegler, G., Weissenhorn, W. (2005). Trimeric Membrane-anchored gp41 Inhibits HIV Membrane Fusion. J. Biol. Chem. 280: 4095-4101 [Abstract] [Full Text]  
  • Zwick, M. B., Jensen, R., Church, S., Wang, M., Stiegler, G., Kunert, R., Katinger, H., Burton, D. R. (2005). Anti-Human Immunodeficiency Virus Type 1 (HIV-1) Antibodies 2F5 and 4E10 Require Surprisingly Few Crucial Residues in the Membrane-Proximal External Region of Glycoprotein gp41 To Neutralize HIV-1. J. Virol. 79: 1252-1261 [Abstract] [Full Text]  
  • York, J., Nunberg, J. H. (2004). Role of Hydrophobic Residues in the Central Ectodomain of gp41 in Maintaining the Association between Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Subunits gp120 and gp41. J. Virol. 78: 4921-4926 [Abstract] [Full Text]  
  • Zwick, M. B., Komori, H. K., Stanfield, R. L., Church, S., Wang, M., Parren, P. W. H. I., Kunert, R., Katinger, H., Wilson, I. A., Burton, D. R. (2004). The Long Third Complementarity-Determining Region of the Heavy Chain Is Important in the Activity of the Broadly Neutralizing Anti-Human Immunodeficiency Virus Type 1 Antibody 2F5. J. Virol. 78: 3155-3161 [Abstract] [Full Text]  
  • de Rosny, E., Vassell, R., Jiang, S., Kunert, R., Weiss, C. D. (2004). Binding of the 2F5 Monoclonal Antibody to Native and Fusion-Intermediate Forms of Human Immunodeficiency Virus Type 1 gp41: Implications for Fusion-Inducing Conformational Changes. J. Virol. 78: 2627-2631 [Abstract] [Full Text]  
  • Jones, T. R., Lee, S.-W., Johann, S. V., Razinkov, V., Visalli, R. J., Feld, B., Bloom, J. D., O'Connell, J. (2004). Specific Inhibition of Human Cytomegalovirus Glycoprotein B-Mediated Fusion by a Novel Thiourea Small Molecule. J. Virol. 78: 1289-1300 [Abstract] [Full Text]  
  • Russell, C. J., Kantor, K. L., Jardetzky, T. S., Lamb, R. A. (2003). A dual-functional paramyxovirus F protein regulatory switch segment: activation and membrane fusion. JCB 163: 363-374 [Abstract] [Full Text]  
  • Duffalo, M. L, James, C. W (2003). Enfuvirtide: A Novel Agent for the Treatment of HIV-1 Infection. The Annals of Pharmacotherapy 37: 1448-1456 [Abstract] [Full Text]  
  • Raja, A., Venturi, M., Kwong, P., Sodroski, J. (2002). CD4 Binding Site Antibodies Inhibit Human Immunodeficiency Virus gp120 Envelope Glycoprotein Interaction with CCR5. J. Virol. 77: 713-718 [Abstract] [Full Text]  
  • Joyce, J. G., Hurni, W. M., Bogusky, M. J., Garsky, V. M., Liang, X., Citron, M. P., Danzeisen, R. C., Miller, M. D., Shiver, J. W., Keller, P. M. (2002). Enhancement of alpha -Helicity in the HIV-1 Inhibitory Peptide DP178 Leads to an Increased Affinity for Human Monoclonal Antibody 2F5 but Does Not Elicit Neutralizing Responses in Vitro. IMPLICATIONS FOR VACCINE DESIGN. J. Biol. Chem. 277: 45811-45820 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»