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Title: A Functional gp41-gp120 Interaction is Observed in Monomeric but not Oligomeric, Uncleaved HIV-1 Env gp140

Authors:
;
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1136672
Report Number(s):
SLAC-REPRINT-2014-217
Journal ID: ISSN 0022-538X
DOE Contract Number:
AC02-76SF00515
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Virology; Journal Volume: 87; Journal Issue: 21
Country of Publication:
United States
Language:
English
Subject:
CHEM

Citation Formats

Guttman, Miklos, and Lee, Kelly K. A Functional gp41-gp120 Interaction is Observed in Monomeric but not Oligomeric, Uncleaved HIV-1 Env gp140. United States: N. p., 2014. Web.
Guttman, Miklos, & Lee, Kelly K. A Functional gp41-gp120 Interaction is Observed in Monomeric but not Oligomeric, Uncleaved HIV-1 Env gp140. United States.
Guttman, Miklos, and Lee, Kelly K. Thu . "A Functional gp41-gp120 Interaction is Observed in Monomeric but not Oligomeric, Uncleaved HIV-1 Env gp140". United States. doi:.
@article{osti_1136672,
title = {A Functional gp41-gp120 Interaction is Observed in Monomeric but not Oligomeric, Uncleaved HIV-1 Env gp140},
author = {Guttman, Miklos and Lee, Kelly K.},
abstractNote = {},
doi = {},
journal = {Journal of Virology},
number = 21,
volume = 87,
place = {United States},
year = {Thu Jul 10 00:00:00 EDT 2014},
month = {Thu Jul 10 00:00:00 EDT 2014}
}
  • The viral spike of HIV-1 is composed of three gp120 envelope glycoproteins attached noncovalently to three gp41 transmembrane molecules. Viral entry is initiated by binding to the CD4 receptor on the cell surface, which induces large conformational changes in gp120. These changes not only provide a model for receptor-triggered entry, but affect spike sensitivity to drug- and antibody-mediated neutralization. Although some of the details of the CD4-induced conformational change have been visualized by crystal structures and cryoelectron tomograms, the critical gp41-interactive region of gp120 was missing from previous atomic-level characterizations. Here we determine the crystal structure of an HIV-1 gp120more » core with intact gp41-interactive region in its CD4-bound state, compare this structure to unliganded and antibody-bound forms to identify structurally invariant and plastic components, and use ligand-oriented cryoelectron tomograms to define component mobility in the viral spike context. Newly defined gp120 elements proximal to the gp41 interface complete a 7-stranded {beta}-sandwich, which appeared invariant in conformation. Loop excursions emanating from the sandwich form three topologically separate - and structurally plastic - layers, topped off by the highly glycosylated gp120 outer domain. Crystal structures, cryoelectron tomograms, and interlayer chemistry were consistent with a mechanism in which the layers act as a shape-changing spacer, facilitating movement between outer domain and gp41-associated {beta}-sandwich and providing for conformational diversity used in immune evasion. A 'layered' gp120 architecture thus allows movement among alternative glycoprotein conformations required for virus entry and immune evasion, whereas a {beta}-sandwich clamp maintains gp120-gp41 interaction and regulates gp41 transitions.« less
  • The isolation of human monoclonal antibodies is providing important insights into the specificities that underlie broad neutralization of HIV-1 (reviewed in ref. 1). Here we report a broad and extremely potent HIV-specific monoclonal antibody, termed 35O22, which binds a novel HIV-1 envelope glycoprotein (Env) epitope. 35O22 neutralized 62% of 181 pseudoviruses with a half-maximum inhibitory concentration (IC 50) <50 μg ml -1. The median IC 50 of neutralized viruses was 0.033 μg ml -1, among the most potent thus far described. 35O22 did not bind monomeric forms of Env tested, but did bind the trimeric BG505 SOSIP.664. Mutagenesis and amore » reconstruction by negative-stain electron microscopy of the Fab in complex with trimer revealed that it bound to a conserved epitope, which stretched across gp120 and gp41. The specificity of 35O22 represents a novel site of vulnerability on HIV Env, which serum analysis indicates to be commonly elicited by natural infection. Binding to this new site of vulnerability may thus be an important complement to current monoclonal-antibody-based approaches to immunotherapies, prophylaxis and vaccine design.« less