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

Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland 20892-4555, USA.
Journal of Virology (Impact Factor: 4.44). 04/2004; 78(5):2627-31. DOI: 10.1128/JVI.78.5.2627-2631.2004
Source: PubMed


We investigated how the broadly neutralizing monoclonal antibody 2F5 affects the human immunodeficiency virus type 1 envelope
glycoprotein as it undergoes receptor-induced conformational changes and show that 2F5 binds both native and fusion-intermediate
conformations, suggesting inhibition of a late step in virus entry. We also demonstrate conformational changes in the C heptad
of gp41.

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    • "The HR1, HR2 and loop domains become available as early as upon CD4 binding and are lost concomitant with the onset of cell-cell fusion. By comparison, the tryptophan-rich membrane-proximal external region (MPER), which is C-terminal to the gp41 HR2 domain, is accessible to the neutralizing antibodies, 2F5 and 4E10, on the native structure, but the MPER accessibility is gradually lost as fusion progresses to the content mixing stage [116,117,125]. The exposure of HR1 and HR2 domains upon interactions with CD4 is also supported by the enhanced binding of C- and N-peptides targeting these domains [117,119,126-128]. "
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    • "Understanding how Env interacts with these receptors and, moreover, how presently available monoclonal antibodies (mAbs) inhibit these interactions would be a step toward this goal. Studies to date have revealed that mAb b12 blocks gp120-CD4 binding [2]; mAbs directed to gp120 epitopes that are induced by sCD4, as well as V3 mAbs, interfere with CCR5 binding [43-45]; and 2F5 and 4E10 appear to prevent fusion events that occur after CD4 and CCR5 binding, though they may also bind to Env in its native form [12,46]. In comparison, relatively little is known about how these mAbs might block virus attachment to various cells, and indeed what Env determinants are important (12). "
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    • "In this context, a β-galactosidase sensor displaying an HIV gp41 epitope and responsive to human HIV-immune sera is preferentially activated by the IgG4 antibody subpopulation [51]. As at least in the case of HIV infection the ability of anti-viral antibodies to modify the epitope's conformation is strongly related to their neutralizing activity [52,53] and probably to the progression of the infection [54], allosteric biosensing could eventually offer a valuable instrument for high-throughput sera analysis for prognostic investigation. "
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