View All Abstracts for Session 58
313 Broadly Neutralizing Antibodies Targeted to the Membrane-Proximal External Region of Human Immunodeficiency Virus Type 1 Glycoprotein gp41
M. B. Zwick1, M. Wang1, C. Spenlehauer2, J. M. Binley1, J. P. Moore2, G. Stiegler3, H. Katinger2, D. R. Burton1, and P. W. H. I. Parren1*
1The Scripps Res. Inst., La Jolla, CA, USA; 2Cornell Univ., New York, NY, USA; and 3Inst. for Applied Microbiology, Univ. of Agriculture, Vienna, Austria
Background: The identification and epitope mapping of broadly neutralizing anti-HIV-1 antibodies (Abs) is important for vaccine design, but, despite much effort, very few such Abs have been forthcoming. Only 1 broadly neutralizing anti-gp41 monoclonal (m) Ab, 2F5, has been described.
Methods: Human antibodies were generated from HIV-1 seropositive individuals using antibody phage-display and hybridoma technology. Antibodies were characterized for neutralization of HIV-1 primary isolates from different clades and for epitope recognized using a gp160 fragment-library displayed on phage, ELISA with recombinant gp41, gp140, HIV-1 virions, and synthetic peptides, and flow cytometry of HIV-1-infected cells.
Results: We report on 2 mAbs (Z13 and 4E10) that recognize a region immediately C-terminal of the 2F5 epitope. Both mAbs recognize a predominantly linear, relatively conserved epitope, compete with each other for binding to synthetic peptides derived from gp41, and bind to HIV-1MN virions. By flow cytometry, these mAbs appear to bind relatively weakly to infected cells and this binding is not perturbed by pretreatment of the infected cells with soluble CD4. Despite the apparent linear nature of the epitopes of Z13 and 4E10, denaturation of recombinant envelope protein reduces the binding of these mAbs, suggesting some conformational requirements for full epitope expression. Most significantly, Z13 and 4E10 are able to neutralize selected primary isolates from diverse subtypes of HIV-1 (e.g., subtypes B, C, and E).
Conclusions: Three broadly neutralizing antibodies against gp41 have now been identified. The results suggest that a rather extensive region of gp41 close to the transmembrane domain is accessible to neutralizing Abs and could form a useful target for vaccine design.
Contact Author about this Abstract
