Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding [electronic resource].

Published: Washington, D.C. : United States. Dept. of Energy. Office of Science, 2012.
Oak Ridge, Tenn. : Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy
Physical Description: pages E69-E78 : digital, PDF file
Additional Creators: SLAC National Accelerator Laboratory, United States. Department of Energy. Office of Science, and United States. Department of Energy. Office of Scientific and Technical Information

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Summary

The HIV-1 envelope glycoprotein (Env) undergoes conformational transitions consequent to CD4 binding and coreceptor engagement during viral entry. The physical steps in this process are becoming defined, but less is known about their significance as targets of antibodies potentially protective against HIV-1 infection. Here we probe the functional significance of transitional epitope exposure by characterizing 41 human mAbs specific for epitopes exposed on trimeric Env after CD4 engagement. These mAbs recognize three epitope clusters: cluster A, the gp120 face occluded by gp41 in trimeric Env; cluster B, a region proximal to the coreceptor-binding site (CoRBS) and involving the V1/V2 domain; and cluster C, the coreceptor-binding site. The mAbs were evaluated functionally by antibody-dependent, cell-mediated cytotoxicity (ADCC) and for neutralization of Tiers 1 and 2 pseudoviruses. All three clusters included mAbs mediating ADCC. However, there was a strong potency bias for cluster A, which harbors at least three potent ADCC epitopes whose cognate mAbs have electropositive paratopes. Cluster A epitopes are functional ADCC targets during viral entry in an assay format using virion-sensitized target cells. In contrast, only cluster C contained epitopes that were recognized by neutralizing mAbs. There was significant diversity in breadth and potency that correlated with epitope fine specificity. In contrast, ADCC potency had no relationship with neutralization potency or breadth for any epitope cluster. In conclusion, Fc-mediated effector function and neutralization coselect with specificity in anti-Env antibody responses, but the nature of selection is distinct for these two antiviral activities.

Report Numbers

E 1.99:slac-reprint--2014-212
slac-reprint--2014-212

Subject(s)

Basic Biological Sciences

Note

Published through SciTech Connect.
12/13/2012.
"slac-reprint--2014-212"
Proceedings of the National Academy of Sciences of the United States of America 110 1 ISSN 0027-8424 AM
Yongjun Guan; Marzena Pazgier; Mohammad M. Sajadi; Roberta Kamin-Lewis; Salma Al-Darmarki; Robin Flinko; Elena Lovo; Xueji Wu; James E. Robinson; Michael S. Seaman; Timothy R. Fouts; Robert C. Gallo; Anthony L. DeVico; George K. Lewis.

Funding Information

AC02-76SF00515

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