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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/01.qai.0000413731.29857.f7
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112 Diversity of Specificity and Function Among Human Antibodies to Transitional Epitopes Altered by CD4 Binding to the HIV-1 Env Glycoprotein.

Guan, Y.; Pazgier, M.; Sajadi, M.; Al Damarki, S.; Meginstu, M.; Wu, X.; Gallo, R. C.; Kamin-Lewis, R.; DeVico, A. L.; Lewis, G. K.

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Abstract

The HIV-1 envelope glycoprotein (Env) undergoes ordered conformational transitions after CD4 binding and co-receptor engagement during viral entry. While the physicochemical steps of viral entry are becoming defined, less is known about their immunochemical correlates and their roles as targets of protective antibodies. We describe studies that define the functional significance of epitope exposure during the first step of viral entry, the binding of gp120 to CD4. A panel of 41 human monoclonal antibodies (mAbs) were isolated that recognize epitopes which become exposed on trimeric Env only after CD4 engagement. These mAbs recognize clusters of epitopes mapping to three regions of gp120: a. Cluster A, the domain of gp120 occluded by interaction with gp41; b. Cluster B, a region proximal to the classical co-receptor binding site (CoRBS) involving the V1/V2 region; and Cluster C, the CoRBS. The mAbs were characterized for neutralization of Tier 1 and Tier 2 pseudoviruses and by antibody dependent cell mediated cytotoxicity (ADCC). mAbs recognizing all three clusters mediated ADCC but there was a strong bias in potency for mAbs that recognize Clusters A and B. Surprisingly, ADCC potency correlated inversely with CDR-H3 length but not with somatic hypermutation. By contrast, mAbs binding Cluster C epitopes were neutralizing but there was significant diversity in breadth and potency that correlated with epitope fine specificity and somatic hypermutation. ADCC potency did not correlate with neutralization breadth or potency. Thus, both neutralization and Fc-mediated effector function are co-selected with specificity but the nature of selection is distinct for these two anti-viral activities.

(C) 2012 Lippincott Williams & Wilkins, Inc.

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