HIV-specific CD4-induced Antibodies Mediate Broad and Potent Antibody-dependent Cellular Cytotoxicity Activity and are Commonly Detected in Plasma from HIV-infected Humans

• Type of Material: Article
• Authors: Katherine L. Williams, Fred Hutchinson Cancer Research Center; Valerie Cortez, Fred Hutchinson Cancer Research Center; Adam S. Dingens, Fred Hutchinson Cancer Research Center; Johannes S. Gach, University of California Irvine; Stephanie Rainwater, Fred Hutchinson Cancer Research Center; Julie F. Weis, Fred Hutchinson Cancer Research Center; Xuemin Chen, Emory University; Paul Spearman, Emory University; Donald N. Forthal, University of California Irvine; Julie Overbaugh, Fred Hutchinson Cancer Research Center
• Language: English
• Date: 2015-10-01
• Publisher: Elsevier: Creative Commons
• Publication Version: Final Published Version
• Copyright Statement: © 2015 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ebiom.2015.09.001
• Title of Journal or Parent Work: EBioMedicine
• ISSN: 2352-3964
• Volume: 2
• Issue: 10
• Start Page: 1464
• End Page: 1477
• Grant/Funding Information: The study was funded by R01 AI103981 and R37 AI038518 to JO, AI111863 to PS, R0 1AI102715 to DNF, T32 AI07140 to KLW, T32 CA080416 to AD and T32 AI083203 to VC.
• Keywords: RF-ADCC; CD4-induced; CD4i; Potency; ADCC; HIV; Breadth; Antibody
• Research Categories: Health Sciences, Immunology; Biology, Cell; Health Sciences, Public Health

Abstract

HIV-specific antibodies (Abs) can reduce viral burden by blocking new rounds of infection or by destroying infected cells via activation of effector cells through Fc-FcR interaction. This latter process, referred to as antibody-dependent cellular cytotoxicity (ADCC), has been associated with viral control and improved clinical outcome following both HIV and SIV infections. Here we describe an HIV viral-like particle (VLP)-based sorting strategy that led to identification of HIV-specific memory B cells encoding Abs that mediate ADCC from a subtype A-infected Kenyan woman at 914 days post-infection. Using this strategy, 12 HIV-envelope-specific monoclonal antibodies (mAbs) were isolated and three mediated potent ADCC activity when compared to well-characterized ADCC mAbs. The ADCC-mediating Abs also mediated antibody-dependent cell-mediated virus inhibition (ADCVI), which provides a net measure of Fc receptor-triggered effects against replicating virus. Two of the three ADCC-mediating Abs targeted a CD4-induced (CD4i) epitope also bound by the mAb C11; the third antibody targeted the N-terminus of V3. Both CD4i Abs identified here demonstrated strong cross-clade breadth with activity against 10 of 11 envelopes tested, including those from clades A, B, C, A/D and C/D, whereas the V3-specific antibody showed more limited breadth. Variants of these CD4i, C11-like mAbs engineered to interrupt binding to FcγRs inhibited a measurable percentage of the donor's ADCC activity starting as early as 189 days post-infection. C11-like antibodies also accounted for between 18-78% of ADCC activity in 9 chronically infected individuals from the same cohort study. Further, the two CD4i Abs originated from unique B cells, suggesting that antibodies targeting this epitope can be commonly produced. Taken together, these data provide strong evidence that CD4i, C11-like antibodies develop within the first 6. months of infection and they can arise from unique B-cell lineages in the same individual. Further, these mAbs mediate potent plasma IgG-specific ADCC breadth and potency and contribute to ADCC activity in other HIV-infected individuals.