Low frequency of broadly neutralizing HIV antibodies during chronic infection even in quaternary epitope targeting antibodies containing large numbers of somatic mutations

• Type of Material: Article
• Authors: Mark D. Hicar, University of Buffalo; Xuemin Chen, Emory University; Spyros A. Kalams, Vanderbilt University; Hakimuddin Sojar, University of Buffalo; Gary Landucci, University of California Irvine; Donald N. Forthal, University of California Irvine; Paul Spearman, Emory University; James E. Crowe, Vanderbilt University
• Language: English
• Date: 2016-02-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Elsevier Ltd.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molimm.2015.12.002
• Title of Journal or Parent Work: Molecular Immunology
• ISSN: 0161-5890
• Volume: 70
• Start Page: 94
• End Page: 103
• Grant/Funding Information: This research was supported by U01 AI-078407 (NIAID, NIH), R01 AI-102715 (NIAID, NIH), P30 AI-054999 (NIAID, NIH; the Vanderbilt-Meharry Center for AIDS Research), and P30-AI50409 (Emory Center for AIDS Research).
• Keywords: ENVELOPE GLYCOPROTEIN; POTENT; CONFORMATION; Immunology; Human; HIV; Antibodies; Monoclonal antibodies; GP120; Neutralization; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; PARTICLES BEARING; IMMUNODEFICIENCY-VIRUS TYPE-1; B cells; Science & Technology; MEMORY B-CELLS; HUMAN MONOCLONAL-ANTIBODIES; GENE USAGE; IDENTIFICATION
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Neutralizing antibodies (Abs) are thought to be a critical component of an appropriate HIV vaccine response. It has been proposed that Abs recognizing conformationally dependent quaternary epitopes on the HIV envelope (Env) trimer may be necessary to neutralize diverse HIV strains. A number of recently described broadly neutralizing monoclonal Abs (mAbs) recognize complex and quaternary epitopes. Generally, many such Abs exhibit extensive numbers of somatic mutations and unique structural characteristics. We sought to characterize the native antibody (Ab) response against circulating HIV focusing on such conformational responses, without a prior selection based on neutralization. Using a capture system based on VLPs incorporating cleaved envelope protein, we identified a selection of B cells that produce quaternary epitope targeting Abs (QtAbs). Similar to a number of broadly neutralizing Abs, the Ab genes encoding these QtAbs showed extensive numbers of somatic mutations. However, when expressed as recombinant molecules, these Abs failed to neutralize virus or mediate ADCVI activity. Molecular analysis showed unusually high numbers of mutations in the Ab heavy chain framework 3 region of the variable genes. The analysis suggests that large numbers of somatic mutations occur in Ab genes encoding HIV Abs in chronically infected individuals in a non-directed, stochastic, manner.