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Molecular evolution of broadly neutralizing llama antibodies to the CD4-binding site of HIV-1

Title: Molecular evolution of broadly neutralizing llama antibodies to the CD4-binding site of HIV-1
Authors: McCoy, LE
Rutten, L
Frampton, D
Anderson, I
Granger, L
Bashford-Rogers, R
Dekkers, G
Strokappe, NM
Seaman, MS
Koh, W
Grippo, V
Kliche, A
Verrips, T
Kellam, P
Fassati, A
Weiss, RA
Item Type: Journal Article
Abstract: To date, no immunization of humans or animals has elicited broadly neutralizing sera able to prevent HIV-1 transmission; however, elicitation of broad and potent heavy chain only antibodies (HCAb) has previously been reported in llamas. In this study, the anti-HIV immune responses in immunized llamas were studied via deep sequencing analysis using broadly neutralizing monoclonal HCAbs as a guides. Distinct neutralizing antibody lineages were identified in each animal, including two defined by novel antibodies (as variable regions called VHH) identified by robotic screening of over 6000 clones. The combined application of five VHH against viruses from clades A, B, C and CRF_AG resulted in neutralization as potent as any of the VHH individually and a predicted 100% coverage with a median IC50 of 0.17 µg/ml for the panel of 60 viruses tested. Molecular analysis of the VHH repertoires of two sets of immunized animals showed that each neutralizing lineage was only observed following immunization, demonstrating that they were elicited de novo. Our results show that immunization can induce potent and broadly neutralizing antibodies in llamas with features similar to human antibodies and provide a framework to analyze the effectiveness of immunization protocols.
Issue Date: 18-Dec-2014
Date of Acceptance: 4-Nov-2014
URI: http://hdl.handle.net/10044/1/69572
DOI: https://dx.doi.org/10.1371/journal.ppat.1004552
ISSN: 1553-7366
Publisher: Public Library of Science (PLoS)
Journal / Book Title: PLoS Pathogens
Volume: 10
Issue: 12
Copyright Statement: © 2014 McCoy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Microbiology
Parasitology
Virology
B-CELL RECEPTORS
MONOCLONAL-ANTIBODIES
STRUCTURAL BASIS
IN-VIVO
VECTORED IMMUNOPROPHYLAXIS
SHIV TRANSMISSION
ENVELOPE PROTEIN
RATIONAL DESIGN
HUMANIZED MICE
POTENT
AIDS Vaccines
Animals
Antibodies, Neutralizing
Antigens, Viral
Binding Sites, Antibody
CD4 Antigens
Camelids, New World
Disease Models, Animal
Evolution, Molecular
HIV Infections
HIV-1
Immunoglobulin Variable Region
Mutation
Antigens, CD4
0605 Microbiology
1107 Immunology
1108 Medical Microbiology
Publication Status: Published
Article Number: e1004552
Online Publication Date: 2014-12-18
Appears in Collections:Department of Medicine



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