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PLoS Pathog. 2014 Dec 18;10(12):e1004552. doi: 10.1371/journal.ppat.1004552. eCollection 2014 Dec.

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

Author information

1
Wohl Virion Centre and Medical Research Council (MRC) Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London, United Kingdom.
2
QVQ B.V., Utrecht, The Netherlands.
3
Department of Infectious Diseases, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
4
Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
5
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
6
Centro de Virología Animal, Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
7
Institute of Medical Microbiology, University of Regensburg, Regensburg, Germany.

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.

PMID:
25522326
PMCID:
PMC4270772
DOI:
10.1371/journal.ppat.1004552
[Indexed for MEDLINE]
Free PMC Article

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