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      Sequential Immunization Elicits Broadly Neutralizing Anti-HIV-1 Antibodies in Ig Knockin Mice.

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          Abstract

          A vaccine that elicits broadly neutralizing antibodies (bNAbs) against HIV-1 is likely to be protective, but this has not been achieved. To explore immunization regimens that might elicit bNAbs, we produced and immunized mice expressing the predicted germline PGT121, a bNAb specific for the V3-loop and surrounding glycans on the HIV-1 spike. Priming with an epitope-modified immunogen designed to activate germline antibody-expressing B cells, followed by ELISA-guided boosting with a sequence of directional immunogens, native-like trimers with decreasing epitope modification, elicited heterologous tier-2-neutralizing responses. In contrast, repeated immunization with the priming immunogen did not. Antibody cloning confirmed elicitation of high levels of somatic mutation and tier-2-neutralizing antibodies resembling the authentic human bNAb. Our data establish that sequential immunization with specifically designed immunogens can induce high levels of somatic mutation and shepherd antibody maturation to produce bNAbs from their inferred germline precursors.

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          Author and article information

          Journal
          Cell
          Cell
          Elsevier BV
          1097-4172
          0092-8674
          Sep 08 2016
          : 166
          : 6
          Affiliations
          [1 ] Laboratory of Molecular Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
          [2 ] Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
          [3 ] Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative, New York, NY 10004, USA.
          [4 ] Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
          [5 ] Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA. Electronic address: schief@scripps.edu.
          [6 ] Laboratory of Molecular Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA. Electronic address: nussen@rockefeller.edu.
          Article
          S0092-8674(16)30976-X NIHMS805610
          10.1016/j.cell.2016.07.030
          5019122
          27610569
          d9e1b9cf-88b9-46f8-84d6-9f5c5c00a73e
          History

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