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      Sequential Immunization Elicits Broadly Neutralizing anti-HIV-1 Antibodies in Ig Knock-in Mice

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          Summary

          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 of PGT121, a bNAb specific for the V3-loop and surrounding glycans on the HIV-1 spike. Priming with an epitope modifiied 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 establishes 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.

          eTOC

          Generation of HIV broadly neutralizing antibodies - a major goal in vaccine research - can be achieved through sequential immunization with HIV envelope glycoproteins designed to engage PGT121 antibody precursors and their intermediates.

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          Author and article information

          Journal
          0413066
          2830
          Cell
          Cell
          Cell
          0092-8674
          1097-4172
          10 August 2016
          8 September 2016
          08 September 2017
          : 166
          : 6
          : 1445-1458.e12
          Affiliations
          [1 ]Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065
          [2 ]Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037
          [3 ]International AIDS Vaccine Initiative, New York, NY 10004
          [4 ]Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139
          [5 ]Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065
          Author notes
          [* or #]

          equal contribution

          [x]

          Lead contact.

          Article
          PMC5019122 PMC5019122 5019122 nihpa805610
          10.1016/j.cell.2016.07.030
          5019122
          27610569
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