Design of immunogens to elicit broadly neutralizing antibodies against HIV targeting the CD4 binding site

Simone Conti, Kevin J. Kaczorowski, Ge Song, Katelyn Porter, Raiees Andrabi, Dennis R. Burton, Arup K. Chakraborty, Martin Karplus

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

A vaccine which is effective against the HIV virus is considered to be the best solution to the ongoing global HIV/AIDS epidemic. In the past thirty years, numerous attempts to develop an effective vaccine have been made with little or no success, due, in large part, to the high mutability of the virus. More recent studies showed that a vaccine able to elicit broadly neutralizing antibodies (bnAbs), that is, antibodies that can neutralize a high fraction of global virus variants, has promise to protect against HIV. Such a vaccine has been proposed to involve at least three separate stages: First, activate the appropriate precursor B cells; second, shepherd affinity maturation along pathways toward bnAbs; and, third, polish the Ab response to bind with high affinity to diverse HIV envelopes (Env). This final stage may require immunization with a mixture of Envs. In this paper, we set up a framework based on theory and modeling to design optimal panels of antigens to use in such a mixture. The designed antigens are characterized experimentally and are shown to be stable and to be recognized by known HIV antibodies.

Original languageEnglish
Article numbere2018338118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number9
DOIs
StatePublished - 2 Mar 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).

Funding

ACKNOWLEDGMENTS. S.C., A.K.C., and M.K. received financial support from the Lawrence Livermore National Laboratory under Grant 17-ERD-043 (LLC Award B620960) and from the CHARMM Development Project. This work was supported by the Consortium for HIV/AIDS Vaccine Development (CHAVD) NIH Award UM1 AI44462 (to D.R.B), the IAVI Neutralizing Antibody Center, and the Bill and Melinda Gates Foundation (Award OPP1196345 to D.R.B.). We are grateful to Victor Ovchinnikov for helpful discussions and comments on the manuscript.

FundersFunder number
IAVI Neutralizing Antibody Center
National Institutes of HealthUM1 AI44462
National Institute of Allergy and Infectious DiseasesUM1AI144462
Bill and Melinda Gates FoundationOPP1196345
Lawrence Livermore National Laboratory17-ERD-043, B620960

    Keywords

    • Broadly neutralizing antibodies
    • HIV
    • Vaccine design

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