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Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1

Nature Medicine volume 24, pages 857–867 (2018)Cite this article

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Abstract

A central goal of HIV-1 vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains. Crystal and cryoelectron microscopy structures of these antibodies revealed fusion peptide conformational diversity as a molecular explanation for the cross-clade neutralization. Immunization of guinea pigs and rhesus macaques induced similarly broad fusion peptide-directed neutralizing responses, suggesting translatability. The N terminus of the HIV-1 fusion peptide is thus a promising target of vaccine efforts aimed at eliciting broadly neutralizing antibodies.

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Fig. 1: Design, properties, and immunogenicity of FP immunogens based on the epitope of antibody VRC34.01.
Fig. 2: FP assumes disparate antibody-bound conformations, with neutralization restricted to a select angle of trimer approach.
Fig. 3: FP-directed vaccine-elicited antibodies neutralize up to 31% of HIV-1.
Fig. 4: Substantial glycan contacts by vaccine-elicited FP-directed antibodies.
Fig. 5: Immunization of guinea pigs and NHPs with FP-coupled carriers and DS-SOSIP trimer elicits heterologous neutralizing responses.
Fig. 6: Patterns of neutralization indicate broad FP-directed responses in mice and NHP are related.

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Acknowledgements

We thank J. Chrzas, U. Chinte, Z. Jin, and staff at SER-CAT (Southeast Regional Collaborative Access Team) for help with X-ray diffraction data collection; B. DeKosky for suggestions on lineage discrimination, W. Rice and SEMC staff for assistance with cryo-EM data collection; and J. Stuckey for assistance with figures. We thank D. Burton and M. Fineberg (International AIDS Vaccine Initiative (IAVI), Neutralizing Antibody Consortium (NAC)) for antibodies, including PGT122 used in cryo-EM studies, B. Haynes (The Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID)) for information on antibody CH07, R. Sanders (Academisch Medisch Centrum Universiteit van Amsterdam (AMC)) for information on antibody ACS202, B. Graham (Vaccine Research Center, NIAID, NIH) for murine antibody 5C4, and the WCMC/AMC/TSRI HIVRAD team for their contributions to the design and validation of near-native mimicry for soluble BG505 SOSIP.664 trimers. We thank members of the Structural Biology Section, Structural Bioinformatics Core Section, and Human Immunology Section of the Vaccine Research Center for helpful comments. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health. This work was also supported in part by IAVI's NAC (J.R.M and P.D.K.) and with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E (Y.T.). I.S.G. received support from NIH grant R01 AI131722. Some of this work was performed at the Simons Electron Microscopy Center and National Resource for Automated Molecular Microscopy, located at the New York Structural Biology Center, supported by grants from the Simons Foundation (SF349247) NYSTAR, and the NIH National Institute of General Medical Sciences (GM103310), with additional support from Agouron Institute (F00316) and NIH (OD019994). Use of insertion device 22 (SER-CAT) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-109-Eng-38.

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Author notes

  1. These authors contributed equally: Kai Xu, Priyamvada Acharya, Rui Kong, Cheng Cheng.

Authors and Affiliations

  1. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Kai Xu, Priyamvada Acharya, Rui Kong, Cheng Cheng, Gwo-Yu Chuang, Kevin Liu, Mark K. Louder, Sijy O’Dell, Reda Rawi, Mallika Sastry, Chen-Hsiang Shen, Baoshan Zhang, Tongqing Zhou, Mangaiarkarasi Asokan, Robert T. Bailer, Michael Chambers, Xuejun Chen, Chang W. Choi, Nicole A. Doria-Rose, Aliaksandr Druz, S. Katie Farney, Kathryn E. Foulds, Hui Geng, Jason Gorman, Kurt R. Hill, Alexander J. Jafari, Young D. Kwon, Yen-Ting Lai, Krisha McKee, Tiffany Y. Ohr, Li Ou, Dongjun Peng, Ariana P. Rowshan, John-Paul Todd, Elise G. Viox, Yiran Wang, Yongping Yang, Amy F. Zhou, Diana G. Scorpio, Adrian B. McDermott, Lawrence Shapiro, John R. Mascola & Peter D. Kwong

  2. National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, USA

    Priyamvada Acharya, Venkata P. Dandey, Edward T. Eng, Hui Wei, Bridget Carragher & Clinton S. Potter

  3. Vanderbilt Vaccine Center, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, and Department of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, TN, USA

    Ivelin S. Georgiev

  4. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA

    Thomas Lemmin

  5. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA

    Zizhang Sheng, Lawrence Shapiro & Peter D. Kwong

  6. Department of Systems Biology, Columbia University, New York, NY, USA

    Zizhang Sheng & Lawrence Shapiro

  7. Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Yaroslav Tsybovsky

  8. GenScript USA, Piscataway, NJ, USA

    Rui Chen & Lu Yang

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  53. John R. Mascola
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  54. Peter D. Kwong
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Contributions

K.X. conceived and led the project and determined crystal structures; P.A. determined cryo-EM structures; R.K. and N.A.D.-R. coordinated neutralization assessments; C.C. coordinated guinea pig and NHP immunization; G.-Y.C. coordinated statistical and bioinformatical analyses; K.L. prepared proteins and co-determined crystal structures; M.K.L. and R.T.B. assessed antibody neutralization in the large panel; C.-H.S. performed antibody sequence analyses; M.S. performed all Alanine–Glycine scans; B.Z. prepared antibodies for the large panel and performed various binding analyses; T.Z. performed SPR analyses, calculated the antibody's approach angle to the trimer, and made antibody neutralization dendrograms; M.A. performed antibody autoreactivity tests; I.S.G. performed antibody neutralization fingerprint analyses; T.L. performed molecular dynamics analyses; S.O’D., K.M., C.W.C., E.G.V., and A.P.R. co-performed neutralization assays; A.D., D.P., B.Z., and Y.Y. helped with protein expression; E.T.E., V.P.D., and H.W. helped with cryo-EM structures; X.C., H.G., J.G., M.S., and Y.D.K. performed protein purification; K.R.H., A.J.J., K.E.F., D.G.S., and J.-P.T. assisted in the NHP study; Y.-T.L. and Y.W. assisted with X-ray crystal dataset processing; B.Z., L.O., and M.C. helped with immunogen preparation and characterization; R.R. and S.K.F. performed statistical and bioinformatical analyses; Z.S. performed antibody gene comparisons; Y.T. performed negative-stain EM; T.Y.O. participated in immunogen binding tests; A.F.Z. helped with SPR assays; R.C. and L.Y. supervised the research team in GenScript; A.B.M. supervised MSD-based immunogen antigenicity characterization; L.S. supervised antibody gene analyses and comparison; B.C. and C.S.P. supervised cryo-EM studies; K.X., L.S., J.R.M., and P.D.K. wrote the manuscript; and all authors read, edited, and approved the manuscript. J.R.M. and P.D.K. conceived and supervised the study.

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Correspondence to John R. Mascola or Peter D. Kwong.

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Xu, K., Acharya, P., Kong, R. et al. Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1. Nat Med 24, 857–867 (2018). https://doi.org/10.1038/s41591-018-0042-6

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