Sequential immunization of macaques elicits heterologous neutralizing antibodies targeting the V3-glycan patch of HIV-1 Env
- Creators
-
Escolano, Amelia
-
Gristick, Harry B.
-
Gautam, Rajeev
-
DeLaitsch, Andrew T.
-
Abernathy, Morgan E.
-
Yang, Zhi
-
Wang, Haoqing
-
Hoffmann, Magnus A. G.
-
Nishimura, Yoshiaki
-
Wang, Zijun
- Koranda, Nicholas
-
Kakutani, Leesa M.
- Gao, Han
- Gnanapragasam, Priyanthi N. P.
-
Raina, Henna
-
Gazumyan, Ana
-
Cipolla, Melissa
-
Oliveira, Thiago Y.
-
Ramos, Victor
-
Irvine, Darrell J.
-
Silva, Murillo
-
West, Anthony P., Jr.
-
Keeffe, Jennifer R.
-
Barnes, Christopher O.
-
Seaman, Michael S.
-
Nussenzweig, Michel C.
-
Martin, Malcolm A.
-
Bjorkman, Pamela J.
Abstract
Broadly neutralizing antibodies (bNAbs) against HIV-1 develop after prolonged virus and antibody coevolution. Previous studies showed that sequential immunization with a V3-glycan patch germline-targeting HIV-1 envelope trimer (Env) followed by variant Envs can reproduce this process in mice carrying V3-glycan bNAb precursor B cells. However, eliciting bNAbs in animals with polyclonal antibody repertoires is more difficult. We used a V3-glycan immunogen multimerized on virus-like particles (VLPs), followed by boosting with increasingly native-like Env-VLPs, to elicit heterologous neutralizing antibodies in nonhuman primates (NHPs). Structures of antibody/Env complexes after prime and boost vaccinations demonstrated target epitope recognition with apparent maturation to accommodate glycans. However, we also observed increasing off-target antibodies with boosting. Eight vaccinated NHPs were subsequently challenged with simian-human immunodeficiency virus (SHIV), and seven of eight animals became infected. The single NHP that remained uninfected after viral challenge exhibited one of the lowest neutralization titers against the challenge virus. These results demonstrate that more potent heterologous neutralization resulting from sequential immunization is necessary for protection in this animal model. Thus, improved prime-boost regimens to increase bNAb potency and stimulate other immune protection mechanisms are essential for developing anti–HIV-1 vaccines.
Additional Information
© 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Submitted 24 June 2021; Resubmitted 12 August 2021; Accepted 20 October 2021; Published 24 November 2021. We thank members of the Bjorkman, Martin, and Nussenzweig laboratories for discussions; M. Howarth (Oxford) for providing plasmids and advice for VLP expression and purification; J. Moore (Weill Cornell Medical College), R. W. Sanders, and M. J. van Gils (Amsterdam UMC) for SOSIP expression plasmids; J. Vielmetter, P. Hoffman, and the Protein Expression Center in the Beckman Institute at Caltech for expression assistance; T. Eisenreich and S. Tittley for animal husbandry; and K. Gordon for flow cytometry. Electron microscopy was performed in the Caltech Cryo-EM Center with assistance from S. Chen and A. Malyutin. This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) Grant HIVRAD P01 AI100148 (to P.J.B. and M.C.N.), the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grant INV-002143 (to P.J.B., M.C.N., and M.A.M.), a Bill and Melinda Gates Foundation grant #OPP1146996 (to M.S.S.), the Intramural Research Program of the NIAID (to M.A.M.), NIH P50 AI150464 (to P.J.B.), and NIH grants UM1 AI144462 and P01 AI048240 (to D.J.I.). A.E. was supported by an NIH K99/R00 grant, A.T.D. and M.E.A. were supported by NSF Graduate Research Fellowships, and C.O.B. was supported by the Hanna Gray Fellowship Program from the Howard Hughes Medical Institute and the Postdoctoral Enrichment Program from the Burroughs Wellcome Fund. M.C.N. is an HHMI investigator. Author contributions: H.B.G., J.R.K., A.E., R.G., A.T.D., A.P.W., C.O.B., M.C.N., M.A.M., and P.J.B. conceived experiments. Immunogens were selected and designed by H.B.G., A.E., and J.R.K. Proteins were expressed by N.K., H.G., A.G., and M.C. Pseudovirus production and neutralization assays were performed and analyzed by M.S.S., R.G., H.R., M.A.G.H., L.M.K., and P.N.P.G. Adjuvants were provided by D.J.I. and M.S. NHP experiments were conducted and interpreted by R.G., Y.N., and M.A.M. nsEMPEM and other structural studies were performed by A.T.D., C.O.B., M.E.A., Z.Y., and H.W. Single B cell cloning and isolation of mAbs were done by A.E., Z.W., and M.C.N. Sequence and statistical analyses were done by A.P.W. Bioinformatics was done by T.Y.O. and V.R. The paper was written by P.J.B., H.B.G., A.T.D., C.O.B., J.R.K., A.E., M.C.N., and M.A.M. with assistance from other authors. Competing interests: H.B.G., P.J.B., A.E., and M.C.N. are coinventors on a patent (HIV Vaccine Immunogens; PCT/US2019/063619) covering RC1 immunogens. All other authors declare that they have no competing interests. Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. nsEMPEM and cryo-EM reconstructions were deposited in the Electron Microscopy Data Bank (EMDB; https://www.emdataresource.org/) and the associated accession numbers are listed in table S3. ISCOMs-like saponin adjuvant is available from Darrell Irvine under a material transfer agreement with MIT.Attached Files
Accepted Version - nihms-1786406.pdf
Supplemental Material - scitranslmed.abk1533_data_file_s1.zip
Supplemental Material - scitranslmed.abk1533_sm.pdf
Files
Additional details
- PMCID
- PMC8932345
- Eprint ID
- 112051
- DOI
- 10.1126/scitranslmed.abk1533
- Resolver ID
- CaltechAUTHORS:20211124-195820111
- P01 AI100148
- NIH
- INV-002143
- Bill and Melinda Gates Foundation
- OPP1146996
- Bill and Melinda Gates Foundation
- P50 AI150464
- NIH
- UM1 AI144462
- NIH
- P01 AI048240
- NIH
- K99/R00
- NIH
- NSF Graduate Research Fellowship
- Howard Hughes Medical Institute (HHMI)
- Burroughs Wellcome Fund
- Created
-
2021-11-24Created from EPrint's datestamp field
- Updated
-
2022-06-01Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering