Anti-V2 antibodies virus vulnerability revealed by envelope V1 deletion in HIV vaccine candidates

Isabela Silva de Castro, Giacomo Gorini, Rosemarie Mason, Jason Gorman, Massimiliano Bissa, Mohammad A. Rahman, Anush Arakelyan, Irene Kalisz, Stephen Whitney, Manuel Becerra-Flores, Eric Ni, Kristina Peachman, Hung V. Trinh, Michael Read, Mei Hue Liu, Donald Van Ryk, Dominic Paquin-Proulx, Zhanna Shubin, Marina Tuyishime, Jennifer PeeleMohammed S. Ahmadi, Raffaello Verardi, Juliane Hill, Margaret Beddall, Richard Nguyen, James D. Stamos, Dai Fujikawa, Susie Min, Luca Schifanella, Monica Vaccari, Veronica Galli, Melvin N. Doster, Namal P.M. Liyanage, Sarkis Sarkis, Francesca Caccuri, Celia LaBranche, David C. Montefiori, Georgia D. Tomaras, Xiaoying Shen, Margherita Rosati, Barbara K. Felber, George N. Pavlakis, David J. Venzon, William Magnanelli, Matthew Breed, Josh Kramer, Brandon F. Keele, Michael A. Eller, Claudia Cicala, James Arthos, Guido Ferrari, Leonid Margolis, Marjorie Robert-Guroff, Peter D. Kwong, Mario Roederer, Mangala Rao, Timothy J. Cardozo, Genoveffa Franchini

Research output: Contribution to journalArticlepeer-review

Abstract

The efficacy of ALVAC-based HIV and SIV vaccines in humans and macaques correlates with antibodies to envelope variable region 2 (V2). We show here that vaccine-induced antibodies to SIV variable region 1 (V1) inhibit anti-V2 antibody-mediated cytotoxicity and reverse their ability to block V2 peptide interaction with the α4β7 integrin. SIV vaccines engineered to delete V1 and favor an α helix, rather than a β sheet V2 conformation, induced V2-specific ADCC correlating with decreased risk of SIV acquisition. Removal of V1 from the HIV-1 clade A/E A244 envelope resulted in decreased binding to antibodies recognizing V2 in the β sheet conformation. Thus, deletion of V1 in HIV envelope immunogens may improve antibody responses to V2 virus vulnerability sites and increase the efficacy of HIV vaccine candidates.

Original languageEnglish (US)
Article number102047
JournaliScience
Volume24
Issue number2
DOIs
StatePublished - Feb 19 2021
Externally publishedYes

Bibliographical note

Funding Information:
We thank D. Ahern for editorial assistance, K. Saunders for providing the vector for antibody expression, and J. Heeney, G. Alter, and S. Phogat for helpful discussion. We also thank Sanofi Pasteur for the ALVAC-SIV vaccine. Funding: This work was supported with federal funds from the National Cancer Institute Intramural Program and the Office of AIDS research, National Institutes of Health (to G.F.) and under contract No. HHSN261200800001E (to B.F.K.); the National Institute on Drug Abuse (DA036478 to T.C.); the National Institute of Allergy and Infectious Diseases Extramural Program (R01AI084119 to T.C. and 5 T32-AI007392-30 to M.T.; the Intramural Program of the Vaccine Research Center (to P.D.K. and M.R.) and funding from the DOD and MHRP (to M.R. and M.A.E). The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, the positions of the US Army, or the Department of Defense, nor does mention of trade names, commercial products, or organization imply endorsement. G. Franchini conceived the study in consultation with T.C.; G. Franchini wrote the paper, with contributions from all authors; T.C. designed the immunogens and diagnostic peptides, and M.B.-F and E.N. performed confirmatory molecular modeling; I.S.d.C. and M. Bissa coordinated and performed the macaque studies with J.K. M. Breed, and W.M. and cellular immune assays with M.V. L.S. F.C. N.P.M.L. M.N.D. and V.G.; I.K. S.W. D.F. and J.D.S. expressed and characterized the ?V1 immunogens with I.S.d.C.; G.G. R.M. J.H. R.V. M. Beddall, R.N. and M. Roederer cloned and characterized simian monoclonal antibodies and performed antigenicity studies; M.B.-F. performed serological assays with peptides; A.A. and L.M. performed SIV capture assays and analyzed data; C.L. H.V.T. K.P. M. Read, and M. Rao performed serological and ?4?7 functional assays; M.L. D.V.R. C.C. S.M. and J.A. performed peptide competition assays; T.C. J.G. M.S.A. and P.D.K. analyzed peptide/antibody structures; M.A.R. and M.R-G. performed ADCC assays; M.A.E. D.P.P. and Z.S. performed ADCP and ADNP assays; D.C.M. and C.L. performed neutralization assays; G.D.T. and X.S. performed mucosal antibody assays; G. Ferrari, M.T, and J.P. performed assays of NCI05 and NCI09 binding to SIV-infected cells and plasma ADCC targeting SIV-infected cells; S.S. performed western blot for env and gag proteins; D.J.V. performed statistical analysis of the data; B.F.K. analyzed the viral variants; M. Rosati. B.K.F. and G.N.P. provided the SIVWT gp160 and the p27 Gag DNA vaccines. The US Government has filed a patent on the V1-deleted immunogens with G.F. T.C. I.S.d.C. M.B.-F. M. Bissa. and R.M.A as inventors.

Funding Information:
We thank D. Ahern for editorial assistance, K. Saunders for providing the vector for antibody expression, and J. Heeney, G. Alter, and S. Phogat for helpful discussion. We also thank Sanofi Pasteur for the ALVAC-SIV vaccine. Funding: This work was supported with federal funds from the National Cancer Institute Intramural Program and the Office of AIDS research, National Institutes of Health (to G.F.) and under contract No. HHSN261200800001E (to B.F.K.); the National Institute on Drug Abuse ( DA036478 to T.C.); the National Institute of Allergy and Infectious Diseases Extramural Program ( R01AI084119 to T.C. and 5 T32-AI007392-30 to M.T.; the Intramural Program of the Vaccine Research Center (to P.D.K. and M.R.) and funding from the DOD and MHRP (to M.R. and M.A.E). The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, the positions of the US Army, or the Department of Defense, nor does mention of trade names, commercial products, or organization imply endorsement.

Publisher Copyright:
© 2021

Keywords

  • Immunology
  • molecular structure
  • virology

Fingerprint

Dive into the research topics of 'Anti-V2 antibodies virus vulnerability revealed by envelope V1 deletion in HIV vaccine candidates'. Together they form a unique fingerprint.

Cite this