Antibody Recognition of CD4-Induced Open HIV-1 Env Trimers

Creators: Yang, Zhi; Dam, Kim-Marie A.; Gershoni, Jonathan M.; Zolla-Pazner, Susan; Bjorkman, Pamela J.¹

1. California Institute of Technology

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Abstract

Human immunodeficiency virus type 1 (HIV-1) envelope (Env), a heterotrimer of gp120-gp41 subunits, mediates fusion of the viral and host cell membranes after interactions with the host receptor CD4 and a coreceptor. CD4 binding induces rearrangements in Env trimer, resulting in a CD4-induced (CD4i) open Env conformation. Structural studies of antibodies isolated from infected donors have defined antibody-Env interactions, with one class of antibodies specifically recognizing the CD4i open Env conformation. In this study, we characterized a group of monoclonal antibodies isolated from HIV-1 infected donors (V2i MAbs) that displayed characteristics of CD4i antibodies. Binding experiments demonstrated that the V2i MAbs preferentially recognize CD4-bound open Env trimers. Structural characterizations of V2i MAb-Env-CD4 trimer complexes using single-particle cryo-electron microscopy showed recognition by V2i MAbs using different angles of approach to the gp120 V1V2 domain and the β2/β3 strands on a CD4i open conformation Env with no direct interactions of the MAbs with CD4. We also characterized CG10, a CD4i antibody that was raised in mice immunized with a gp120-CD4 complex, bound to an Env trimer plus CD4. CG10 exhibited characteristics similar to those of the V2i antibodies, i.e., recognition of the open Env conformation, but showed direct contacts to both CD4 and gp120. Structural comparisons of these and previously characterized CD4i antibody interactions with Env provide a suggested mechanism for how these antibodies are elicited during HIV-1 infection. IMPORTANCE: The RV144 HIV-1 clinical vaccination trial showed modest protection against viral infection. Antibody responses to the V1V2 region of HIV-1 Env gp120 were correlated inversely with the risk of infection, and data from three other clinical vaccine trials suggested a similar signal. In addition, antibodies targeting V1V2 have been correlated with protections from simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) infections in nonhuman primates. We structurally characterized V2i antibodies directed against V1V2 isolated from HIV-1 infected humans in complex with open Env trimers bound to the host receptor CD4. We also characterized a CD4i antibody that interacts with CD4 as well as the gp120 subunit of an open Env trimer. Our study suggests how V2i and CD4i antibodies were elicited during HIV-1 infection.

Additional Information

We thank Jost Vielmetter at the Beckman Institute Protein Expression Center at Caltech for protein production, John Moore (Weill Cornell Medical College) for the B41 stable cell line, and James Robinson (Tulane University) for the JR-52 MAb. Cryo-EM studies were performed in the Beckman Institute Resource Center for Transmission Electron Microscopy at Caltech with assistance from S. Chen (director). We thank the Gordon and Betty Moore and Beckman Foundations for the gifts to Caltech to support the Molecular Observatory (Jens Kaiser, director) and the Stanford Synchrotron Radiation Lightsource (SSRL) beamline staff for data collection. Use of the SSRL, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-c76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the National Institutes of Health, National Institute of General Medical Sciences (P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. This work was supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID) (HIVRAD P01 AI100148 [P.J.B.], NIH P50 AI150464 [P.J.B.], and R01AI145655 [S.Z.-P.]), a Gates CAVD grant (INV-002143 [P.J.B.]), support from the Department of Medicine, Icahn School of Medicine at Mount Sinai (S.Z.-P.), and the generous support of Peter Kraus (J.M.G.). Z.Y., K.-M.A.D., J.M.G., S.Z.-P., and P.J.B. designed the research. Z.Y. and K.-M.A.D. performed experiments and analyzed results. Z.Y., K.-M.A.D., and P.J.B. wrote the paper with input from coauthors. We declare no competing interests.

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Contributions

Zhi Yang and Kim-Marie A. Dam contributed equally to this work and are co-first authors. Author order was determined by them.

Z.Y., K.-M.A.D., J.M.G., S.Z.-P., and P.J.B. designed the research. Z.Y. and K.-M.A.D. performed experiments and analyzed results. Z.Y., K.-M.A.D., and P.J.B. wrote the paper with input from coauthors.

Data Availability

Cryo-EM maps generated in this study have been deposited in the Electron Microscopy Data Bank (EMDB) with accession codes EMD-27209, EMD-27210, EMD-27211, and EMD-27212 for V2i Fab complexes 1393A-BG505-sCD4, 1361-BG505-sCD4, 697D-BG505-sCD4, and 830A-BG505-sCD4, respectively. The cryo-EM map for CG10-B41-sCD4 complex was deposited in the EMDB under the accession code EMD-27208, and atomic model coordinates were deposited in the Protein Data Bank (PDB) under code 8D5C. The X-ray structure of CG10 Fab was deposited in the PDB under the code of 8D54.

Conflict of Interest

The authors declare no conflict of interest.

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