Isolation and Structure of an Antibody that Fully Neutralizes Isolate SIVmac239 Reveals Functional Similarity of SIV and HIV Glycan Shields

Author:

Gorman, Jason

Mason, Rosemarie D

Nettey, Leonard

Cavett, Nicole

Chuang, Gwo-Yu

Peng, Dongjun

Tsybovsky,Yaroslav

Verardi, Raffaello

Nguyen, Richard

Ambrozak, David

Biris, Kristin

LaBranche, Celia C

Ramesh, Akshaya

Schramm, Chaim A

Zhou, Jing

Bailer, Robert T

Kepler, Thomas B

Montefiori, David C

Shapiro, Lawrence

Douek, Daniel C

Mascola, John R

Roederer, Mario

Kwong, Peter D
Author Address

Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA., Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Duke Human Vaccine Institute, Duke University School of Medicine, Duke University, Durham, NC 27710, USA., Boston University School of Medicine, Boston University, Boston, MA 02118, USA., Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA., Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: roederer@nih.gov., Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: pdkwong@nih.gov.,

Abstract:

HIV- and SIV-envelope (Env) trimers are both extensively glycosylated, and antibodies identified to date have been unable to fully neutralize SIVmac239. Here, we report the isolation, structure, and glycan interactions of antibody ITS90.03, a monoclonal antibody that completely neutralized the highly neutralization-resistant isolate, SIVmac239. The co-crystal structure of a fully glycosylated SIVmac239-gp120 core in complex with rhesus CD4 and the antigen-binding fragment of ITS90.03 at 2.5-Å resolution revealed that ITS90 recognized an epitope comprised of 45% glycan. SIV-gp120 core, rhesus CD4, and their complex could each be aligned structurally to their human counterparts. The structure revealed that glycans masked most of the SIV Env protein surface, with ITS90 targeting a glycan hole, which is occupied in ~83% of SIV strains by glycan N238. Overall, the SIV glycan shield appears to functionally resemble its HIV counterpart in coverage of spike, shielding from antibody, and modulation of receptor accessibility. Published by Elsevier Inc.

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