Soluble prefusion-closed HIV-envelope trimers with glycan-covered bases

Author:

Olia, Adam S

Cheng, Cheng

Zhou, Tongqing

Biju, Andrea

Harris, Darcy R

Changela, Anita

Duan, Hongying

Ivleva, Vera B

Kong, Wing-Pui

Ou, Li

Rawi, Reda

Tsybovsky,Yaroslav

Van Wazer, David J

Corrigan, Angela R

Gonelli, Christopher A

Lee, Myungjin

McKee, Krisha

Narpala, Sandeep

O'Dell, Sijy

Parchment, Danealle K

Stancofski, Erik-Stephane D

Stephens,Tyler

Tan, Ivy

Teng, I-Ting

Wang, Shuishu

Wei, Qing

Yang, Yongping

Yang, Zhengrong

Zhang, Baoshan

Novak, Jan

Renfrow, Matthew B

Doria-Rose, Nicole A

Koup, Richard A

McDermott, Adrian B

Gall, Jason G

Lei, Q Paula

Mascola, John R

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., Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA., Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.,

Abstract:

Soluble HIV-1-envelope (Env) trimers elicit immune responses that target their solvent-exposed protein bases, the result of removing these trimers from their native membrane-bound context. To assess whether glycosylation could limit these base responses, we introduced sequons encoding potential N-linked glycosylation sites (PNGSs) into base-proximal regions. Expression and antigenic analyses indicated trimers bearing six-introduced PNGSs to have reduced base recognition. Cryo-EM analysis revealed trimers with introduced PNGSs to be prone to disassembly and introduced PNGS to be disordered. Protein-base and glycan-base trimers induced reciprocally symmetric ELISA responses, in which only a small fraction of the antibody response to glycan-base trimers recognized protein-base trimers and vice versa. EM polyclonal epitope mapping revealed glycan-base trimers 160;-even those that were stable biochemically- to elicit antibodies that recognized disassembled trimers. Introduced glycans can thus mask the protein base but their introduction may yield neo-epitopes that dominate the immune response.

See More

Author Address