Structure-guided changes at the V2 apex of HIV-1 clade C trimer enhance elicitation of autologous neutralizing and broad V1V2-scaffold antibodies.

Autor:	Sahoo A; Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Microbiology and Immunology, Emory School of Medicine, Emory University, Atlanta, GA 30322, USA., Hodge EA; Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA., LaBranche CC; Department of Surgery, Duke University Medical School, Duke University, Durham, NC 27710, USA., Styles TM; Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Microbiology and Immunology, Emory School of Medicine, Emory University, Atlanta, GA 30322, USA., Shen X; Department of Surgery, Duke University Medical School, Duke University, Durham, NC 27710, USA., Cheedarla N; Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Microbiology and Immunology, Emory School of Medicine, Emory University, Atlanta, GA 30322, USA., Shiferaw A; Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Microbiology and Immunology, Emory School of Medicine, Emory University, Atlanta, GA 30322, USA., Ozorowski G; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, San Diego, CA 92121, USA., Lee WH; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, San Diego, CA 92121, USA., Ward AB; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, San Diego, CA 92121, USA., Tomaras GD; Department of Surgery, Duke University Medical School, Duke University, Durham, NC 27710, USA., Montefiori DC; Department of Surgery, Duke University Medical School, Duke University, Durham, NC 27710, USA., Irvine DJ; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Lee KK; Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA., Amara RR; Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Microbiology and Immunology, Emory School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: ramara@emory.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2022 Mar 01; Vol. 38 (9), pp. 110436.
DOI:	10.1016/j.celrep.2022.110436
Abstrakt:	HIV-1 clade C envelope immunogens that elicit both neutralizing and non-neutralizing V1V2-scaffold-specific antibodies (protective correlates from RV144 human trial) are urgently needed due to the prevalence of this clade in the most impacted regions worldwide. To achieve this, we introduce structure-guided changes followed by consensus-C-sequence-guided optimizations at the V2 region to generate UFO-v2-RQH 173 trimer. This improves the abundance of well-formed trimers. Following the immunization of rabbits, the wild-type protein fails to elicit any autologous neutralizing antibodies, but UFO-v2-RQH 173 elicits both autologous neutralizing and broad V1V2-scaffold antibodies. The variant with a 173Y modification in the V2 region, most prevalent among HIV-1 sequences, shows decreased ability in displaying a native-like V1V2 epitope with time in vitro and elicited antibodies with lower neutralizing and higher V1V2-scaffold activities. Our results identify a stabilized clade C trimer capable of eliciting improved neutralizing and V1V2-scaffold antibodies and reveal the importance of the V2 region in tuning this. Competing Interests: Declaration of interests A patent has been filed on the C.1086 UFO trimers developed in the study, and R.R.A., A. Sahoo, and T.M.S. are co-inventors of this technology. The other authors declare no competing interests. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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