Polyfunctional Tier 2-Neutralizing Antibodies Cloned following HIV-1 Env Macaque Immunization Mirror Native Antibodies in a Human Donor.

Autor: Spencer DA; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006., Malherbe DC; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006., Vázquez Bernat N; Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 65 Solna, Stockholm, Sweden., Ádori M; Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 65 Solna, Stockholm, Sweden., Goldberg B; Thayer School of Engineering, Dartmouth College, Hanover, NH 03755., Dambrauskas N; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA 98109., Henderson H; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006., Pandey S; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006., Cheever T; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006., Barnette P; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006., Sutton WF; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006., Ackerman ME; Thayer School of Engineering, Dartmouth College, Hanover, NH 03755., Kobie JJ; Infectious Diseases, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294., Sather DN; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA 98109.; Department of Pediatrics, University of Washington, Seattle, WA 98105; and., Karlsson Hedestam GB; Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 65 Solna, Stockholm, Sweden., Haigwood NL; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006.; Molecular Microbiology and Immunology, School of Medicine, Oregon Health & Science University, Portland, OR 97239., Hessell AJ; Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; hessell@ohsu.edu.
Jazyk: angličtina
Zdroj: Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2021 Mar 01; Vol. 206 (5), pp. 999-1012. Date of Electronic Publication: 2021 Jan 20.
DOI: 10.4049/jimmunol.2001082
Abstrakt: Vaccine efforts to combat HIV are challenged by the global diversity of viral strains and shielding of neutralization epitopes on the viral envelope glycoprotein trimer. Even so, the isolation of broadly neutralizing Abs from infected individuals suggests the potential for eliciting protective Abs through vaccination. This study reports a panel of 58 mAbs cloned from a rhesus macaque ( Macaca mulatta ) immunized with envelope glycoprotein immunogens curated from an HIV-1 clade C-infected volunteer. Twenty mAbs showed neutralizing activity, and the strongest neutralizer displayed 92% breadth with a median IC 50 of 1.35 μg/ml against a 13-virus panel. Neutralizing mAbs predominantly targeted linear epitopes in the V3 region in the cradle orientation (V3C) with others targeting the V3 ladle orientation (V3L), the CD4 binding site (CD4bs), C1, C4, or gp41. Nonneutralizing mAbs bound C1, C5, or undetermined conformational epitopes. Neutralization potency strongly correlated with the magnitude of binding to infected primary macaque splenocytes and to the level of Ab-dependent cellular cytotoxicity, but did not predict the degree of Ab-dependent cellular phagocytosis. Using an individualized germline gene database, mAbs were traced to 23 of 72 functional IgHV alleles. Neutralizing V3C Abs displayed minimal nucleotide somatic hypermutation in the H chain V region (3.77%), indicating that relatively little affinity maturation was needed to achieve in-clade neutralization breadth. Overall, this study underscores the polyfunctional nature of vaccine-elicited tier 2-neutralizing V3 Abs and demonstrates partial reproduction of the human donor's humoral immune response through nonhuman primate vaccination.
(Copyright © 2021 by The American Association of Immunologists, Inc.)
Databáze: MEDLINE
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