Determinants of HIV-1 broadly neutralizing antibody induction.
Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that three parameters that reflect the exposure to antigen-viral load, length of untreated infection and viral diversity-independently drive bnAb evolution. Notably, black participants showed significantly (P = 0.0086-0.038) higher rates of bnAb induction than white participants. Neutralization fingerprint analysis, which was used to delineate plasma specificity, identified strong virus subtype dependencies, with higher frequencies of CD4-binding-site bnAbs in infection with subtype B viruses (P = 0.02) and higher frequencies of V2-glycan-specific bnAbs in infection with non-subtype B viruses (P = 1 × 10-5). Thus, key host, disease and viral determinants, including subtype-specific envelope features that determine bnAb specificity, remain to be unraveled and harnessed for bnAb-based vaccine design.
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Peter
P
Rusert
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.|Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
Roger D
RD
Kouyos
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.|Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
Claus
C
Kadelka
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Hanna
H
Ebner
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Merle
M
Schanz
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Michael
M
Huber
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.|Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
Dominique L
DL
Braun
Institute of Integrative Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.
Nathanael
N
Hozé
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.|Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
Alexandra
A
Scherrer
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Carsten
C
Magnus
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Jacqueline
J
Weber
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Therese
T
Uhr
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Valentina
V
Cippa
Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Christian W
CW
Thorball
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.|Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
Herbert
H
Kuster
University Hospital Lausanne, University of Lausanne, Lausanne, Switzerland.
Matthias
M
Cavassini
Division of Infectious Diseases, Regional Hospital of Lugano, Lugano, Switzerland.
Enos
E
Bernasconi
Division of Infectious Diseases, Cantonal Hospital of St. Gallen, St. Gallen, Switzerland.
Matthias
M
Hoffmann
Division of Infectious Diseases, University Hospital of Geneva, Geneva, Switzerland.
Alexandra
A
Calmy
Division of Infectious Diseases, University Hospital of Basel, Basel, Switzerland.
Manuel
M
Battegay
Department of Infectious Diseases, Inselspital, Bern University Hospital, Bern, Switzerland.
Andri
A
Rauch
Laboratory of Virology, Division of Infectious Diseases, Geneva University Hospital, Geneva, Switzerland.
Sabine
S
Yerly
Division of Immunology and Allergy, University Hospital Lausanne, Lausanne, Switzerland.
Vincent
V
Aubert
Department of Biomedicine-Petersplatz, University of Basel, Basel, Switzerland.
Thomas
T
Klimkait
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Jürg
J
Böni
Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Jacques
0000-0002-8240-939X
J
Fellay
Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Roland R
RR
Regoes
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.|Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
Huldrych F
0000-0002-1142-6723
HF
Günthard
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Alexandra
A
Trkola
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing / Q000276:immunology*; D044383:Black People; D015704:CD4 Antigens / Q000276:immunology; D055808:Drug Discovery; D005260:Female; D014644:Genetic Variation; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D015999:Multivariate Analysis; D011134:Polysaccharides / Q000276:immunology; D011446:Prospective Studies; D012367:RNA, Viral / Q000097:blood; D013557:Switzerland; D013997:Time Factors; D019562:Viral Load; D044465:White People
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D015483:HIV Antibodies; D011134:Polysaccharides; D012367:RNA, Viral
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