Initiation of immune tolerance-controlled HIV gp41 neutralizing B cell lineages.
Development of an HIV vaccine is a global priority. A major roadblock to a vaccine is an inability to induce protective broadly neutralizing antibodies (bnAbs). HIV gp41 bnAbs have characteristics that predispose them to be controlled by tolerance. We used gp41 2F5 bnAb germline knock-in mice and macaques vaccinated with immunogens reactive with germline precursors to activate neutralizing antibodies. In germline knock-in mice, bnAb precursors were deleted, with remaining anergic B cells capable of being activated by germline-binding immunogens to make gp41-reactive immunoglobulin M (IgM). Immunized macaques made B cell clonal lineages targeted to the 2F5 bnAb epitope, but 2F5-like antibodies were either deleted or did not attain sufficient affinity for gp41-lipid complexes to achieve the neutralization potency of 2F5. Structural analysis of members of a vaccine-induced antibody lineage revealed that heavy chain complementarity-determining region 3 (HCDR3) hydrophobicity was important for neutralization. Thus, gp41 bnAbs are controlled by immune tolerance, requiring vaccination strategies to transiently circumvent tolerance controls.
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Ruijun
R
Zhang
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA. Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Laurent
L
Verkoczy
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Kevin
K
Wiehe
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA. Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
S
S
Munir Alam
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Nathan I
NI
Nicely
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Sampa
S
Santra
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Todd
T
Bradley
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Charles W
CW
Pemble
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Jinsong
J
Zhang
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Feng
F
Gao
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
David C
DC
Montefiori
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Hilary
H
Bouton-Verville
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA.
Garnett
G
Kelsoe
Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109, USA.
Kevin
K
Larimore
Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109, USA.
Phillip D
PD
Greenberg
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Robert
R
Parks
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Andrew
A
Foulger
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Jessica N
JN
Peel
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Kan
K
Luo
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Xiaozhi
X
Lu
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Ashley M
AM
Trama
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Nathan
N
Vandergrift
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
Georgia D
GD
Tomaras
Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA.
Thomas B
TB
Kepler
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA. Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
M Anthony
MA
Moody
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. barton.haynes@duke.edu l.liao@dm.duke.edu.
Hua-Xin
HX
Liao
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA. Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. barton.haynes@duke.edu l.liao@dm.duke.edu.
Barton F
BF
Haynes
D016915:AIDS Vaccines / Q000276:immunology / Q000627:therapeutic use; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D018985:Epitopes, B-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005260:Female; D015483:HIV Antibodies / Q000276:immunology / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000276:immunology* / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D000939:Epitopes; D018985:Epitopes, B-Lymphocyte; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D007075:Immunoglobulin M