Initiation of immune tolerance–controlled HIV gp41 neutralizing B cell lineages

Zhang, Ruijun; Verkoczy, Laurent; Wiehe, Kevin; Alam, S. Munir; Nicely, Nathan I.; Santra, Sampa; Bradley, Todd; Pemble, IV, Charles W.; Zhang, Jinsong; Gao, Feng; Montefiori, David C.; Bouton-Verville, Hilary; Kelsoe, Garnett; Larimore, Kevin; Greenberg, Phillip D.; Parks, Robert; Foulger, Andrew; Peel, Jessica N.; Luo, Kan; Lu, Xiaozhi; Trama, Ashley M.; Vandergrift, Nathan; Tomaras, Georgia D.; Kepler, Thomas B.; Moody, M. Anthony; Liao, Hua-Xin; Haynes, Barton F.

doi:10.1126/scitranslmed.aaf0618

Initiation of immune tolerance–controlled HIV gp41 neutralizing B cell lineages

Journal Article · Wed Apr 27 00:00:00 EDT 2016 · Science Translational Medicine

DOI:https://doi.org/10.1126/scitranslmed.aaf0618· OSTI ID:1257467

Zhang, Ruijun ^[1]; Verkoczy, Laurent ^[1]; Wiehe, Kevin ^[1]; Alam, S. Munir ^[1]; Nicely, Nathan I. ^[1]; Santra, Sampa ^[2]; Bradley, Todd ^[1]; Pemble, IV, Charles W. ^[1]; Zhang, Jinsong ^[1]; Gao, Feng ^[1]; Montefiori, David C. ^[1]; Bouton-Verville, Hilary ^[1]; Kelsoe, Garnett ^[1]; Larimore, Kevin ^[3]; Greenberg, Phillip D. ^[4]; Parks, Robert ^[1]; Foulger, Andrew ^[1]; Peel, Jessica N. ^[1]; Luo, Kan ^[1]; Lu, Xiaozhi ^[1] more »

Duke Univ. School of Medicine, Durham, NC (United States)
Beth Israel Deaconess Medical Center, Boston, MA (United States)
Univ. of Washington, Seattle, WA (United States); BioMarin Pharmaceutical Inc., Novato, CA (United States)
Univ. of Washington, Seattle, WA (United States)
Boston Univ. School of Medicine, Boston, MA (United States)

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. Furthermore, gp41 bnAbs are controlled by immune tolerance, requiring vaccination strategies to transiently circumvent tolerance controls.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; NIH; National Inst. of Allergy and Infectious Diseases; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: W-31109-ENG-38

OSTI ID:: 1257467

Journal Information:: Science Translational Medicine, Journal Name: Science Translational Medicine Journal Issue: 336 Vol. 8; ISSN 1946-6234

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies LaBranche, Celia C.; McGuire, Andrew T.; Gray, Matthew D. PLOS Pathogens, Vol. 14, Issue 11 https://doi.org/10.1371/journal.ppat.1007431	journal	November 2018
Human Immunodeficiency Virus Proteins Mimic Human T Cell Receptors Inducing Cross-Reactive Antibodies Root-Bernstein, Robert International Journal of Molecular Sciences, Vol. 18, Issue 10 https://doi.org/10.3390/ijms18102091	journal	October 2017
Cross-Reactivity to Kynureninase Tolerizes B Cells That Express the HIV-1 Broadly Neutralizing Antibody 2F5 Finney, Joel; Yang, Guang; Kuraoka, Masayuki The Journal of Immunology, Vol. 203, Issue 12 https://doi.org/10.4049/jimmunol.1900069	journal	November 2019
Optimal Development of Mature B Cells Requires Recognition of Endogenous Antigens Noviski, Mark; Tan, Corey; Huizar, John The Journal of Immunology, Vol. 203, Issue 2 https://doi.org/10.4049/jimmunol.1900175	journal	June 2019
Distinct, IgG1-driven antibody response landscapes demarcate individuals with broadly HIV-1 neutralizing activity Kadelka, Claus; Liechti, Thomas; Ebner, Hanna Rockefeller University Press https://doi.org/10.5167/uzh-151852	text	January 2018
Widespread B cell perturbations in HIV-1 infection afflict naive and marginal zone B cells Liechti, Thomas; Kadelka, Claus; Braun, Dominique L. Rockefeller University Press https://doi.org/10.5167/uzh-176092	text	January 2019
Distinct, IgG1-driven antibody response landscapes demarcate individuals with broadly HIV-1 neutralizing activity. Kadelka, Claus; Liechti, Thomas; Ebner, Hanna Rockefeller University Press https://doi.org/10.7892/boris.117015	text	January 2018

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