scholarly journals High-Resolution Definition of Vaccine-Elicited B Cell Responses Against the HIV Primary Receptor Binding Site

2012 ◽  
Vol 4 (142) ◽  
pp. 142ra96-142ra96 ◽  
Author(s):  
C. Sundling ◽  
Y. Li ◽  
N. Huynh ◽  
C. Poulsen ◽  
R. Wilson ◽  
...  
Keyword(s):  
High Resolution ◽  
B Cell ◽  
Binding Site ◽  
Receptor Binding ◽  
Receptor Binding Site ◽  
Cell Responses ◽  
Primary Receptor ◽  
B Cell Responses ◽  
Definition Of

scholarly journals Mechanisms of antibody binding revealed by asymmetric Fab-virus complexes

2020 ◽  
Author(s):  
Daniel J. Goetschius ◽  
Samantha R. Hartmann ◽  
Lindsey J. Organtini ◽  
Heather Callaway ◽  
Kai Huang ◽  
...  
Keyword(s):  
High Resolution ◽  
Binding Site ◽  
Receptor Binding ◽  
Antibody Binding ◽  
Antigenic Epitope ◽  
Receptor Binding Site ◽  
Local Structures ◽  
Antigenic Sites ◽  
High Resolution Map ◽  
Feline Parvovirus

AbstractOverlap on the surface of parvovirus capsids between the antigenic epitope and the receptor binding site contributes to species jumping. Mab 14 strongly binds and neutralizes canine, but not feline parvovirus. The high resolution map of the canine parvovirus capsid complexed with Fab 14 was used to solve local structures of the Fab-bound and -unbound antigenic sites extracted from the same complex. The subsequent analysis includes a new method for using cryo EM to investigate complementarity of antibody binding.

scholarly journals Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site

2017 ◽  
Vol 91 (19) ◽  
Author(s):  
Willy M. J. M. Bogers ◽  
Susan W. Barnett ◽  
Herman Oostermeijer ◽  
Ivonne G. Nieuwenhuis ◽  
Niels Beenhakker ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Binding Site ◽  
T Helper ◽  
Cell Responses ◽  
Cd4 Receptor ◽  
Cd4 Binding Site ◽  
B Cell Responses ◽  
Hiv Envelope ◽  
Hiv 1

ABSTRACT Strategies are needed to improve the immunogenicity of HIV-1 envelope (Env) antigens (Ag) for more long-lived, efficacious HIV-1 vaccine-induced B-cell responses. HIV-1 Env gp140 (native or uncleaved molecules) or gp120 monomeric proteins elicit relatively poor B-cell responses which are short-lived. We hypothesized that Env engagement of the CD4 receptor on T-helper cells results in anergic effects on T-cell recruitment and consequently a lack of strong, robust, and durable B-memory responses. To test this hypothesis, we occluded the CD4 binding site (CD4bs) of gp140 by stable cross-linking with a 3-kDa CD4 miniprotein mimetic, serving to block ligation of gp140 on CD4+ T cells while preserving CD4-inducible (CDi) neutralizing epitopes targeted by antibody-dependent cellular cytotoxicity (ADCC) effector responses. Importantly, immunization of rhesus macaques consistently gave superior B-cell (P < 0.001) response kinetics and superior ADCC (P < 0.014) in a group receiving the CD4bs-occluded vaccine compared to those of animals immunized with gp140. Of the cytokines examined, Ag-specific interleukin-4 (IL-4) T-helper enzyme-linked immunosorbent spot (ELISpot) assays of the CD4bs-occluded group increased earlier (P = 0.025) during the inductive phase. Importantly, CD4bs-occluded gp140 antigen induced superior B-cell and ADCC responses, and the elevated B-cell responses proved to be remarkably durable, lasting more than 60 weeks postimmunization. IMPORTANCE Attempts to develop HIV vaccines capable of inducing potent and durable B-cell responses have been unsuccessful until now. Antigen-specific B-cell development and affinity maturation occurs in germinal centers in lymphoid follicles through a critical interaction between B cells and T follicular helper cells. The HIV envelope binds the CD4 receptor on T cells as soluble shed antigen or as antigen-antibody complexes, causing impairment in the activation of these specialized CD4-positive T cells. We proposed that CD4-binding impairment is partly responsible for the relatively poor B-cell responses to HIV envelope-based vaccines. To test this hypothesis, we blocked the CD4 binding site of the envelope antigen and compared it to currently used unblocked envelope protein. We found superior and durable B-cell responses in macaques vaccinated with an occluded CD4 binding site on the HIV envelope antigen, demonstrating a potentially important new direction in future design of new HIV vaccines.

scholarly journals B Cell Recognition of the Conserved HIV-1 Co-Receptor Binding Site Is Altered by Endogenous Primate CD4

2008 ◽  
Vol 4 (10) ◽  
pp. e1000171 ◽  
Author(s):  
Mattias N. E. Forsell ◽  
Barna Dey ◽  
Andreas Mörner ◽  
Krisha Svehla ◽  
Sijy O'dell ◽  
...  
Keyword(s):  
B Cell ◽  
Binding Site ◽  
Receptor Binding ◽  
Cell Recognition ◽  
Receptor Binding Site ◽  
Hiv 1

scholarly journals Vaccine-elicited primate antibodies use a distinct approach to the HIV-1 primary receptor binding site informing vaccine redesign

2014 ◽  
Vol 111 (7) ◽  
pp. E738-E747 ◽  
Author(s):  
K. Tran ◽  
C. Poulsen ◽  
J. Guenaga ◽  
N. de Val ◽  
R. Wilson ◽  
...  
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Receptor Binding Site ◽  
Primary Receptor ◽  
Hiv 1 ◽  
Distinct Approach

scholarly journals High-resolution asymmetric structure of a Fab–virus complex reveals overlap with the receptor binding site

2021 ◽  
Vol 118 (23) ◽  
pp. e2025452118
Author(s):  
Daniel J. Goetschius ◽  
Samantha R. Hartmann ◽  
Lindsey J. Organtini ◽  
Heather Callaway ◽  
Kai Huang ◽  
...  
Keyword(s):  
High Resolution ◽  
Binding Site ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Antigenic Site ◽  
Conformational Epitope ◽  
Asymmetric Structure ◽  
Antigenic Epitope ◽  
Receptor Binding Site ◽  
Virus Complex

Canine parvovirus is an important pathogen causing severe diseases in dogs, including acute hemorrhagic enteritis, myocarditis, and cerebellar disease. Overlap on the surface of parvovirus capsids between the antigenic epitope and the receptor binding site has contributed to cross-species transmission, giving rise to closely related variants. It has been shown that Mab 14 strongly binds and neutralizes canine but not feline parvovirus, suggesting this antigenic site also controls species-specific receptor binding. To visualize the conformational epitope at high resolution, we solved the cryogenic electron microscopy (cryo-EM) structure of the Fab–virus complex. We also created custom software, Icosahedral Subparticle Extraction and Correlated Classification, to solve a Fab–virus complex with only a few Fab bound per capsid and visualize local structures of the Fab-bound and -unbound antigenic sites extracted from the same complex map. Our results identified the antigenic epitope that had significant overlap with the receptor binding site, and the structures revealed that binding of Fab induced conformational changes to the virus. We were also able to assign the order and position of attached Fabs to allow assessment of complementarity between the Fabs bound to different positions. This approach therefore provides a method for using cryo-EM to investigate complementarity of antibody binding.

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