Journal
SCIENCE ADVANCES
Volume 8, Issue 18, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abm3948
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Funding
- NIH [R01AI081625, R01AI104384, P01 AI138212, U19 AI128914, UM1AI144462, UM1AI068618]
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This study demonstrates that the activation of naive B cells is crucial for the development of broadly neutralizing HIV-1 antibodies. Only one antibody displayed homology to VRC01-class antibodies, but required alterations in certain domains to switch epitope recognition. Germ line-targeting Env immunogens efficiently activated VRC01 B cells, highlighting their importance in B cell activation.
Broadly HIV-1-neutralizing VRC01-class antibodies bind the CD4-binding site of Env and contain V(H)1-2*02-derived heavy chains paired with light chains expressing five-amino acid-long CDRL3s. Their unmutated germline forms do not recognize HIV-1 Env, and their lack of elicitation in human clinical trials could be due to the absence of activation of the corresponding naive B cells by the vaccine immunogens. To address this point, we examined Env-specific B cell receptor sequences from participants in the HVTN 100 clinical trial. Of all the sequences analyzed, only one displayed homology to VRC01-class antibodies, but the corresponding antibody (FH1) recognized the C1C2 gp120 domain. For FH1 to switch epitope recognition to the CD4-binding site, alterations in the CDRH3 and CDRL3 were necessary. Only germ line-targeting Env immunogens efficiently activated VRC01 B cells, even in the presence of FH1 B cells. Our findings support the use of these immunogens to activate VRC01 B cells in humans.
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