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Anti-HIV B cell lines as candidate vaccine biosensors


Abstract

Challenge studies following passive immunization with neutralizing Abs suggest that an HIV vaccine could be efficacious were it able to elicit broadly neutralizing Abs bNAbs).To betterunderstand the requirementsfor activation ofB cells producing bNAbs,we generated cell lines expressing bNAbs or their germline-revertedversions gl-bNAbs)as BCRs. We thentestedthe abilitiesof the bNAb-expressing cells to recognize HIV pseudovirions and vaccine candidate proteins by binding and activation assays. The results suggest that HIV envelope (Env) Ag-expressing, infection-competent virions are poorly recognized by high-affinity bNAb-expressing cells, as measured by the inability of Ags to induce rapid increases in intracellular calcium levels. Other Ag forms appear to be highly stimulatory, in particular, soluble gp140 trimers and a multimerized, scaffolded epitope protein. Virions failed to efficiently activate bNAb-expressing B cells owing to delayed or inefficient BCR recognition, most likely caused by the low density of Env spikes. Importantly, B cells carrying gl-bNAb BCRs were not stimulated by any of the tested vaccine candidates. These data provide insight into why many HIV immunogens, as well as natural HIV infections, fail to rapidly stimulate bNAb responses and suggest that bNAb-expressing cell lines might be useful tools in evaluation of vaccine Ags for infectious diseases. Because soluble Env trimers or multimerized scaffolded epitopes are best at activating B cell-expressing bNAbs, these antigenic forms should be considered as preferred vaccine components, although they should be modified to better target naive gl-bNAb B cells.

Abstract

Challenge studies following passive immunization with neutralizing Abs suggest that an HIV vaccine could be efficacious were it able to elicit broadly neutralizing Abs bNAbs).To betterunderstand the requirementsfor activation ofB cells producing bNAbs,we generated cell lines expressing bNAbs or their germline-revertedversions gl-bNAbs)as BCRs. We thentestedthe abilitiesof the bNAb-expressing cells to recognize HIV pseudovirions and vaccine candidate proteins by binding and activation assays. The results suggest that HIV envelope (Env) Ag-expressing, infection-competent virions are poorly recognized by high-affinity bNAb-expressing cells, as measured by the inability of Ags to induce rapid increases in intracellular calcium levels. Other Ag forms appear to be highly stimulatory, in particular, soluble gp140 trimers and a multimerized, scaffolded epitope protein. Virions failed to efficiently activate bNAb-expressing B cells owing to delayed or inefficient BCR recognition, most likely caused by the low density of Env spikes. Importantly, B cells carrying gl-bNAb BCRs were not stimulated by any of the tested vaccine candidates. These data provide insight into why many HIV immunogens, as well as natural HIV infections, fail to rapidly stimulate bNAb responses and suggest that bNAb-expressing cell lines might be useful tools in evaluation of vaccine Ags for infectious diseases. Because soluble Env trimers or multimerized scaffolded epitopes are best at activating B cell-expressing bNAbs, these antigenic forms should be considered as preferred vaccine components, although they should be modified to better target naive gl-bNAb B cells.

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23 citations in Web of Science®
27 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Virology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:12 October 2012
Deposited On:22 Apr 2015 15:23
Last Modified:05 Apr 2016 19:13
Publisher:American Association of Immunologists
ISSN:0022-1767
Funders:National Institutes of Health Research Grants R01 AI073148, U01 AI078224, and UM1 AI100663, International AIDS Vaccine Initiative Neutralizing Antibody Center, Ragon Institute of MGH, MIT and Harvard
Publisher DOI:https://doi.org/10.4049/jimmunol.1202165
Related URLs:http://www.jimmunol.org/content/189/10/4816.full.pdf+html?sid=65115ed0-c850-48b0-8e4b-09137274df22
http://www.jimmunol.org

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