Anti-HIV B Cell lines as candidate vaccine biosensors.

TitleAnti-HIV B Cell lines as candidate vaccine biosensors.
Publication TypeJournal Article
Year of Publication2012
AuthorsOta T, Doyle-Cooper C, Cooper AB, Huber M, Falkowska E, Doores KJ, Hangartner L, Le K, Sok D, Jardine J, Lifson J, Wu X, Mascola JR, Poignard P, Binley JM, Chakrabarti BK, Schief WR, Wyatt RT, Burton DR, Nemazee D
JournalJ Immunol
Volume189
Issue10
Pagination4816-24
Date Published11/15/2012
ISSN1550-6606
KeywordsAIDS Vaccines, Animals, Antibodies, Neutralizing, B-Lymphocytes, Biological Assay, Biosensing Techniques, env Gene Products, Human Immunodeficiency Virus, HIV Antibodies, HIV Antigens, HIV-1, Humans, Mice
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 better understand the requirements for activation of B cells producing bNAbs, we generated cell lines expressing bNAbs or their germline-reverted versions (gl-bNAbs) as BCRs. We then tested the abilities of 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.

DOI10.4049/jimmunol.1202165
Alternate JournalJ. Immunol.
PubMed ID23066156
Grant ListR01 AI073148 / AI / NIAID NIH HHS / United States
R01 AI093278 / AI / NIAID NIH HHS / United States
R01 AI100790 / AI / NIAID NIH HHS / United States
U01 AI078224 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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