Anti-HIV B Cell lines as candidate vaccine biosensors.
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.
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
Takayuki
T
Ota
Colleen
C
Doyle-Cooper
Anthony B
AB
Cooper
Michael
M
Huber
Emilia
E
Falkowska
Katherine J
KJ
Doores
Lars
L
Hangartner
Khoa
K
Le
Devin
D
Sok
Joseph
J
Jardine
Jeffrey
J
Lifson
Xueling
X
Wu
John R
JR
Mascola
Pascal
P
Poignard
James M
JM
Binley
Bimal K
BK
Chakrabarti
William R
WR
Schief
Richard T
RT
Wyatt
Dennis R
DR
Burton
David
D
Nemazee
D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D001681:Biological Assay / Q000379:methods*; D015374:Biosensing Techniques / Q000379:methods*; D015483:HIV Antibodies / Q000276:immunology*; D015488:HIV Antigens / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D051379:Mice; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015488:HIV Antigens; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1