Induction of specific T-helper and cytolytic responses to epitopes displayed on a virus-like protein scaffold derived from the pyruvate dehydrogenase multienzyme complex.
The icosahedral protein scaffold (1.5MDa) generated by self-assembly of the catalytic domains of the dihydrolipoyl acetyltransferase core of the pyruvate dehydrogenase multienzyme complex from Bacillus stearothermophilus has been engineered to display 60 copies of one or more peptide epitopes on a single molecule (E2DISP). An E2DISP scaffold displaying pep23, a 15-residue B- and T-helper epitope from the reverse transcriptase of HIV-1, was able to induce a pep23-specific T-helper response in cell lines in vitro. The same scaffold displaying both pep23 and peptide RT2, a nine-residue CTL epitope from HIV-1 reverse transcriptase, was able to prime an RT2-specific CD8(+) T-cell response in human cell lines in vitro and in HLA-A2 transgenic mice in vivo. This was accompanied by a humoral antibody response specific for E2DISP-presented epitopes. Thus, the icosahedral acetyltransferase core constitutes a simple and flexible scaffold for multiple epitope display with access to both cellular and humoral immune response pathways.
Domingo
Gonzalo J
GJ
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, UK.
Caivano
Antonella
A
Sartorius
Rossella
R
Barba
Pasquale
P
Bäckström
Malin
M
Piatier-Tonneau
Dominique
D
Guardiola
John
J
De Berardinis
Piergiuseppe
P
Perham
Richard N
RN
D000123:Acetyltransferases / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology*; D020134:Catalytic Domain; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D018984:Epitopes, T-Lymphocyte; D001411:Geobacillus stearothermophilus / Q000201:enzymology*; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D051379:Mice; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D001426:Bacterial Proteins; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D011768:Pyruvate Dehydrogenase Complex; D000123:Acetyltransferases; D051047:Dihydrolipoyllysine-Residue Acetyltransferase