Abstract:
:The core shell of hepatitis B virus is a potent immune stimulator, giving a strong neutralizing immune response to foreign epitopes inserted at the immunodominant region, located at the tips of spikes on the exterior of the shell. Here, we analyze structures of core shells with a model epitope inserted at two alternative positions in the immunodominant region. Recombinantly expressed core protein assembles into T=3 and T=4 icosahedral shells, and atomic coordinates are available for the T=4 shell. Since the modified protein assembles predominantly into T=3 shells, a quasi-atomic model of the native T=3 shell was made. The spikes in this T=3 structure resemble those in T=4 shells crystallized from expressed protein. However, the spikes in the modified shells exhibit an altered conformation, similar to the DNA containing shells in virions. Both constructs allow full access of antibodies to the foreign epitope, DPAFR from the preS1 region of hepatitis B virus surface antigen. However, one induces a 10-fold weaker immune response when injected into mice. In this construct, the epitope is less constrained by the flanking linker regions and is positioned so that the symmetry of the shell causes pairs of epitopes to come close enough to interfere with one another. In the other construct, the epitope mimics the native epitope conformation and position. The interaction of native core shells with an antibody specific to the immunodominant epitope is compared to the constructs with an antibody against the foreign epitope. Our findings have implications for the design of vaccines based on virus-like particles.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Roseman AM,Borschukova O,Berriman JA,Wynne SA,Pumpens P,Crowther RAdoi
10.1016/j.jmb.2012.06.032subject
Has Abstractpub_date
2012-10-12 00:00:00pages
63-78issue
1eissn
0022-2836issn
1089-8638pii
S0022-2836(12)00524-4journal_volume
423pub_type
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