一項研究說，把一些病原體的抗原決定部位嫁接到經(jīng)過改造的蛋白質(zhì)骨架上可能有助于改善針對病原體的保護(hù)性抗體的產(chǎn)量。一些病原體的表面可能改變形狀,，讓免疫系統(tǒng)很難識別病原體并制造出能殺死它們的抗體,。通過使用原子層次的設(shè)計,，Peter D. Kwong及其同事開發(fā)出了一種技術(shù),，提取出了病原體表面被抗體識別的部分，并把這個表面片斷——稱為抗原決定部位——放進(jìn)了一種經(jīng)過改造的蛋白質(zhì)骨架,。這種骨架幫助抗原決定部位維持中和抗體識別的形狀,。
這組作者把他們的技術(shù)應(yīng)用到2F5抗體識別的HIV-1病毒表面的一種能改變形狀的抗原決定部位。2F5抗體已經(jīng)被證明可以中和這種病毒,。當(dāng)這組作者給豚鼠接種了2F5抗原決定部位骨架之后,，這種骨架不僅引發(fā)了與HIV-1的2F5抗原決定部位緊密結(jié)合的抗體，而且還誘導(dǎo)產(chǎn)生了靈活版本的這種抗原決定部位,，具有類似于被2F5抗體識別的抗原決定部位的形狀,。這組作者說，這些發(fā)現(xiàn)描繪了一種使用原子層次的設(shè)計精確操縱疫苗免疫原從而改善疫苗設(shè)計的策略,。（生物谷Bioon.com）
生物谷推薦英文摘要：
PNAS doi: 10.1073/pnas.1004728107
Elicitation of structure-specific antibodies by epitope scaffolds
Gilad Ofeka,1, F. Javier Guenagaa,1,3, William R. Schiefb,1, Jeff Skinnerc, David Bakerb, Richard Wyatta,3, and Peter D. Kwonga,2
aVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
bDepartment of Biochemistry, University of Washington, Seattle, WA 98195; and
cBioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Elicitation of antibodies against targets that are immunorecessive, cryptic, or transient in their native context has been a challenge for vaccine design. Here we demonstrate the elicitation of structure-specific antibodies against the HIV-1 gp41 epitope of the broadly neutralizing antibody 2F5. This conformationally flexible region of gp41 assumes mostly helical conformations but adopts a kinked, extended structure when bound by antibody 2F5. Computational techniques were employed to transplant the 2F5 epitope into select acceptor scaffolds. The resultant “2F5-epitope scaffolds” possessed nanomolar affinity for antibody 2F5 and a range of epitope flexibilities and antigenic specificities. Crystallographic characterization of the epitope scaffold with highest affinity and antigenic discrimination confirmed good to near perfect attainment of the target conformation for the gp41 molecular graft in free and 2F5-bound states, respectively. Animals immunized with 2F5-epitope scaffolds showed levels of graft-specific immune responses that correlated with graft flexibility (p < 0.04), while antibody responses against the graft—as dissected residue-by-residue with alanine substitutions—resembled more closely those of 2F5 than sera elicited with flexible or cyclized peptides, a resemblance heightened by heterologous prime-boost. Lastly, crystal structures of a gp41 peptide in complex with monoclonal antibodies elicited by the 2F5-epitope scaffolds revealed that the elicited antibodies induce gp41 to assume its 2F5-recognized shape. Epitope scaffolds thus provide a means to elicit antibodies that recognize a predetermined target shape and sequence, even if that shape is transient in nature, and a means by which to dissect factors influencing such elicitation.
PNAS doi: 10.1073/pnas.1004728107
Elicitation of structure-specific antibodies by epitope scaffolds
Gilad Ofeka,1, F. Javier Guenagaa,1,3, William R. Schiefb,1, Jeff Skinnerc, David Bakerb, Richard Wyatta,3, and Peter D. Kwonga,2
aVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
bDepartment of Biochemistry, University of Washington, Seattle, WA 98195; and
cBioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Elicitation of antibodies against targets that are immunorecessive, cryptic, or transient in their native context has been a challenge for vaccine design. Here we demonstrate the elicitation of structure-specific antibodies against the HIV-1 gp41 epitope of the broadly neutralizing antibody 2F5. This conformationally flexible region of gp41 assumes mostly helical conformations but adopts a kinked, extended structure when bound by antibody 2F5. Computational techniques were employed to transplant the 2F5 epitope into select acceptor scaffolds. The resultant “2F5-epitope scaffolds” possessed nanomolar affinity for antibody 2F5 and a range of epitope flexibilities and antigenic specificities. Crystallographic characterization of the epitope scaffold with highest affinity and antigenic discrimination confirmed good to near perfect attainment of the target conformation for the gp41 molecular graft in free and 2F5-bound states, respectively. Animals immunized with 2F5-epitope scaffolds showed levels of graft-specific immune responses that correlated with graft flexibility (p < 0.04), while antibody responses against the graft—as dissected residue-by-residue with alanine substitutions—resembled more closely those of 2F5 than sera elicited with flexible or cyclized peptides, a resemblance heightened by heterologous prime-boost. Lastly, crystal structures of a gp41 peptide in complex with monoclonal antibodies elicited by the 2F5-epitope scaffolds revealed that the elicited antibodies induce gp41 to assume its 2F5-recognized shape. Epitope scaffolds thus provide a means to elicit antibodies that recognize a predetermined target shape and sequence, even if that shape is transient in nature, and a means by which to dissect factors influencing such elicitation.
