Structure-guided design and immunological characterization of immunogens presenting the HIV-1 gp120 V3 loop on a CTB scaffold.
Structure-guided design and immunological characterization of immunogens presenting the HIV-1 gp120 V3 loop on a CTB scaffold.
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DOI：
10.1016/j.virol.2010.06.027
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发表时间：
2010-09-30
期刊：
影响因子：
3.7
通讯作者：
Zolla-Pazner S
中科院分区：
文献类型：
--
作者：
Totrov M;Jiang X;Kong XP;Cohen S;Krachmarov C;Salomon A;Williams C;Seaman MS;Abagyan R;Cardozo T;Gorny MK;Wang S;Lu S;Pinter A;Zolla-Pazner S
V3环是HIV-1 gp120的主要中和决定因素。利用霍乱毒素B亚单位(CTB)、gp120中完整的V3和与单抗(MAb)结合的V3的三维结构，我们设计了两个V3-支架免疫原构建物(V3-CTB)。全长V3-CTB在模仿gp120的结构背景下呈现完整的V3，得到了我们24个单抗小组的绝大多数人的认可。在与447-52d Fab形成的复合体中，呈现V3片段的短V3-CTB与该单抗具有高亲和力。用DNA-Prime/Protein-Boost方案对免疫原在兔体内进行评价。用全长V3-CTB加强免疫可以诱导血清中高滴度的抗V3抗体，从而有效地中和多种HIV病毒株。短路V3-CTB治疗无效。结果表明，免疫原的抗原谱非常窄与抗体反应差有关。一种具有更广泛抗原性的免疫原可引起较强的抗体反应。
V3 loop is a major neutralizing determinant of the HIV-1 gp120. Using 3D structures of cholera toxin B subunit (CTB), complete V3 in the gp120 context and V3 bound to a monoclonal antibody (mAb) we designed two V3-scaffold immunogen constructs (V3-CTB). The full-length V3-CTB presenting the complete V3 in a structural context mimicking gp120, was recognized by the large majority of our panel of 24 mAbs. The short V3-CTB presenting a V3 fragment in the conformation observed in the complex with the 447-52D Fab, exhibited high affinity binding to this mAb. The immunogens were evaluated in rabbits using DNA-prime/protein-boost protocol. Boosting with the full-length V3-CTB induced high anti-V3 titers in sera that potently neutralize multiple HIV virus strains. The short V3-CTB was ineffective. The results suggest that very narrow antigenic profile of an immunogen is associated with poor Ab response. An immunogen with broader antigenic activity elicits robust Ab response.
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