An engineered mutant of HIV-1 gp120 formulated with adjuvant Quil A promotes elicitation of antibody responses overlapping the CD4-binding site.
An engineered mutant of HIV-1 gp120 formulated with adjuvant Quil A promotes elicitation of antibody responses overlapping the CD4-binding site.
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DOI：
10.1016/j.vaccine.2011.11.089
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发表时间：
2012-01-20
期刊：
影响因子：
5.5
通讯作者：
Pantophlet R
中科院分区：
文献类型：
--
作者：
Ahmed FK;Clark BE;Burton DR;Pantophlet R
艾滋病疫苗研究的一个主要重点是开发一种免疫原以诱导广泛中和抗体（NAbs）。单克隆抗体（mAb）b12是目前几种广泛中和的单克隆抗体之一，它结合在HIV - 1 gp120上与CD4结合位点（CD4bs）重叠的表位，并作为模板来设计有效的免疫原。我们正在探索一种策略，即在gp120上添加额外的聚糖以遮蔽非中和性单克隆抗体的表位，同时保持b12位点的暴露。假设用这些所谓的高糖基化gp120进行免疫可优先诱导出类似b12的广泛中和抗体。在此，介绍了两种佐剂——单磷酰脂质A（MPL）和Quil A在与一种新的高糖基化突变体ΔN2mCHO(Q105N)配制成制剂时对诱导类似b12反应的影响。用ΔN2mCHO(Q105N)_MPL免疫的动物的血清比用ΔN2mCHO(Q105N) QuilA免疫的动物的血清更优先地结合同源抗原ΔN2mCHO(Q105N)，这表明这两种佐剂对抗体精细特异性的调节作用。我们还发现，用ΔN2mCHO(Q105N)_QuilA免疫的动物的血清与一种重新修饰的HIV gp120核心蛋白结合最佳，在该核心蛋白上非CD4bs表位被非HIV残基取代，这表明这些血清含有相对较大比例的CD4bs特异性抗体。与这些数据一致，抑制试验显示其表位与CD4bs特异性抗体b12、b13和VRC03的结合位点重叠。出乎意料的是，这些血清对一组HIV - 1原代毒株没有表现出显著的中和活性。我们的结果表明，尽管用Quil A配制突变体ΔN2mCHO(Q105N)相对于野生型gp120促进了CD4bs导向抗体的诱导，但需要调整免疫方案以产生强大的、以CD4bs为重点的广泛中和抗体。
A major priority in HIV vaccine research is the development of an immunogen to elicit broadly neutralizing antibodies (NAbs). Monoclonal antibody (mAb) b12 is one of now several broadly neutralizing mAbs that bind epitopes overlapping the CD4-binding site (CD4bs) on HIV-1 gp120 and that serve as templates to engineer effective immunogens. We are exploring a strategy whereby extra glycans are incorporated onto gp120 to occlude the epitopes of non-neutralizing mAbs while maintaining exposure of the b12 site. Immunizing with these so-called hyperglycosylated gp120s is hypothesized to preferentially elicit b12-like NAbs. Here, the effects of two adjuvants, monophosphoryl lipid A (MPL) and Quil A, on eliciting b12-like responses when formulated with a new hyperglycosylated mutant, ΔN2mCHO(Q105N), is presented. Sera from ΔN2mCHO(Q105N)_MPL immunized animals bound the homologous antigen ΔN2mCHO(Q105N) with greater preference than sera from ΔN2mCHO(Q105N) QuilA immunized animals, demonstrating the modulation of antibody fine specificity by these two adjuvants. We also found that sera from ΔN2mCHO(Q105N)_QuilA immunized animals bound best to a resurfaced HIV gp120 core protein on which non-CD4bs epitopes are substituted with non-HIV residues, suggesting that these sera contain a relatively larger fraction of CD4bs-specific antibodies. Consistent with these data, inhibition assays revealed epitope overlap with the binding sites of the CD4bs-specific antibodies b12, b13 and VRC03. Unexpectedly, these sera did not exhibit significant neutralizing activity against a set of HIV-1 primary strains. Our results show that although formulating mutant ΔN2mCHO(Q105N) with Quil A promotes the elicitation of CD4bs-directed antibodies relative to wild-type gp120, tweaking of the immunization regimen is needed to yield robust, CD4bs-focused NAbs.
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影响因子：
4.4
作者：
Dosenovic, Pia;Chakrabarti, Bimal;Hedestam, Gunilla B. Karlsson
通讯作者：
Hedestam, Gunilla B. Karlsson
影响因子：
3.7
作者：
Guenaga J;Dosenovic P;Ofek G;Baker D;Schief WR;Kwong PD;Karlsson Hedestam GB;Wyatt RT
通讯作者：
Wyatt RT
影响因子：
3.7
作者：
Corti D;Langedijk JP;Hinz A;Seaman MS;Vanzetta F;Fernandez-Rodriguez BM;Silacci C;Pinna D;Jarrossay D;Balla-Jhagjhoorsingh S;Willems B;Zekveld MJ;Dreja H;O'Sullivan E;Pade C;Orkin C;Jeffs SA;Montefiori DC;Davis D;Weissenhorn W;McKnight A;Heeney JL;Sallusto F;Sattentau QJ;Weiss RA;Lanzavecchia A
通讯作者：
Lanzavecchia A
DOI：
10.1126/science.1175868
发表时间：
2009-11-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen L;Kwon YD;Zhou T;Wu X;O'Dell S;Cavacini L;Hessell AJ;Pancera M;Tang M;Xu L;Yang ZY;Zhang MY;Arthos J;Burton DR;Dimitrov DS;Nabel GJ;Posner MR;Sodroski J;Wyatt R;Mascola JR;Kwong PD
通讯作者：
Kwong PD
影响因子：
4.8
作者：
Bhattacharyya, Sanchari;Rajan, Roshan Elizabeth;Varadarajan, Raghavan
通讯作者：
Varadarajan, Raghavan