A Strategy for Eliciting Antibodies against Cryptic, Conserved, Conformationally Dependent Epitopes of HIV Envelope Glycoprotein
A Strategy for Eliciting Antibodies against Cryptic, Conserved, Conformationally Dependent Epitopes of HIV Envelope Glycoprotein
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DOI：
10.1371/journal.pone.0008555
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发表时间：
2010-01-05
期刊：
影响因子：
3.7
通讯作者：
Valentine, Fred T.
中科院分区：
文献类型：
--
作者：
Kelker, Hanna C.;Itri, Vincenza R.;Valentine, Fred T.
背景：需要新的策略来诱导针对HIV包膜糖蛋白gp 120的广泛中和抗体。实验证据表明，在体外具有广泛中和性的抗体组合可以保护非人灵长类动物免受HIV的攻击，并且通过B细胞的库采样和通过来自一些长期疾病患者的抗血清的分级分离，已经选择了少量这些抗体。然而，迄今为止，用于鉴定保守表位、引发针对这些表位的抗体以及确定这些表位是否可被抗体接近的其他策略还没有成功。定义额外的保守的、可接近的表位（针对这些表位可以引发抗体）将增加一些表位可能成为广泛中和抗体的靶标的概率。我们假设存在gp 120的另外的隐蔽表位，针对这些表位的中和抗体可能被引发，即使这些抗体不是由gp 120引发的，并且这些表位中的许多表位可以被抗体接近，如果它们形成的话。我们证明了一种策略，用于诱导小鼠对选定的隐蔽，构象依赖的保守表位的gp 120的抗体免疫与多个相同的拷贝的共价连接的肽（MCP）。这已经用代表gp 120的3个不同结构域的MCP实现。我们发现，gp 120上的一些隐蔽表位可被引发的抗体接近，而CD 4结合区中的一些表位不可接近。这些抗体以相对高的亲和力与gp 120结合，并与感染细胞表面的寡聚gp 120结合。结论/意义：用由HIV gp 120的选定肽组成的MCP免疫能够激发针对gp 120的保守、构象依赖性表位的抗体，这些表位在以gp 120形式呈现时没有免疫原性。其中一些隐蔽表位可以被引发的抗体所接近。
Background: Novel strategies are needed for the elicitation of broadly neutralizing antibodies to the HIV envelope glycoprotein, gp120. Experimental evidence suggests that combinations of antibodies that are broadly neutralizing in vitro may protect against challenge with HIV in nonhuman primates, and a small number of these antibodies have been selected by repertoire sampling of B cells and by the fractionation of antiserum from some patients with prolonged disease. Yet no additional strategies for identifying conserved epitopes, eliciting antibodies to these epitopes, and determining whether these epitopes are accessible to antibodies have been successful to date. The defining of additional conserved, accessible epitopes against which one can elicit antibodies will increase the probability that some may be the targets of broadly neutralizing antibodies.Methodology/Principal Findings: We postulate that additional cryptic epitopes of gp120 are present, against which neutralizing antibodies might be elicited even though these antibodies are not elicited by gp120, and that many of these epitopes may be accessible to antibodies should they be formed. We demonstrate a strategy for eliciting antibodies in mice against selected cryptic, conformationally dependent conserved epitopes of gp120 by immunizing with multiple identical copies of covalently linked peptides (MCPs). This has been achieved with MCPs representing 3 different domains of gp120. We show that some cryptic epitopes on gp120 are accessible to the elicited antibodies, and some epitopes in the CD4 binding region are not accessible. The antibodies bind to gp120 with relatively high affinity, and bind to oligomeric gp120 on the surface of infected cells.Conclusions/Significance: Immunization with MCPs comprised of selected peptides of HIV gp120 is able to elicit antibodies against conserved, conformationally dependent epitopes of gp120 that are not immunogenic when presented as gp120. Some of these cryptic epitopes are accessible to the elicited antibodies.