Department of Medicine, New York University School of Medicine, New York, New York, United States of America.
PLoS One. 2010 Jan 5;5(1):e8555. doi: 10.1371/journal.pone.0008555.
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.
需要新的策略来诱导针对 HIV 包膜糖蛋白 gp120 的广泛中和抗体。实验证据表明，体外广泛中和的抗体组合可能在非人类灵长类动物中预防 HIV 感染，并且已经从一些疾病持续时间较长的患者的 B 细胞 repertoire 取样和抗血清的分离中选择了少数这些抗体。然而，到目前为止，还没有其他用于鉴定保守表位、诱导针对这些表位的抗体以及确定这些表位是否可被抗体识别的策略是成功的。定义更多针对可诱导抗体的保守、可及的表位将增加某些表位可能成为广泛中和抗体靶标的可能性。
方法/主要发现：我们假设 gp120 存在额外的隐蔽表位，针对这些表位可以诱导中和抗体，尽管这些抗体不能被 gp120 诱导产生，而且如果形成这些表位，许多表位可能对抗体是可及的。我们通过用多个共价连接的肽（MCP）免疫来证明在小鼠中针对 gp120 的选定隐蔽、构象依赖性保守表位诱导抗体的策略。这已经通过代表 gp120 的 3 个不同结构域的 MCP 来实现。我们表明，gp120 上的一些隐蔽表位可被诱导的抗体识别，而 CD4 结合区中的一些表位不可识别。这些抗体与 gp120 具有相对高的亲和力，并与感染细胞表面的寡聚 gp120 结合。
结论/意义：用由 HIV gp120 的选定肽组成的 MCP 免疫能够诱导针对 gp120 的保守、构象依赖性表位的抗体，当作为 gp120 呈现时这些表位没有免疫原性。这些隐蔽表位中的一些是可被诱导的抗体识别的。
