Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.
PLoS Pathog. 2010 Aug 5;6(8):e1001028. doi: 10.1371/journal.ppat.1001028.
A protective vaccine against HIV-1 will likely require the elicitation of a broadly neutralizing antibody (bNAb) response. Although the development of an immunogen that elicits such antibodies remains elusive, a proportion of HIV-1 infected individuals evolve broadly neutralizing serum responses over time, demonstrating that the human immune system can recognize and generate NAbs to conserved epitopes on the virus. Understanding the specificities that mediate broad neutralization will provide insight into which epitopes should be targeted for immunogen design and aid in the isolation of broadly neutralizing monoclonal antibodies from these donors. Here, we have used a number of new and established technologies to map the bNAb specificities in the sera of 19 donors who exhibit among the most potent cross-clade serum neutralizing activities observed to date. The results suggest that broad and potent serum neutralization arises in most donors through a limited number of specificities (1-2 per donor). The major targets recognized are an epitope defined by the bNAbs PG9 and PG16 that is associated with conserved regions of the V1, V2 and V3 loops, an epitope overlapping the CD4 binding site and possibly the coreceptor binding site, an epitope sensitive to a loss of the glycan at N332 and distinct from that recognized by the bNAb 2G12 and an epitope sensitive to an I165A substitution. In approximately half of the donors, key N-linked glycans were critical for expression of the epitopes recognized by the bNAb specificities in the sera.
一种针对 HIV-1 的保护性疫苗可能需要引发广泛中和抗体(bNAb)反应。尽管开发能引发此类抗体的免疫原仍然难以捉摸,但随着时间的推移,一部分 HIV-1 感染个体逐渐产生广泛中和的血清反应,这表明人体免疫系统能够识别和产生针对病毒保守表位的 NAbs。了解介导广泛中和的特异性将为针对免疫原设计的哪些表位提供见解,并有助于从这些供体中分离广泛中和的单克隆抗体。在这里,我们使用了一些新的和已建立的技术来绘制 19 名供体血清中 bNAb 特异性,这些供体表现出迄今为止观察到的最有效的跨谱系血清中和活性。结果表明,大多数供体中广泛而有效的血清中和作用是通过少数几种特异性(每个供体 1-2 种)产生的。主要识别的靶标是由 bNAb PG9 和 PG16 定义的表位,该表位与 V1、V2 和 V3 环的保守区域相关,与 CD4 结合位点重叠,可能与核心受体结合位点重叠,一个对 N332 上糖基丢失敏感的表位,与 bNAb 2G12 识别的表位不同,以及一个对 I165A 取代敏感的表位。在大约一半的供体中,关键的 N 连接糖基对于血清中 bNAb 特异性识别的表位的表达至关重要。