Structural Definition of an Antibody-Dependent Cellular Cytotoxicity Response Implicated in Reduced Risk for HIV-1 Infection
Structural Definition of an Antibody-Dependent Cellular Cytotoxicity Response Implicated in Reduced Risk for HIV-1 Infection
复制标题
DOI：
10.1128/jvi.02194-14
复制
发表时间：
2014-11-01
影响因子：
5.4
通讯作者：
Pazgier, Marzena
中科院分区：
文献类型：
--
作者：
Acharya, Priyamvada;Tolbert, William D.;Pazgier, Marzena
RV144疫苗试验暗示gp120 C1区的表位（a32样表位）是潜在保护性抗体依赖性细胞毒性（ADCC）反应的靶标。a32样表位具有高度的免疫原性，因为感染或接种的个体经常产生针对这些决定因子的特异性抗体。然而，通过酶联免疫吸附试验（ELISA）测定的针对这些表位的抗体滴度并不总是与保护相关。在这里，我们报道了cd4稳定的gp120核心与两种非中和的a32样单克隆抗体（N5-i5和2.2c）的Fab片段络合的晶体结构，这两种单克隆抗体竞争抗原结合，具有相似的抗原结合亲和力，但表现出75倍的ADCC效力差异。我们发现这些单克隆抗体识别gp120内部结构域的移动层1和2形成的重叠表位，包括C1和C2区域，但通过并列的V-H和V-L接触面以不同角度结合gp120。结构和免疫学数据的比较进一步表明，抗体在结合抗原上的定向和在靶细胞上形成多价抗原-抗体复合物的能力是ADCC效价的关键决定因素，后者的影响更大。这些研究提供了在RV144中作为保护性抗体靶点的a32样表位的原子水平定义。此外，这些研究表明，表位结构和抗体结合方式可以显著影响fc介导的效应物对抗HIV-1的效力。这些结果为理解、完善和改善HIV疫苗试验的结果提供了关键见解，在这些试验中，相关的免疫反应是由a32样诱导反应促进的。HIV-1 Env是感染期间引发的抗体的主要靶标。尽管少数受感染个体会引发广泛中和的抗体，但大部分体液反应由不能中和或广度有限的抗体组成，但可能通过Fc受体依赖的过程（如抗体依赖的细胞毒性（ADCC））产生保护作用。了解这些非中和反应是阐明针对HIV-1感染的免疫反应的完整谱的一个重要方面。在本报告中，我们首次在原子水平上定义了HIV-1 gp120 n端区域非中和性cd4诱导的表位（a32样表位）。此外，我们的研究指出，即使涉及到大量重叠的表位，精确的表位靶向和抗体附着模式在ADCC应答中也起着主导作用。这些信息为了解fc介导的HIV-1抗体功能的机制提供了关键见解，并将帮助我们了解基于体液免疫的疫苗试验的结果。
The RV144 vaccine trial implicated epitopes in the C1 region of gp120 (A32-like epitopes) as targets of potentially protective antibody-dependent cellular cytotoxicity (ADCC) responses. A32-like epitopes are highly immunogenic, as infected or vaccinated individuals frequently produce antibodies specific for these determinants. Antibody titers, as measured by enzyme-linked immunosorbent assay (ELISA) against these epitopes, however, do not consistently correlate with protection. Here, we report crystal structures of CD4-stabilized gp120 cores complexed with the Fab fragments of two nonneutralizing, A32-like monoclonal antibodies (MAbs), N5-i5 and 2.2c, that compete for antigen binding and have similar antigen-binding affinities yet exhibit a 75-fold difference in ADCC potency. We find that these MAbs recognize overlapping epitopes formed by mobile layers 1 and 2 of the gp120 inner domain, including the C1 and C2 regions, but bind gp120 at different angles via juxtaposed V-H and V-L contact surfaces. A comparison of structural and immunological data further showed that antibody orientation on bound antigen and the capacity to form multivalent antigen-antibody complexes on target cells were key determinants of ADCC potency, with the latter process having the greater impact. These studies provide atomic-level definition of A32-like epitopes implicated as targets of protective antibodies in RV144. Moreover, these studies establish that epitope structure and mode of antibody binding can dramatically affect the potency of Fc-mediated effector function against HIV-1. These results provide key insights for understanding, refining, and improving the outcome of HIV vaccine trials, in which relevant immune responses are facilitated by A32-like elicited responses.IMPORTANCE HIV-1 Env is a primary target for antibodies elicited during infection. Although a small number of infected individuals elicit broadly neutralizing antibodies, the bulk of the humoral response consists of antibodies that do not neutralize or do so with limited breadth but may effect protection through Fc receptor-dependent processes, such as antibody-dependent cellular cytotoxicity (ADCC). Understanding these nonneutralizing responses is an important aspect of elucidating the complete spectrum of immune response against HIV-1 infection. With this report, we provide the first atomic-level definition of nonneutralizing CD4-induced epitopes in the N-terminal region of the HIV-1 gp120 (A32-like epitopes). Further, our studies point to the dominant role of precise epitope targeting and mode of antibody attachment in ADCC responses even when largely overlapping epitopes are involved. Such information provides key insights into the mechanisms of Fc-mediated function of antibodies to HIV-1 and will help us understand the outcome of vaccine trials based on humoral immunity.