Infectious Disease Division, Department of Medicine of Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
Division of Vaccine Research of Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
mBio. 2020 Jun 30;11(3):e00208-20. doi: 10.1128/mBio.00208-20.
Antibodies (Abs) specific for CD4-induced envelope (Env) epitopes within constant region 1 and 2 (C1/C2) were induced in the RV144 vaccine trial, where antibody-dependent cellular cytotoxicity (ADCC) correlated with reduced risk of HIV-1 infection. We combined X-ray crystallography and fluorescence resonance energy transfer-fluorescence correlation spectroscopy to describe the molecular basis for epitopes of seven RV144 Abs and compared them to A32 and C11, C1/C2 Abs induced in HIV infection. Our data indicate that most vaccine Abs recognize the 7-stranded β-sandwich of gp120, a unique hybrid epitope bridging A32 and C11 binding sites. Although primarily directed at the 7-stranded β-sandwich, some accommodate the gp120 N terminus in C11-bound 8-stranded conformation and therefore recognize a broader range of CD4-triggered Env conformations. Our data also suggest that Abs of RV144 and RV305, the RV144 follow-up study, although likely initially induced by the ALVAC-HIV prime encoding full-length gp120, matured through boosting with truncated AIDSVAX gp120 variants. Antibody-dependent cellular cytotoxicity (ADCC) correlated with a reduced risk of infection from HIV-1 in the RV144 vaccine trial, the only HIV-1 vaccine trial to date to show any efficacy. Antibodies specific for CD4-induced envelope (Env) epitopes within constant region 1 and 2 (cluster A region) were induced in the RV144 trial and their ADCC activities were implicated in the vaccine efficacy. We present structural analyses of the antigen epitope targets of several RV144 antibodies specific for this region and C11, an antibody induced in natural infection, to show what the differences are in epitope specificities, mechanism of antigen recognition, and ADCC activities of antibodies induced by vaccination and during the course of HIV infection. Our data suggest that the truncated AIDSVAX gp120 variants used in the boost of the RV144 regimen may have shaped the vaccine response to this region, which could also have contributed to vaccine efficacy.
在 RV144 疫苗试验中诱导了针对 CD4 诱导的包膜 (Env) 恒定区 1 和 2 (C1/C2) 内表位的抗体 (Abs)，其中抗体依赖的细胞细胞毒性 (ADCC) 与 HIV-1 感染风险降低相关。我们结合 X 射线晶体学和荧光共振能量转移-荧光相关光谱法来描述七个 RV144 Abs 的表位的分子基础，并将其与 HIV 感染中诱导的 A32 和 C11、C1/C2 Abs 进行比较。我们的数据表明，大多数疫苗 Abs 识别 gp120 的 7 股 β-三明治，这是一种独特的杂交表位，连接 A32 和 C11 结合位点。尽管主要针对 7 股 β-三明治，但有些 Abs 可以适应 C11 结合的 8 股构象中的 gp120 N 末端，因此可以识别更广泛的 CD4 触发的 Env 构象。我们的数据还表明，尽管 RV144 和 RV305（RV144 的后续研究）的 Abs 可能最初是由编码全长 gp120 的 ALVAC-HIV 引发产生的，但通过用截短的 AIDSVAX gp120 变体进行增强，它们已经成熟。在 RV144 疫苗试验中，抗体依赖的细胞细胞毒性 (ADCC) 与 HIV-1 感染风险降低相关，这是迄今为止唯一显示出任何疗效的 HIV-1 疫苗试验。在 RV144 试验中诱导了针对恒定区 1 和 2（簇 A 区）内 CD4 诱导的包膜 (Env) 表位的特异性抗体，并且其 ADCC 活性与疫苗的疗效有关。我们介绍了针对该区域和 C11 的几种 RV144 抗体的抗原表位目标的结构分析，C11 是在自然感染中诱导的抗体，以显示疫苗和 HIV 感染过程中诱导的抗体的表位特异性、抗原识别机制和 ADCC 活性的差异。我们的数据表明，RV144 方案增强中使用的截短的 AIDSVAX gp120 变体可能影响了对该区域的疫苗反应，这也可能有助于疫苗的疗效。
