Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
J Virol. 2014 Jul;88(14):7715-26. doi: 10.1128/JVI.00156-14. Epub 2014 May 7.
The RV144 ALVAC/AIDSVax HIV-1 vaccine clinical trial showed an estimated vaccine efficacy of 31.2%. Viral genetic analysis identified a vaccine-induced site of immune pressure in the HIV-1 envelope (Env) variable region 2 (V2) focused on residue 169, which is included in the epitope recognized by vaccinee-derived V2 monoclonal antibodies. The ALVAC/AIDSVax vaccine induced antibody-dependent cellular cytotoxicity (ADCC) against the Env V2 and constant 1 (C1) regions. In the presence of low IgA Env antibody levels, plasma levels of ADCC activity correlated with lower risk of infection. In this study, we demonstrate that C1 and V2 monoclonal antibodies isolated from RV144 vaccinees synergized for neutralization, infectious virus capture, and ADCC. Importantly, synergy increased the HIV-1 ADCC activity of V2 monoclonal antibody CH58 at concentrations similar to that observed in plasma of RV144 vaccinees. These findings raise the hypothesis that synergy among vaccine-induced antibodies with different epitope specificities contributes to HIV-1 antiviral antibody responses and is important to induce for reduction in the risk of HIV-1 transmission. Importance: The Thai RV144 ALVAC/AIDSVax prime-boost vaccine efficacy trial represents the only example of HIV-1 vaccine efficacy in humans to date. Studies aimed at identifying immune correlates involved in the modest vaccine-mediated protection identified HIV-1 envelope (Env) variable region 2-binding antibodies as inversely correlated with infection risk, and genetic analysis identified a site of immune pressure within the region recognized by these antibodies. Despite this evidence, the antiviral mechanisms by which variable region 2-specific antibodies may have contributed to lower rates of infection remain unclear. In this study, we demonstrate that vaccine-induced HIV-1 envelope variable region 2 and constant region 1 antibodies synergize for recognition of virus-infected cells, infectious virion capture, virus neutralization, and antibody-dependent cellular cytotoxicity. This is a major step in understanding how these types of antibodies may have cooperatively contributed to reducing infection risk and should be considered in the context of prospective vaccine design.
RV144 ALVAC/AIDSVax HIV-1 疫苗临床试验显示，疫苗的估计效力为 31.2%。病毒遗传分析鉴定出 HIV-1 包膜（Env）可变区 2（V2）中受疫苗诱导产生免疫压力的部位，该部位集中在残基 169 上，该残基包含在疫苗接种者衍生的 V2 单克隆抗体识别的表位中。ALVAC/AIDSVax 疫苗诱导针对 Env V2 和恒定区 1（C1）的抗体依赖细胞毒性（ADCC）。在 IgA Env 抗体水平较低的情况下，ADCC 活性的血浆水平与较低的感染风险相关。在这项研究中，我们证明了从 RV144 疫苗接种者中分离出的 C1 和 V2 单克隆抗体在中和、感染性病毒捕获和 ADCC 方面具有协同作用。重要的是，协同作用增加了 V2 单克隆抗体 CH58 的 HIV-1 ADCC 活性，其浓度与 RV144 疫苗接种者血浆中观察到的浓度相似。这些发现提出了一个假设，即具有不同表位特异性的疫苗诱导抗体之间的协同作用有助于 HIV-1 抗病毒抗体反应，对于降低 HIV-1 传播风险很重要。重要意义：泰国 RV144 ALVAC/AIDSVax 疫苗的初免-加强免疫有效性试验是迄今为止人类 HIV-1 疫苗有效性的唯一例子。旨在确定与适度疫苗介导保护相关的免疫相关性的研究将 HIV-1 包膜（Env）可变区 2 结合抗体鉴定为与感染风险呈负相关，遗传分析鉴定出该抗体识别的区域内存在免疫压力部位。尽管有这些证据，但可变区 2 特异性抗体可能有助于降低感染率的抗病毒机制仍不清楚。在这项研究中，我们证明了疫苗诱导的 HIV-1 包膜可变区 2 和恒定区 1 抗体协同作用，以识别感染病毒的细胞、感染性病毒粒子的捕获、病毒中和和抗体依赖性细胞毒性。这是理解这些类型的抗体如何可能协同作用降低感染风险的重要一步，应该在前瞻性疫苗设计的背景下进行考虑。
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