Division of Vaccine Research of Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States.
Front Immunol. 2019 Apr 2;10:677. doi: 10.3389/fimmu.2019.00677. eCollection 2019.
Recent clinical trials and studies using nonhuman primates (NHPs) suggest that antibody-mediated protection against HIV-1 will require α-HIV envelope humoral immunity beyond direct neutralization to include Fc-receptor (FcR) mediated effector functions such as antibody-dependent cellular cytotoxicity (ADCC). There is also strong evidence indicating that the most potent ADCC response in humans is directed toward transitional non-neutralizing epitopes associated with the gp41-interactive face of gp120, particularly those within the first and second constant (C1-C2) region (A32-like epitopes). These epitopes were shown to be major targets of ADCC responses during natural infection and have been implicated in vaccine-induced protective immunity. Here we describe the immunogenicity of ID2, an immunogen consisting of the inner domain of the clade A/E 93TH057 HIV-1 gp120 expressed independently of the outer domain (OD) and stabilized in the CD4-bound conformation to harbor conformational A32 region epitopes within a minimal structural unit of HIV-1 Env. ID2 induced A32-specific antibody responses in BALB/c mice when injected alone or in the presence of the adjuvants Alum or GLA-SE. Low α-ID2 titers were detected in mice immunized with ID2 alone whereas robust responses were observed with ID2 plus adjuvant, with the greatest ID2 and A32-specific titers observed in the GLA-SE group. Only sera from groups immunized in the presence of GLA-SE were capable of mediating significant ADCC using NKr cells sensitized with recombinant BaL gp120 as targets and human PBMCs as effectors. A neutralization response to a tier 2 virus was not observed. Altogether, our studies demonstrate that ID2 is highly immunogenic and elicits A32-specific ADCC responses in an animal host. The ID2 immunogen has significant translational value as it can be used in challenge studies to evaluate the role of non-neutralizing antibodies directed at the A32 subregion in HIV-1 protection.
最近使用非人类灵长类动物（NHPs）的临床试验和研究表明，针对 HIV-1 的抗体介导的保护作用除了直接中和作用外，还需要 α-HIV 包膜体液免疫，包括 Fc 受体（FcR）介导的效应功能，如抗体依赖性细胞毒性（ADCC）。也有强有力的证据表明，人类最强的 ADCC 反应是针对 gp41 相互作用面的 gp120 上的过渡性非中和表位，特别是第一和第二恒定区（C1-C2）内的表位（A32 样表位）。这些表位是在自然感染期间 ADCC 反应的主要靶标，并且与疫苗诱导的保护性免疫有关。在这里，我们描述了 ID2 的免疫原性，ID2 是一种免疫原，由 A/E 93TH057 HIV-1 gp120 的内结构域组成，与外结构域（OD）独立表达，并在 CD4 结合构象中稳定，以在 HIV-1 Env 的最小结构单元中携带构象 A32 区表位。当单独注射或在佐剂 Alum 或 GLA-SE 存在下注射时，ID2 会在 BALB/c 小鼠中诱导 A32 特异性抗体反应。在单独免疫 ID2 的小鼠中检测到低水平的 α-ID2 滴度，而在 ID2 加佐剂的情况下观察到强烈的反应，在 GLA-SE 组中观察到最大的 ID2 和 A32 特异性滴度。只有在 GLA-SE 存在下免疫的组的血清才能介导使用用重组 BaL gp120 作为靶标和人 PBMC 作为效应物的 NKr 细胞的显著 ADCC。未观察到针对 2 级病毒的中和反应。总之，我们的研究表明，ID2 具有高度的免疫原性，并在动物宿主中诱导 A32 特异性 ADCC 反应。ID2 免疫原具有重要的转化价值，因为它可用于挑战研究，以评估针对 HIV-1 保护的 A32 亚区的非中和抗体的作用。
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