Centre de Recherche du CHUM, Montréal, Québec, Canada.
Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
J Virol. 2024 Oct 22;98(10):e0101624. doi: 10.1128/jvi.01016-24. Epub 2024 Sep 9.
The majority of naturally elicited antibodies against the HIV-1 envelope glycoproteins (Env) are non-neutralizing (nnAbs) because they are unable to recognize the Env trimer in its native "closed" conformation. Nevertheless, it has been shown that nnAbs have the potential to eliminate HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC) provided that Env is present on the cell surface in its "open" conformation. This is because most nnAbs recognize epitopes that become accessible only after Env interaction with CD4 and the exposure of epitopes that are normally occluded in the closed trimer. HIV-1 limits this vulnerability by downregulating CD4 from the surface of infected cells, thus preventing a premature encounter of Env with CD4. Small CD4-mimetics (CD4mc) sensitize HIV-1-infected cells to ADCC by opening the Env glycoprotein and exposing CD4-induced (CD4i) epitopes. There are two families of CD4i nnAbs, termed anti-cluster A and anti-CoRBS Abs, which are known to mediate ADCC in the presence of CD4mc. Here, we performed Fab competition experiments and found that anti-gp41 cluster I antibodies comprise a major fraction of the plasma ADCC activity in people living with HIV (PLWH). Moreover, addition of gp41 cluster I antibodies to cluster A and CoRBS antibodies greatly enhanced ADCC-mediated cell killing in the presence of a potent indoline CD4mc, CJF-III-288. This cocktail outperformed broadly neutralizing antibodies and even showed activity against HIV-1-infected monocyte-derived macrophages. Thus, combining CD4i antibodies with different specificities achieves maximal ADCC activity, which may be of utility in HIV cure strategies.IMPORTANCEThe elimination of HIV-1-infected cells remains an important medical goal. Although current antiretroviral therapy decreases viral loads below detection levels, it does not eliminate latently infected cells that form the viral reservoir. Here, we developed a cocktail of non-neutralizing antibodies targeting highly conserved Env regions and combined it with a potent indoline CD4mc. This combination exhibited potent ADCC activity against HIV-1-infected primary CD4 + T cells as well as monocyte-derived macrophages, suggesting its potential utility in decreasing the size of the viral reservoir.
大多数针对 HIV-1 包膜糖蛋白（Env）的天然诱导抗体是非中和性的（nnAbs），因为它们无法识别 Env 三聚体在其天然的“封闭”构象中的结构。然而，已经表明 nnAbs 具有通过抗体依赖性细胞毒性（ADCC）消除 HIV-1 感染细胞的潜力，前提是 Env 以其“开放”构象存在于细胞表面。这是因为大多数 nnAbs 识别的表位只有在 Env 与 CD4 相互作用并暴露通常在封闭三聚体中被掩盖的表位后才变得可及。HIV-1 通过从感染细胞表面下调 CD4 来限制这种脆弱性，从而防止 Env 与 CD4 过早相遇。小的 CD4 模拟物（CD4mc）通过打开 Env 糖蛋白并暴露 CD4 诱导的（CD4i）表位，使 HIV-1 感染的细胞对 ADCC 敏感。有两种 CD4i nnAb 家族，称为抗簇 A 和抗 CoRBS Abs，已知在存在 CD4mc 的情况下介导 ADCC。在这里，我们进行了 Fab 竞争实验，发现 gp41 簇 I 抗体构成了 HIV 感染者（PLWH）血浆 ADCC 活性的主要部分。此外，在存在有效的吲哚啉 CD4mc CJF-III-288 的情况下，向簇 A 和 CoRBS 抗体中添加 gp41 簇 I 抗体大大增强了 ADCC 介导的细胞杀伤作用。这种鸡尾酒的效果优于广泛中和抗体，甚至对感染 HIV-1 的单核细胞衍生的巨噬细胞显示出活性。因此，结合具有不同特异性的 CD4i 抗体可实现最大的 ADCC 活性，这可能对 HIV 治愈策略有用。
重要性
消除 HIV-1 感染的细胞仍然是一个重要的医学目标。尽管目前的抗逆转录病毒疗法将病毒载量降低到检测不到的水平，但它并不能消除形成病毒储存库的潜伏感染细胞。在这里，我们开发了一种针对高度保守的 Env 区域的非中和抗体鸡尾酒，并将其与一种有效的吲哚啉 CD4mc 结合。这种组合对 HIV-1 感染的原代 CD4+T 细胞和单核细胞衍生的巨噬细胞表现出有效的 ADCC 活性，表明其在减小病毒储存库方面具有潜在的用途。
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