大多数针对HIV-1包膜糖蛋白(Env)的天然抗体是非中和(nnAbs),因为它们无法识别Env三聚体的天然“封闭”构象。然而,研究表明,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识别仅在Env与CD4相互作用和暴露通常封闭在封闭三聚体中的表位之后才变得可接近的表位。HIV-1通过下调受感染细胞表面的CD4来限制这种脆弱性,从而防止Env过早接触CD4。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。CD4innAbs有两个家族,称为抗簇A和抗CoRBSAbs,已知在CD4mc存在下介导ADCC。这里,我们进行了Fab竞争实验,发现抗gp41簇I抗体占HIV感染者(PLWH)血浆ADCC活性的主要部分.此外,在存在强效二氢吲哚啉CD4mc的情况下,将gp41簇I抗体添加到簇A和CoRBS抗体中,极大地增强了ADCC介导的细胞杀伤,CJF-III-288。这种混合物的性能优于广泛的中和抗体,甚至显示出对HIV-1感染的单核细胞衍生的巨噬细胞的活性。因此,结合具有不同特异性的CD4i抗体可实现最大的ADCC活性,这可能是有用的艾滋病毒治疗策略。重要意义消除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水平以下,它不能消除形成病毒库的潜伏感染细胞。这里,我们开发了一种针对高度保守的Env区的非中和抗体混合物,并将其与强效的二氢吲哚酮CD4mc相结合.这种组合对HIV-1感染的原代CD4+T细胞以及单核细胞衍生的巨噬细胞表现出有效的ADCC活性。表明其在减少病毒库大小方面的潜在效用。
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.