Relationships between Neutralization, Binding, and ADCC of Broadly Neutralizing Antibodies against Reservoir HIV.
Relationships between Neutralization, Binding, and ADCC of Broadly Neutralizing Antibodies against Reservoir HIV.
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针对水库 HIV 的广泛中和抗体的中和、结合和 ADCC 之间的关系。
DOI：
10.1128/jvi.01808-20
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发表时间：
2020
影响因子：
5.4
通讯作者：
Jones,RBrad
中科院分区：
文献类型：
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作者：
Ren,Yanqin;Korom,Maria;Ward,AdamR;Truong,Ronald;Chan,Dora;Huang,Szu-Han;Kovacs,ColinM;Benko,Erika;Safrit,JeffreyT;Lee,John;Garbán,Hermes;Lynch,Rebecca;Jones,RBrad
HIV特异性抗体(Abs)可通过与重新激活的细胞结合并靶向抗体依赖的细胞介导的细胞毒(ADCC)(1，2)，从而有助于消除HIV宿主。广谱中和抗体(BNAbs)可能特别有效，它通过与ADCC一起对多种HIV毒株进行病毒中和(在未经治疗的猿人免疫缺陷病毒[SHIV]感染的背景下，中和而不是ADCC似乎主导了bNAb输注的抗病毒效果[3，4])。很少有研究评估bNAbs对水库衍生病毒的活性。感染的原代CD4T细胞的中和活性、ADCC功能和与病毒的结合之间的关系还没有得到全面的研究。在Ren等人之前发表的一项研究中(5)，我们测试了一组14个bNAbs对36个来自水库的病毒分离物的作用，表明广谱中和抗体对中和的敏感性通常与从潜伏病毒库中重新激活的一组B分支HIV病毒的感染细胞结合有关。我们最初的研究还使用9个bNAbs和两种类型的效应细胞(包括初级NK细胞和Hank细胞系)测试了2个病毒分离物的ADCC，并证明了与感染细胞结合的高度显著和直接相关(5)。在这里，我们应用相同的方法将这些结果扩展到所有36个病毒分离株和所有14个bNAbs的全部面板，使用Hank细胞作为体外检测的效应器。我们报告了用CD4结合位点(CD4bs)靶向的bNAbs以及V3糖链靶向的bNAbs PGT121和10-1074处理的感染细胞的相对广泛和中等效力的ADCC(图1)。V1/V2 bNAb PG9也表现出显著的ADCC活性，但对病毒分离株的覆盖率略低。其余的bNAbs，包括那些靶向膜近端外部区域(MPER)的bNAbs，对该病毒面板显示出稀少的ADCC活性(图1)。综合考虑所有bNAbs，我们观察到ADCC与感染细胞结合(图2A，Spearman‘s r0.49，P 0.0001)和中和80%抑制浓度(IC80)与ADCC(图3A，Spearman’s r0.46，P 0.0001)之间存在中等相关性。在单个bNAbs水平上，7/15显示ADCC与感染细胞结合显著相关(图2B)。尽管ADCC和中和之间总体上有显著的相关性，但只有10-1074Ab在单个bNAb水平上显示出显著的相关性(图3b，Spearman‘s r0.66，P 0.0001)，尽管其他几种bNAbs显示出趋势。按结合部位分组，每类抗体在中和和ADCC之间显示出显著的相关性，尽管这些抗体的范围从V3糖蛋白抗体的中等强度到MPER抗体的边缘(表1)。类似的渐变
HIV-specific antibodies (Abs) may contribute to the elimination of HIV reservoirs by binding to reactivated cells and targeting them for antibody-dependent cell-mediated cytotoxicity (ADCC)(1, 2). Broadly neutralizing antibodies (bNAbs) may be particularly efficacious, by mediating virus neutralization alongside ADCC for multiple HIV strains (in the context of untreated simian-human immunodeficiency virus [SHIV] infection, neutralization rather than ADCC appears to dominate the antiviral effect of bNAb infusion [3, 4]). Few studies have assessed the activities of bNAbs against reservoir-derived viruses. The relationships between neutralizing activity, ADCC function, and binding to reservoir virus in infected primary CD4 T cells have not been comprehensively studied. In a study previously published by Ren et al.(5), we tested a panel of 14 bNAbs against 36 reservoir-derived viral isolates, demonstrating that susceptibility to neutralization by broadly neutralizing antibodies generally correlated with infected-cell binding for a panel of clade B HIV reactivated from latent reservoirs.Our original study also tested ADCC with 2 viral isolates using 9 bNAbs and two types of effector cells, comprising primary NK cells and a haNK cell line, and demonstrated highly significant and direct correlations with infected-cell binding (5). Here, we applied the same methods to extend these results to all 36 viral isolates and the full panel of all 14 bNAbs, using haNK cells as effectors in in vitro assays. We report relatively broad and moderately potent ADCC of infected cells treated with CD4 binding site (CD4bs)-targeted bNAbs, as well as with the V3 glycan-targeted bNAbs PGT121 and 10-1074 (Fig. 1). The V1/V2 bNAb PG9 also exhibited substantial ADCC activity but with somewhat less coverage of viral isolates. The remaining bNAbs, including those targeting the membrane-proximal external region (MPER), exhibited sparse ADCC activity against this virus panel (Fig. 1). Considering all the bNAbs together, we observed moderate correlations between ADCC and infected-cell binding (Fig. 2A, Spearman’s r 0.49, P 0.0001) and between neutralization 80% inhibitory concentration (IC80) and ADCC (Fig. 3A, Spearman’s r 0.46, P 0.0001). At the level of individual bNAbs, 7/15 showed significant correlations between ADCC and infected-cell binding (Fig. 2B). Despite the overall significant correlation between ADCC and neutralization, only the 10-1074 Ab displayed a significant correlation on the individual bNAb level (Fig. 3B, Spearman’s r 0.66, P 0.0001), though several other bNAbs displayed trends. Grouped by binding site, each class of antibodies showed significant correlations between neutralization and ADCC, though these ranged from moderately strong for V3 glycan antibodies to marginal for MPER antibodies (Table 1). A similar gradient