Differences in the Binding Affinity of an HIV-1 V2 Apex-Specific Antibody for the SIVsmm/mac Envelope Glycoprotein Uncouple Antibody-Dependent Cellular Cytotoxicity from Neutralization.
Differences in the Binding Affinity of an HIV-1 V2 Apex-Specific Antibody for the SIVsmm/mac Envelope Glycoprotein Uncouple Antibody-Dependent Cellular Cytotoxicity from Neutralization.
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HIV-1 V2 Apex 特异性抗体与 SIVsmm/mac 包膜糖蛋白的结合亲和力的差异将抗体依赖性细胞毒性与中和作用解耦。
DOI：
10.1128/mbio.01255-19
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发表时间：
2019
期刊：
影响因子：
6.4
通讯作者：
Evans,DavidT
中科院分区：
文献类型：
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作者：
vonBredow,Benjamin;Andrabi,Raiees;Grunst,Michael;Grandea3rd,AndresG;Le,Khoa;Song,Ge;Berndsen,ZacharyT;Porter,Katelyn;Pallesen,Jesper;Ward,AndrewB;Burton,DennisR;Evans,DavidT
人类免疫缺陷病毒1型（HIV-1）和类人猿免疫缺陷病毒（SIVsmm/maclineage）由于其独立的进化起源是猿和旧大陆猴，它们在系统发育和抗原性上表达不同的包膜糖蛋白。因此，HIV-1 Env特异性抗体通常不会与SIVsmm/ macs分离株的Env蛋白发生交叉反应。在这里，我们发现PGT145是一种广泛中和HIV-1 Env V2顶点的四元表位的抗体，通过抗体依赖性细胞毒性（ADCC）指导SIVsmm/mac感染细胞的裂解，但不中和SIVsmm/mac的传染性。HIV-1 Env中与PGT145表位对应的SIVmac239 V2环上的氨基酸替换调节了对该抗体的敏感性。然而，在保守的n链糖基化位点（N171Q）上的取代消除了对ADCC的敏感性，而在该区域（K180S）上的赖氨酸到丝氨酸的取代增加了ADCC，使病毒对中和敏感。这些功能上的差异与PGT145与病毒感染细胞表面的Env和可溶性Env三聚体结合的亲和力增加有关。据我们所知，这是HIV-1 Env特异性抗体与SIVsmm/macEnv交叉反应的第一个实例，并说明了Env抗体结合亲和力的差异如何区分对ADCC的敏感性和中和。在这里，我们发现PGT145，一种有效的广泛中和HIV-1的抗体，通过抗体依赖的细胞毒性指导SIV感染细胞的裂解，但不能中和SIV的传染性。这是HIV-1 env特异性抗体与SIVsmm/macEnv交叉反应的第一个实例，表明抗体结合亲和力可以区分对ADCC的敏感性和中和性。
As a consequence of their independent evolutionary origins in apes and Old World monkeys, human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency viruses of the SIVsmm/maclineage express phylogenetically and antigenically distinct envelope glycoproteins. Thus, HIV-1 Env-specific antibodies do not typically cross-react with the Env proteins of SIVsmm/macisolates. Here we show that PGT145, a broadly neutralizing antibody to a quaternary epitope at the V2 apex of HIV-1 Env, directs the lysis of SIVsmm/mac-infected cells by antibody-dependent cellular cytotoxicity (ADCC) but does not neutralize SIVsmm/macinfectivity. Amino acid substitutions in the V2 loop of SIVmac239 corresponding to the epitope for PGT145 in HIV-1 Env modulate sensitivity to this antibody. Whereas a substitution in a conserved N-linked glycosylation site (N171Q) eliminates sensitivity to ADCC, a lysine-to-serine substitution in this region (K180S) increases ADCC and renders the virus susceptible to neutralization. These differences in function correlate with an increase in the affinity of PGT145 binding to Env on the surface of virus-infected cells and to soluble Env trimers. To our knowledge, this represents the first instance of an HIV-1 Env-specific antibody that cross-reacts with SIVsmm/macEnv and illustrates how differences in antibody binding affinity for Env can differentiate sensitivity to ADCC from neutralization.IMPORTANCEHere we show that PGT145, a potent broadly neutralizing antibody to HIV-1, directs the lysis of SIV-infected cells by antibody-dependent cellular cytotoxicity but does not neutralize SIV infectivity. This represents the first instance of cross-reactivity of an HIV-1 Env-specific antibody with SIVsmm/macEnv and reveals that antibody binding affinity can differentiate sensitivity to ADCC from neutralization.