Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109, United States of America; Molecular and Cellular Biology Program, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, United States of America; Medical Scientist Training Program, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, United States of America.
Department of Global Health, University of Washington, 325 9(th) Avenue, Seattle, WA 98104, United States of America; Department of Epidemiology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, United States of America.
EBioMedicine. 2019 Sep;47:257-268. doi: 10.1016/j.ebiom.2019.08.072.
Antibody-dependent cellular cytotoxicity (ADCC) has been associated with improved infant outcome in mother-to-child transmission (MTCT) of HIV-1. Epitopes of these ADCC-mediating antibodies remain unidentified. CD4-inducible (CD4i) epitopes on gp120 are common ADCC targets in natural infection and vaccination. We tested whether CD4i epitope-specific ADCC mediated by maternal antibodies or passively-acquired antibodies in infants is associated with reduced MTCT and improved infant survival.
We used variants of CD4i cluster A-specific antibodies, A32 and C11, and a cluster C-specific antibody, 17b, with mutations abolishing Fc-Fc receptor interactions as inhibitors in a competition rapid and fluorometric ADCC assay using gp120-coated CEM-nkr target cells with plasma from 51 non-transmitting and 21 transmitting breastfeeding mother-infant pairs.
Cluster A-specific ADCC was common. Individually, neither A32-like nor C11-like ADCC was statistically significantly associated with risk of MTCT or infected infant survival. In combination, total maternal cluster A-specific ADCC was statistically significantly associated with decreased infected infant survival in a log-rank test (p = 0·017). There was a non-significant association for infant passively-acquired total cluster A-specific ADCC and decreased infected infant survival (p = 0·14). Surprisingly, plasma ADCC was enhanced in the presence of the defective Fc 17b competitor. Defective Fc 17b competitor-mediated maternal ADCC enhancement was statistically significantly associated with reduced infected infant survival (p = 0·011). A non-significant association was observed for passively-acquired infant ADCC enhancement and decreased survival (p = 0·19).
These data suggest that ADCC targeting CD4i epitopes is not associated with protection against breast milk HIV transmission but is associated with decreased survival of infected infants. FUND: This study was funded by NIH grant R01AI076105 and NIH fellowship F30AI136636.
抗体依赖的细胞细胞毒性（ADCC）与 HIV-1 母婴传播（MTCT）中婴儿结局的改善有关。这些 ADCC 介导抗体的表位仍然未知。gp120 上的 CD4 诱导（CD4i）表位是自然感染和疫苗接种中常见的 ADCC 靶标。我们测试了母体抗体或婴儿被动获得的抗体介导的 CD4i 表位特异性 ADCC 是否与降低 MTCT 和改善婴儿生存相关。
我们使用 CD4i 簇 A 特异性抗体 A32 和 C11 的变体，以及一种簇 C 特异性抗体 17b，用突变消除 Fc-Fc 受体相互作用作为抑制剂，在使用 gp120 包被的 CEM-nkr 靶细胞的快速荧光 ADCC 测定中使用来自 51 名非传播和 21 名传播母乳喂养母婴对的血浆。
簇 A 特异性 ADCC 很常见。单独的 A32 样或 C11 样 ADCC 均与 MTCT 风险或感染婴儿的生存无统计学显著相关。在组合中，总母体簇 A 特异性 ADCC 与感染婴儿生存的对数秩检验呈统计学显著相关（p=0.017）。婴儿被动获得的总簇 A 特异性 ADCC 与感染婴儿生存的降低呈非显著相关（p=0.14）。令人惊讶的是，存在缺陷的 Fc 17b 竞争物时，血浆 ADCC 增强。缺陷的 Fc 17b 竞争物介导的母体 ADCC 增强与感染婴儿生存的降低呈统计学显著相关（p=0.011）。观察到被动获得的婴儿 ADCC 增强与生存降低之间存在非显著相关性（p=0.19）。
这些数据表明，针对 CD4i 表位的 ADCC 与预防母乳中 HIV 传播无关，但与感染婴儿的生存降低有关。资金：本研究由 NIH 授予 R01AI076105 资助，并由 NIH 奖学金 F30AI136636 资助。
