Tomescu Costin, Tebas Pablo, Montaner Luis J
HIV Immunopathogenesis Laboratory, The Wistar Institute
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
AIDS. 2017 Mar 13;31(5):613-622. doi: 10.1097/QAD.0000000000001380.
We have previously shown that IFN-α stimulation augments direct natural killer (NK) cell lysis of autologous CD4 primary T cells infected with certain HIV-1 isolates based upon major histocompatibility complex class 1 (MHC-1) downregulation capacity. Here, we investigated if antibody-dependent cellular cytotoxicity (ADCC) could trigger lysis of HIV-1 isolates that were resistant to direct NK lysis and if IFN-α prestimulation of NK cells could further enhance ADCC.
Using broadly neutralizing monoclonal antibodies against gp120 (VRC01 or PGV04) or plasma from HIV-1-infected patients (ART-suppressed or elite controller) to trigger ADCC, we measured NK cell chromium release cytotoxicity against HIV-1-infected autologous CD4 primary T cells and NK cell CD107a degranulation against gp120-coated CD4 T cells. Total or NK-depleted peripheral blood mononuclear cells were used as effectors in the presence or absence of IFN-α prestimulation.
Plasma from HIV-1-infected patients and monoclonal antibodies against gp120 could trigger NK-dependent ADCC lysis of viral isolates that were resistant to direct NK cell lysis following IFN-α stimulation. In contrast, viral isolates that exhibited potent MHC-I downregulation capacity could be lysed by NK cells through either IFN-α stimulated direct cytotoxicity or through ADCC. When utilized in combination, IFN-α prestimulation significantly augmented ADCC lysis of HIV-1-infected target cells and increased NK cell CD107a degranulation against gp120-coated ADCC targets (P < 0.05, n = 6).
HIV-1 isolates with lower MHC-I downregulation capacity are resistant to direct lysis following IFN-α stimulation but retain sensitivity to ADCC. IFN-α prestimulation can significantly increase NK-mediated clearance of HIV-1-infected target cells by both ADCC and/or direct cytotoxicity depending on MHC downregulation status.
我们之前已经表明，基于主要组织相容性复合体1类（MHC-1）下调能力，干扰素-α（IFN-α）刺激可增强自然杀伤（NK）细胞对感染某些HIV-1分离株的自体CD4原代T细胞的直接杀伤作用。在此，我们研究了抗体依赖性细胞毒性（ADCC）是否能触发对直接NK杀伤具有抗性的HIV-1分离株的杀伤，以及NK细胞的IFN-α预刺激是否能进一步增强ADCC。
使用针对gp120的广泛中和单克隆抗体（VRC01或PGV04）或来自HIV-1感染患者（接受抗逆转录病毒治疗抑制或精英控制者）的血浆来触发ADCC，我们测量了NK细胞对感染HIV-1的自体CD4原代T细胞的铬释放细胞毒性以及NK细胞对gp120包被的CD4 T细胞的CD107a脱颗粒情况。在有或没有IFN-α预刺激的情况下，使用总外周血单核细胞或NK细胞耗竭的外周血单核细胞作为效应细胞。
来自HIV-1感染患者的血浆和针对gp120的单克隆抗体可触发NK依赖性ADCC对IFN-α刺激后对直接NK细胞杀伤具有抗性的病毒分离株的杀伤作用。相比之下，表现出强大MHC-I下调能力的病毒分离株可被NK细胞通过IFN-α刺激的直接细胞毒性或通过ADCC杀伤。当联合使用时，IFN-α预刺激显著增强了对感染HIV-1的靶细胞的ADCC杀伤作用，并增加了NK细胞对gp120包被的ADCC靶标的CD107a脱颗粒（P<0.05，n = 6）。
MHC-I下调能力较低的HIV-1分离株在IFN-α刺激后对直接杀伤具有抗性，但对ADCC仍保持敏感性。IFN-α预刺激可根据MHC下调状态通过ADCC和/或直接细胞毒性显著增加NK介导的对感染HIV-1的靶细胞的清除。
