Tay Matthew Zirui, Liu Pinghuang, Williams LaTonya D, McRaven Michael D, Sawant Sheetal, Gurley Thaddeus C, Xu Thomas T, Dennison S Moses, Liao Hua-Xin, Chenine Agnès-Laurence, Alam S Munir, Moody M Anthony, Hope Thomas J, Haynes Barton F, Tomaras Georgia D
Duke Human Vaccine Institute, Duke University, Durham, North Carolina, United States of America.
Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, United States of America.
PLoS Pathog. 2016 Aug 31;12(8):e1005817. doi: 10.1371/journal.ppat.1005817. eCollection 2016 Aug.
Emerging data support a role for antibody Fc-mediated antiviral activity in vaccine efficacy and in the control of HIV-1 replication by broadly neutralizing antibodies. Antibody-mediated virus internalization is an Fc-mediated function that may act at the portal of entry whereby effector cells may be triggered by pre-existing antibodies to prevent HIV-1 acquisition. Understanding the capacity of HIV-1 antibodies in mediating internalization of HIV-1 virions by primary monocytes is critical to understanding their full antiviral potency. Antibody isotypes/subclasses differ in functional profile, with consequences for their antiviral activity. For instance, in the RV144 vaccine trial that achieved partial efficacy, Env IgA correlated with increased risk of HIV-1 infection (i.e. decreased vaccine efficacy), whereas V1-V2 IgG3 correlated with decreased risk of HIV-1 infection (i.e. increased vaccine efficacy). Thus, understanding the different functional attributes of HIV-1 specific IgG1, IgG3 and IgA antibodies will help define the mechanisms of immune protection. Here, we utilized an in vitro flow cytometric method utilizing primary monocytes as phagocytes and infectious HIV-1 virions as targets to determine the capacity of Env IgA (IgA1, IgA2), IgG1 and IgG3 antibodies to mediate HIV-1 infectious virion internalization. Importantly, both broadly neutralizing antibodies (i.e. PG9, 2G12, CH31, VRC01 IgG) and non-broadly neutralizing antibodies (i.e. 7B2 mAb, mucosal HIV-1+ IgG) mediated internalization of HIV-1 virions. Furthermore, we found that Env IgG3 of multiple specificities (i.e. CD4bs, V1-V2 and gp41) mediated increased infectious virion internalization over Env IgG1 of the same specificity, while Env IgA mediated decreased infectious virion internalization compared to IgG1. These data demonstrate that antibody-mediated internalization of HIV-1 virions depends on antibody specificity and isotype. Evaluation of the phagocytic potency of vaccine-induced antibodies and therapeutic antibodies will enable a better understanding of their capacity to prevent and/or control HIV-1 infection in vivo.
新出现的数据支持抗体Fc介导的抗病毒活性在疫苗效力以及通过广泛中和抗体控制HIV-1复制方面发挥作用。抗体介导的病毒内化是一种Fc介导的功能，可能在病毒进入门户起作用，效应细胞可能被预先存在的抗体触发，以防止HIV-1感染。了解HIV-1抗体介导原代单核细胞内化HIV-1病毒体的能力对于理解其全部抗病毒效力至关重要。抗体同种型/亚类在功能特征上存在差异，这会影响它们的抗病毒活性。例如，在达到部分效力的RV144疫苗试验中，Env IgA与HIV-1感染风险增加相关（即疫苗效力降低），而V1-V2 IgG3与HIV-1感染风险降低相关（即疫苗效力增加）。因此，了解HIV-1特异性IgG1、IgG3和IgA抗体的不同功能特性将有助于确定免疫保护机制。在此，我们利用一种体外流式细胞术方法，以原代单核细胞作为吞噬细胞，以感染性HIV-1病毒体作为靶标，来确定Env IgA（IgA1、IgA2）、IgG1和IgG3抗体介导HIV-1感染性病毒体内化的能力。重要的是，广泛中和抗体（即PG9、2G12、CH31、VRC01 IgG）和非广泛中和抗体（即7B2单克隆抗体、黏膜HIV-1+ IgG）均介导HIV-1病毒体的内化。此外，我们发现多种特异性（即CD4bs、V1-V2和gp41）的Env IgG3比相同特异性的Env IgG1介导更多的感染性病毒体内化，而与IgG1相比，Env IgA介导的感染性病毒体内化减少。这些数据表明，抗体介导的HIV-1病毒体内化取决于抗体特异性和同种型。评估疫苗诱导抗体和治疗性抗体的吞噬效力将有助于更好地理解它们在体内预防和/或控制HIV-1感染的能力。
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