Department of Medicine, Division of Infectious Diseases, University of California, Irvine School of Medicine, Irvine, California, United States of America.
Department of Biomedical Engineering, University of California, Irvine, Irvine, California, United States of America.
PLoS Pathog. 2017 Dec 27;13(12):e1006793. doi: 10.1371/journal.ppat.1006793. eCollection 2017 Dec.
Fc gamma receptor (FcyR)-mediated antibody functions play a crucial role in preventing HIV infection. One such function, antibody-dependent phagocytosis (ADP), is thought to be involved in controlling other viral infections, but its role in HIV infection is unknown. We measured the ability of HIV-specific polyclonal and monoclonal antibodies (mAbs) to mediate the internalization of HIV-1 virions and HIV-1-decorated cells by phagocytes. To measure ADP of virions, we primarily used a green-fluorescent protein-expressing molecular clone of HIV-1JRFL, an R5, clinical isolate, in combination with polyclonal HIVIG or mAbs known to capture and/or neutralize HIV-1. THP-1 and U937 cells, as well as freshly isolated primary monocytes from healthy individuals, were used as phagocytic effector cells, and uptake of virions was measured by cytometry. We surprisingly found minimal or no ADP of virions with any of the antibodies. However, after coating virions with gp41 or with gp41-derived peptides, gp41- (but not gp120-) specific mAbs efficiently mediated phagocytosis. We estimated that a minimum of a few hundred gp41 molecules were needed for successful phagocytosis, which is similar to the number of envelope spikes on viruses that are readily phagocytosed (e.g. influenza virus). Furthermore, by employing fluorescence correlation spectroscopy, a well-established technique to measure particle sizes and aggregation phenomena, we found a clear association between virus aggregation and ADP. In contrast to virions themselves, virion-decorated cells were targets for ADP or trogocytosis in the presence of HIV-specific antibodies. Our findings indicate that ADP of virions may not play a role in preventing HIV infection, likely due to the paucity of trimers and the consequent inability of virion-bound antibody to cross-link FcyRs on phagocytes. However, ADP or trogocytosis could play a role in clearing HIV-infected cells and cells on the verge of infection.
Fc 受体（FcyR）介导的抗体功能在预防 HIV 感染中起着至关重要的作用。其中一种功能，抗体依赖性吞噬作用（ADCP），被认为参与控制其他病毒感染，但它在 HIV 感染中的作用尚不清楚。我们测量了 HIV 特异性多克隆和单克隆抗体（mAbs）介导吞噬细胞内化 HIV-1 病毒粒子和 HIV-1 装饰细胞的能力。为了测量病毒粒子的 ADCP，我们主要使用了 HIV-1JRFL 的一个绿色荧光蛋白表达分子克隆，这是一种 R5、临床分离株，与已知捕获和/或中和 HIV-1 的多克隆 HIVIG 或 mAbs 结合使用。THP-1 和 U937 细胞以及来自健康个体的新鲜分离的原代单核细胞被用作吞噬效应细胞，通过流式细胞术测量病毒粒子的摄取。我们惊讶地发现，任何抗体对病毒粒子的 ADCP 都很少或没有。然而，在用 gp41 或 gp41 衍生肽包被病毒粒子后，gp41-（而不是 gp120-）特异性 mAbs 能够有效地介导吞噬作用。我们估计，成功吞噬需要至少几百个 gp41 分子，这与易于吞噬的病毒（例如流感病毒）上的包膜刺突数量相似。此外，通过使用荧光相关光谱学，一种测量颗粒大小和聚集现象的成熟技术，我们发现病毒聚集与 ADCP 之间存在明显的关联。与病毒粒子本身相比，在 HIV 特异性抗体存在的情况下，病毒粒子装饰的细胞是 ADCP 或 trogocytosis 的靶标。我们的发现表明，ADCP 可能不会在预防 HIV 感染中发挥作用，这可能是由于三聚体的缺乏以及病毒结合抗体在吞噬细胞上交联 FcyR 的能力不足所致。然而，ADCP 或 trogocytosis 可能在清除 HIV 感染的细胞和即将感染的细胞方面发挥作用。
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