Wu Zeguang, Qin Ruifang, Wang Li, Bosso Matteo, Scherer Myriam, Stamminger Thomas, Hotter Dominik, Mertens Thomas, Frascaroli Giada
Institute of Virology, Ulm University Medical Center, Ulm, Germany.
International Graduate School in Molecular Medicine Ulm, Ulm, Germany.
J Virol. 2017 Oct 27;91(22). doi: 10.1128/JVI.00678-17. Print 2017 Nov 15.
Human cytomegalovirus (HCMV) persistently infects 40% to 100% of the human population worldwide. Experimental and clinical evidence indicates that humoral immunity to HCMV plays an important role in restricting virus dissemination and protecting the infected host from disease. Specific immunoglobulin preparations from pooled plasma of adults selected for high titers of HCMV antibodies have been used for the prevention of CMV disease in transplant recipients and pregnant women. Even though incubation of HCMV particles with these preparations leads to the neutralization of viral infectivity, it is still unclear whether the antibody-treated HCMV particles (referred to here as HCMV-Ab) enter the cells and modulate antiviral immune responses. Here we demonstrate that HCMV-Ab did enter macrophages. HCMV-Ab did not initiate the expression of immediate early antigens (IEAs) in macrophages, but they induced an antiviral state and rendered the cells less susceptible to HCMV infection upon challenge. Resistance to HCMV infection seemed to be due to the activation of intrinsic restriction factors and was independent of interferons. In contrast to actively infected cells, autologous NK cells did not degranulate against HCMV-Ab-treated macrophages, suggesting that these cells may not be eliminated by innate effector cells. Interestingly, HCMV-Ab-treated macrophages stimulated the proliferation of autologous adaptive CD4 and CD8 T cells. Our findings not only expand the current knowledge on virus-antibody immunity but may also be relevant for future vaccination strategies. Human cytomegalovirus (HCMV), a common herpesvirus, establishes benign but persistent infections in immunocompetent hosts. However, in subjects with an immature or dysfunctional immune system, HCMV is a major cause of morbidity and mortality. Passive immunization has been used in different clinical settings with variable clinical results. Intravenous hyperimmune globulin preparations (IVIg) are obtained from pooled adult human plasma selected for high anti-CMV antibody titers. While HCMV neutralization can be shown using different systems, data are lacking regarding the cross-influence of IVIg administration on the cellular immune responses. The aim of this study was to evaluate the effects of IVIg on distinct components of the immune response against HCMV, including antigen presentation by macrophages, degranulation of innate natural killer cells, and proliferation of adaptive CD4 and CD8 T cells.
人巨细胞病毒（HCMV）持续感染全球40%至100%的人群。实验和临床证据表明，针对HCMV的体液免疫在限制病毒传播以及保护受感染宿主免受疾病侵害方面发挥着重要作用。从经筛选具有高滴度HCMV抗体的成年人混合血浆中制备的特异性免疫球蛋白制剂，已被用于预防移植受者和孕妇的巨细胞病毒疾病。尽管将HCMV颗粒与这些制剂孵育会导致病毒感染性的中和，但仍不清楚经抗体处理的HCMV颗粒（此处称为HCMV-Ab）是否进入细胞并调节抗病毒免疫反应。在此，我们证明HCMV-Ab确实进入了巨噬细胞。HCMV-Ab并未在巨噬细胞中引发即刻早期抗原（IEA）的表达，但它们诱导了一种抗病毒状态，并使细胞在受到攻击时对HCMV感染的敏感性降低。对HCMV感染的抗性似乎归因于内在限制因子的激活，且与干扰素无关。与活跃感染的细胞不同，自体自然杀伤细胞不会对经HCMV-Ab处理的巨噬细胞脱颗粒，这表明这些细胞可能不会被先天性效应细胞清除。有趣的是，经HCMV-Ab处理的巨噬细胞刺激了自体适应性CD4和CD8 T细胞的增殖。我们的发现不仅扩展了当前关于病毒-抗体免疫的知识，还可能与未来的疫苗接种策略相关。人巨细胞病毒（HCMV）是一种常见的疱疹病毒，在免疫功能正常的宿主中建立良性但持续的感染。然而，在免疫系统不成熟或功能失调的个体中，HCMV是发病和死亡的主要原因。被动免疫已在不同临床环境中使用，临床结果各异。静脉注射高免疫球蛋白制剂（IVIg）是从经筛选具有高抗CMV抗体滴度的成年人混合血浆中获得的。虽然使用不同系统可以显示HCMV中和，但缺乏关于IVIg给药对细胞免疫反应的交叉影响的数据。本研究的目的是评估IVIg对针对HCMV的免疫反应不同组成部分的影响，包括巨噬细胞的抗原呈递、先天性自然杀伤细胞的脱颗粒以及适应性CD4和CD8 T细胞的增殖。
