Highly differentiated, resting gn-specific memory CD8+ T cells persist years after infection by andes hantavirus.
Highly differentiated, resting gn-specific memory CD8+ T cells persist years after infection by andes hantavirus.
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DOI：
10.1371/journal.ppat.1000779
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发表时间：
2010-02-19
期刊：
影响因子：
6.7
通讯作者：
Vial P
中科院分区：
文献类型：
--
作者：
Manigold T;Mori A;Graumann R;Llop E;Simon V;Ferrés M;Valdivieso F;Castillo C;Hjelle B;Vial P
在人类中，感染南美安第斯山脉病毒（ANDV）可引起汉坦病毒心肺综合征（HCPS）。由ANDV引起的HCPS在智利南部和阿根廷大部分地区流行，南美洲各地报告的病例数量不断增加。约36%的病死率加上缺乏成功的抗病毒治疗，促使开发疫苗。尽管在小鼠模型中，T细胞应答被证明与汉坦病毒的免疫力密切相关，但没有关于患者中ANDV特异性记忆T细胞应答的幅度、特异性和寿命的数据。在IFN-γ ELISPOT测定中使用重叠肽组，我们在此显示在78名智利恢复期患者中，与来自N-和GC-蛋白的表位相比，来自Gn的表位是免疫显性的。此外，虽然随着时间的推移，N-特异性反应的相对贡献显着下降，Gn-特异性反应仍然很容易检测到离体长达13年后的急性感染。四聚体分析进一步显示，在急性感染后473年，高达16.8%的所有循环CD3 + CD8 + T细胞对单个HLA-B * 3501限制性表位Gn465具有特异性。值得注意的是，Gn465 - 473特异性细胞在刺激后容易分泌IFN-γ、颗粒酶B和TNF-α，但不分泌IL-2，并显示出"回复突变体" CD45 RA + CD27 − CD28 − CCR7 − CD127 −效应记忆表型，从而类似于在其他潜伏病毒感染中观察到的表型。最有趣的是，中和抗体的滴度在急性感染后数月至数年内随时间推移而增加，并且与他们是否是流行地区的居民无关。因此，我们的数据表明固有的，潜在的抗原刺激的Gn特异性T细胞。然而，这仍然是一个主要的任务，为未来的研究，以证明这一假设，确定病毒抗原在康复期患者。此外，Gn-specific T细胞是否对病毒控制和保护性免疫至关重要还有待观察。如果是这样的话，Gn-derived免疫优势表位可能是未来的ANDV疫苗的高价值。在人类中，由安第斯山脉病毒（ANDV）引起的汉坦病毒心肺综合征（HCPS）在智利和阿根廷的南锥体地区是地方性的，但自1995年以来，整个南美洲越来越多地报告了HCPS病例。HCPS的特征是暴发性肺水肿，约36%的HCPS患者进展为休克和死亡。然而，迄今为止，无论是抗病毒治疗还是诱导中和抗体（NAb）的疫苗都没有证明对引起HCP的汉坦病毒有效。我们开始了对78例ANDV感染的恢复期幸存者的人类细胞免疫的首次研究。我们发现，Gn-specific反应占主导地位相比，N-和GC-特异性反应，甚至长达13年后的感染。令人惊讶的是，大多数Gn特异性反应仅限于Gn羧基末端内的两个相邻表位。有趣的是，在HLA-B * 3501+患者中，Gn465 − 473特异性CD8 + T细胞表现出高度分化但静止的表型和功能。在未来的研究中，Gn-specific T细胞的免疫优势是否对保护性免疫至关重要还有待观察。最有趣的是，中和抗体的滴度在急性感染后数月至数年内增加，并且与他们是否是流行区的居民无关。因此，我们的数据表明，在部分ANDV恢复期患者中存在病毒持续存在或潜伏期。然而，它仍然是未来研究的主要任务，以证明潜伏/持续的人ANDV感染的概念，通过确定恢复期患者的病毒抗原。
In man, infection with South American Andes virus (ANDV) causes hantavirus cardiopulmonary syndrome (HCPS). HCPS due to ANDV is endemic in Southern Chile and much of Argentina and increasing numbers of cases are reported all over South America. A case-fatality rate of about 36% together with the absence of successful antiviral therapies urge the development of a vaccine. Although T-cell responses were shown to be critically involved in immunity to hantaviruses in mouse models, no data are available on the magnitude, specificity and longevity of ANDV-specific memory T-cell responses in patients. Using sets of overlapping peptides in IFN-γ ELISPOT assays, we herein show in 78 Chilean convalescent patients that Gn-derived epitopes were immunodominant as compared to those from the N- and Gc-proteins. Furthermore, while the relative contribution of the N-specific response significantly declined over time, Gn-specific responses remained readily detectable ex vivo up to 13 years after the acute infection. Tetramer analysis further showed that up to 16.8% of all circulating CD3+CD8+ T cells were specific for the single HLA-B*3501-restricted epitope Gn465–473 years after the acute infection. Remarkably, Gn465–473–specific cells readily secreted IFN-γ, granzyme B and TNF-α but not IL-2 upon stimulation and showed a ‘revertant’ CD45RA+CD27−CD28−CCR7−CD127− effector memory phenotype, thereby resembling a phenotype seen in other latent virus infections. Most intriguingly, titers of neutralizing antibodies increased over time in 10/17 individuals months to years after the acute infection and independently of whether they were residents of endemic areas or not. Thus, our data suggest intrinsic, latent antigenic stimulation of Gn-specific T-cells. However, it remains a major task for future studies to proof this hypothesis by determination of viral antigen in convalescent patients. Furthermore, it remains to be seen whether Gn-specific T cells are critical for viral control and protective immunity. If so, Gn-derived immunodominant epitopes could be of high value for future ANDV vaccines. In man, hantavirus cardiopulmonary syndrome (HCPS) caused by Andes Virus (ANDV) is endemic in the Southern cone of Chile and Argentina but cases of HCPS are being increasingly reported all over South America since 1995. HCPS is characterized by fulminant pulmonary edema which progresses to shock and death in about 36% of patients with HCPS. Nevertheless, to date, neither antiviral treatments nor vaccines inducing neutralizing antibodies (NAb) have proven effective against HCPS-causing hantaviruses. We set out for the first study on human cellular immunity towards ANDV in 78 convalescent survivors of ANDV infection. We found that Gn-specific responses were predominant as compared to N- and Gc-specific responses, even up to 13 years after the infection. Surprisingly, most of the Gn-specific responses were restricted to two neighboring epitopes within the Gn carboxyterminus. Interestingly, among HLA-B*3501+ patients, Gn465−473-specific CD8+ T-cells showed highly differentiated but resting phenotype and functions. It remains to be seen in future studies whether the immunodominace of Gn-specific T-cells is crucial for protective immunity. Most intriguingly, titers of neutralizing antibodies increased in 10/17 individuals months to years after the acute infection and independently of whether they were residents of endemic areas or not. Thus, our data suggest viral persistence or latency in part of ANDV-convalescent patients. However, it remains a major task for future studies to proof the concept of latent/persistent human ANDV infection by the determination of viral antigen in convalescent patients.
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