Sci Trans Med:同期两篇文章分别报道研制JC多瘤病毒疫苗和抗体

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JCV是一种通常无害的病毒，大多数成人的泌尿道和肾脏会感染这种病毒。然而，在免疫系统严重削弱的人体中（最常见的是HIV/AIDS 患者或多发性硬化患者，他们接受了高剂量免疫抑制药物的治疗），该病毒可入侵和损害脑部，导致进行性多灶性白质脑病（PML）。引起疾病的病毒株已知在一个关键蛋白中含有突变基因，但这些突变如何使得JCV失控则仍然未知。

因感染JC多瘤病毒（JCV）而罹患某种罕见且常常致命脑病的患者无法产生可根除该病毒的抗体，从而制造让JCV逃避免疫监测的“盲点”。现在，有两则研究比较了PML患者和健康人的血液及脑脊液，并发现了患者对JCV的抗体反应存在着盲点。PML患者的抗体对突变病毒视而不见（无法识别），使得该病毒能在未被发现的情况下入侵脑部。这些发现提示，疫苗或抗体治疗或能消除这些盲点，从而为预防和治疗这种灾难性疾病铺设了一条道路。

在第一项研究中，据Upasana Ray和同事的研究披露，这些盲点有可能被疫苗所逆转。给小鼠和一位PML患者接种一种疫苗（它含有一个模仿JCV的病毒样颗粒）可促使小鼠和患者体内产生广谱中和抗体。该实验疫苗阻断了病毒感染并终止了脑部损害，为保护有风险者（如感染HIV的患者）提供了一种可能的免于发生PML的策略。

在第二项研究中，Ivan Jelcic和同事试图利用患者体内的保护性抗体，这些患者能够产生一种保护性的抗体反应并从PML中康复。应用采自一位这样的、在接种一种实验性JCV疫苗后恢复的患者的记忆B细胞，研究人员研发出了JCV特异性的人类单克隆抗体。这些抗体能在人的细胞中阻断多株JCV病毒感染，从而提供了一类新的可能治疗PML的广谱中和抗体。

来源：生物360

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JC polyomavirus mutants escape antibody-mediated neutralization

Upasana Ray1, Paola Cinque2, Simonetta Gerevini3, Valeria Longo2, Adriano Lazzarin2,4, Sven Schippling5, Roland Martin5, Christopher B. Buck1,* and Diana V. Pastrana1,*

JC polyomavirus (JCV) persistently infects the urinary tract of most adults. Under conditions of immune impairment, JCV causes an opportunistic brain disease, progressive multifocal leukoencephalopathy (PML). JCV strains found in the cerebrospinal fluid of PML patients contain distinctive mutations in surface loops of the major capsid protein, VP1. We hypothesized that VP1 mutations might allow the virus to evade antibody-mediated neutralization. Consistent with this hypothesis, neutralization serology revealed that plasma samples from PML patients neutralized wild-type JCV strains but failed to neutralize patient-cognate PML-mutant JCV strains. This contrasted with serological results for healthy individuals, most of whom robustly cross-neutralized all tested JCV variants. Mice administered a JCV virus-like particle (VLP) vaccine initially showed neutralizing “blind spots” (akin to those observed in PML patients) that closed after booster immunization. A PML patient administered an experimental JCV VLP vaccine likewise showed markedly increased neutralizing titer against her cognate PML-mutant JCV. The results indicate that deficient humoral immunity is a common aspect of PML pathogenesis and that vaccination may overcome this humoral deficiency. Thus, vaccination with JCV VLPs might prevent the development of PML.

http://stm.sciencemag.org/conten ... 0-8ab9-de21fdd76dfd

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Broadly neutralizing human monoclonal JC polyomavirus VP1–specific antibodies as candidate therapeutics for progressive multifocal leukoencephalopathy

Ivan Jelcic1,*, Benoit Combaluzier2,*, Ilijas Jelcic1, Wolfgang Faigle1, Luzia Senn2, Brenda J. Reinhart1, Luisa Ströh3, Roger M. Nitsch2,4, Thilo Stehle3,5, Mireia Sospedra1, Jan Grimm2,†,‡ and Roland Martin1,†,‡

In immunocompromised individuals, JC polyomavirus (JCPyV) may mutate and gain access to the central nervous system resulting in progressive multifocal leukoencephalopathy (PML), an often fatal opportunistic infection for which no treatments are currently available. Despite recent progress, the contribution of JCPyV-specific humoral immunity to controlling asymptomatic infection throughout life and to eliminating JCPyV from the brain is poorly understood. We examined antibody responses against JCPyV major capsid protein VP1 (viral protein 1) variants in the serum and cerebrospinal fluid (CSF) of healthy donors (HDs), JCPyV-positive multiple sclerosis patients treated with the anti–VLA-4 monoclonal antibody natalizumab (NAT), and patients with NAT-associated PML. Before and during PML, CSF antibody responses against JCPyV VP1 variants show “recognition holes”; however, upon immune reconstitution, CSF antibody titers rise, then recognize PML-associated JCPyV VP1 variants, and may be involved in elimination of the virus. We therefore reasoned that the memory B cell repertoire of individuals who recovered from PML could be a source for the molecular cloning of broadly neutralizing antibodies for passive immunization. We generated a series of memory B cell–derived JCPyV VP1–specific human monoclonal antibodies from HDs and a patient with NAT-associated PML–immune reconstitution inflammatory syndrome (IRIS). These antibodies exhibited diverse binding affinity, cross-reactivity with the closely related BK polyomavirus, recognition of PML-causing VP1 variants, and JCPyV neutralization. Almost all antibodies with exquisite specificity for JCPyV, neutralizing activity, recognition of all tested JCPyV PML variants, and high affinity were derived from one patient who had recovered from PML. These antibodies are promising drug candidates for the development of a treatment of PML.

http://stm.sciencemag.org/content/7/306/306ra150.full