Soluble rhesus lymphocryptovirus gp350 protects against infection and reduces viral loads in animals that become infected with virus after challenge.
Soluble rhesus lymphocryptovirus gp350 protects against infection and reduces viral loads in animals that become infected with virus after challenge.
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DOI：
10.1371/journal.ppat.1002308
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发表时间：
2011-10
期刊：
影响因子：
6.7
通讯作者：
Cohen JI
中科院分区：
文献类型：
--
作者：
Sashihara J;Hoshino Y;Bowman JJ;Krogmann T;Burbelo PD;Coffield VM;Kamrud K;Cohen JI
EB病毒（EBV）是一种与多种恶性肿瘤相关的人类淋巴腺病毒。在移植前和移植后淋巴组织增生性疾病时，在移植受者中观察到血液中EBV DNA升高;因此，预防EBV感染或降低病毒载量的疫苗可能会减少某些EBV恶性肿瘤。已经提出了两种用于EBV疫苗的主要方法-用EBV糖蛋白350（gp350）或EBV潜伏蛋白（例如EBV核抗原[EBNAs]）免疫。然而，没有进行比较试验。恒河猴淋巴隐病毒（LCV）编码EBV中每个基因的同源物，猴感染可再现急性和潜伏性EBV感染的临床、免疫学和病毒学特征。我们在0、4和12周用（a）可溶性恒河猴LCV gp350，（B）表达恒河猴LCV gp350的病毒样复制子颗粒（VRP），（c）表达恒河猴LCV gp350、EBNA-3A和EBNA-3 B的VRP，或（d）PBS对恒河猴进行疫苗接种。用可溶性gp350接种的动物比用表达gp350的VRP接种的动物产生更高水平的糖蛋白抗体。用表达EBNA-3A和EBNA-3B的VRP接种的动物产生了对这些蛋白质的LCV特异性CD4和CD8 T细胞免疫，而表达gp350的VRP没有诱导可检测的对gp350的T细胞免疫。在用恒河猴LCV攻击后，基于攻击后血液中的血清转化、病毒DNA和病毒RNA，用可溶性恒河猴LCV gp350接种的动物具有最佳水平的抗感染保护。令人惊讶的是，在攻击后23个月，用gp350疫苗接种的被感染的动物在血液中具有最低的LCV DNA载量。这些研究表明，gp350对于保护免受恒河猴LCV感染和降低攻毒后感染动物的病毒载量至关重要。我们的研究结果表明，应考虑单独使用可溶性EBV gp350或与其他EBV蛋白联合使用的额外试验，以减少人类EBV感染或病毒相关恶性肿瘤。EB病毒（EBV）是传染性单核细胞增多症的主要原因，并与几种癌症有关。目前还没有获得许可的疫苗来预防EBV疾病。两种类型的候选疫苗正在开发中;一种涉及用病毒外部的主要糖蛋白（gp350）进行免疫，而另一种涉及用潜伏期期间表达的EBV蛋白进行免疫。我们在EB病毒恒河猴模型中比较了这两种类型的候选疫苗，发现gp350疫苗诱导了更好的感染保护作用。此外，接受恒河猴EBV糖蛋白并被感染的动物在攻击后23个月血液中的恒河猴EBV DNA水平低于接受恒河猴EBV潜伏蛋白疫苗随后被感染的动物。由于血液中的EBV DNA水平已经预测了移植患者的EBV淋巴瘤，因此恒河猴EBV gp350在感染后降低血液中恒河猴EBV水平的能力表明EBV gp350可能在减少某些EBV相关癌症中发挥作用。这是候选疫苗在EBV恒河猴模型中的首次测试，表明该模型在进一步评价EBV疫苗中应该是有用的。
Epstein-Barr virus (EBV) is a human lymphocryptovirus that is associated with several malignancies. Elevated EBV DNA in the blood is observed in transplant recipients prior to, and at the time of post-transplant lymphoproliferative disease; thus, a vaccine that either prevents EBV infection or lowers the viral load might reduce certain EBV malignancies. Two major approaches have been suggested for an EBV vaccine- immunization with either EBV glycoprotein 350 (gp350) or EBV latency proteins (e.g. EBV nuclear antigens [EBNAs]). No comparative trials, however, have been performed. Rhesus lymphocryptovirus (LCV) encodes a homolog for each gene in EBV and infection of monkeys reproduces the clinical, immunologic, and virologic features of both acute and latent EBV infection. We vaccinated rhesus monkeys at 0, 4 and 12 weeks with (a) soluble rhesus LCV gp350, (b) virus-like replicon particles (VRPs) expressing rhesus LCV gp350, (c) VRPs expressing rhesus LCV gp350, EBNA-3A, and EBNA-3B, or (d) PBS. Animals vaccinated with soluble gp350 produced higher levels of antibody to the glycoprotein than those vaccinated with VRPs expressing gp350. Animals vaccinated with VRPs expressing EBNA-3A and EBNA-3B developed LCV-specific CD4 and CD8 T cell immunity to these proteins, while VRPs expressing gp350 did not induce detectable T cell immunity to gp350. After challenge with rhesus LCV, animals vaccinated with soluble rhesus LCV gp350 had the best level of protection against infection based on seroconversion, viral DNA, and viral RNA in the blood after challenge. Surprisingly, animals vaccinated with gp350 that became infected had the lowest LCV DNA loads in the blood at 23 months after challenge. These studies indicate that gp350 is critical for both protection against infection with rhesus LCV and for reducing the viral load in animals that become infected after challenge. Our results suggest that additional trials with soluble EBV gp350 alone, or in combination with other EBV proteins, should be considered to reduce EBV infection or virus-associated malignancies in humans. Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and is associated with several cancers. Presently there is no licensed vaccine to prevent EBV diseases. Two types of candidate vaccines are under development; one involves immunization with the major glycoprotein (gp350) on the outside of the virus, while the other involves vaccination with EBV proteins expressed during latency. We compared these two types of candidate vaccines in a rhesus monkey model of EBV and found that the gp350 vaccine induced better protection from infection. In addition, animals that received the rhesus EBV glycoprotein and became infected had a lower level of rhesus EBV DNA in the blood at 23 months after challenge than animals that received the rhesus EBV latency protein vaccine that subsequently were infected. Since levels of EBV DNA in the blood have been predictive for EBV lymphomas in transplant patients, the ability of rhesus EBV gp350 to reduce levels of rhesus EBV in the blood after infection suggests the EBV gp350 could have a role in reducing certain EBV-associated cancers. This is the first test of candidate vaccines in the rhesus monkey model of EBV and shows that this model should be useful in further evaluation of EBV vaccines.
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影响因子：
3.8
作者：
FINERTY, S;TARLTON, J;MORGAN, AJ
通讯作者：
MORGAN, AJ
影响因子：
5.4
作者：
Gedey, Roderick;Jin, Xiao-Lu;Shisler, Joanna L.
通讯作者：
Shisler, Joanna L.
影响因子：
64.8
作者：
EPSTEIN, MA;MORGAN, AJ;KIRKWOOD, JK
通讯作者：
KIRKWOOD, JK
影响因子：
20.3
作者：
Gottschalk, S;Ng, CYC;Rooney, CM
通讯作者：
Rooney, CM
影响因子：
5.5
作者：
FINERTY, S;MACKETT, M;MORGAN, AJ
通讯作者：
MORGAN, AJ