Infection of Common Marmosets with GB Virus B Chimeric Virus Encoding the Major Nonstructural Proteins NS2 to NS4A of Hepatitis C Virus
Infection of Common Marmosets with GB Virus B Chimeric Virus Encoding the Major Nonstructural Proteins NS2 to NS4A of Hepatitis C Virus
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编码丙型肝炎病毒主要非结构蛋白NS2至NS4A的GB病毒B嵌合病毒感染普通狨猴
DOI：
10.1128/jvi.02653-15
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发表时间：
2016-07
影响因子：
5.4
通讯作者：
Li Chengyao
中科院分区：
文献类型：
--
作者：
Zhu Shaomei;Li Tingting;Liu Bochao;Xu Yuxia;Sun Yachun;Wang Yilin;Wang Yuanzhan;Shuai Lifang;Chen Zixuan;Allain Jean-Pierre;Li Chengyao
缺乏具有免疫能力的小型灵长类动物模型一直是开发丙型肝炎病毒（HCV）疫苗和负担得起的抗病毒药物的障碍。本研究制备了携带主要非结构蛋白NS2 - NS4A的HCV/GB病毒B （GBV-B）嵌合病毒（HCV NS2 - -4A嵌合病毒），用于感染普通狨猴，因为HCV NS2 - NS4A蛋白是关键蛋白酶和主要抗原。将7只狨猴肝内接种HCV NS2 -4A嵌合体RNA进行原发性感染，或静脉注射含嵌合体血清进行传代感染。作为对照的3只动物分别注射磷酸盐缓冲盐水（PBS）或GBV-B。7只HCV NS2 -4A嵌合体感染的狨猴中有6只表现出一致的病毒血症，1只在后续检测过程中表现出短暂的病毒血症。所有6只持续循环病毒血症的感染动物都表现出典型的病毒性肝炎特征，包括肝细胞中的病毒RNA和蛋白质以及肝组织的组织病理学改变。在5至54周的随访中持续检测到病毒血症。FK506免疫抑制促进了狨猴嵌合体持续感染的建立。嵌合体感染的动物在第一次接种后7周自动清除了血液中的病毒，但病毒rna持久性、低水平病毒蛋白和肝组织中仍存在轻度坏死性炎症。在这只病毒血症解决的狨猴中，特异性抗体和t细胞对HCV NS3的反应通过再挑战得到增强，但在57周的随访中未检测到病毒血症。所描述的嵌合体感染狨猴可以作为研究新型抗病毒药物和基于t细胞的HCV感染疫苗的合适的小型灵长类动物模型。丙型肝炎病毒感染导致约70%的慢性肝炎，并且在全球范围内经常与原发性肝癌相关。黑猩猩已被用作HCV感染的可靠灵长类动物模型，但伦理方面的考虑限制了它们在生物医学研究中的应用。GB病毒B （GBV-B）是一种与HCV相关的黄病毒。它可以感染普通狨猴，一种新世界的小型灵长类动物，并在人类中引起类似HCV感染的病毒性肝炎。为了尽量减少GBV-B和HCV之间的差异，我们生成了HCV NS2 -4A/GBV-B嵌合病毒，并建立了嵌合感染狨猴模型。HCV NS2 -4A嵌合感染的狨猴为评估靶向HCV NS3-NS4A蛋白酶的新型抗病毒药物和基于t细胞的HCV疫苗提供了一个小动物模型。
A lack of immunocompetent-small-primate models has been an obstacle for developing hepatitis C virus (HCV) vaccines and affordable antiviral drugs. In this study, HCV/GB virus B (GBV-B) chimeric virus carrying the major nonstructural proteins NS2 to NS4A (HCV NS2 to -4A chimera) was produced and used to infect common marmosets, since HCV NS2 to NS4A proteins are critical proteases and major antigens. Seven marmosets were inoculated intrahepatically with HCV NS2 to -4A chimera RNA for primary infection or intravenously injected with chimera-containing serum for passage infection. Three animals used as controls were injected with phosphate-buffered saline (PBS) or GBV-B, respectively. Six of seven HCV NS2 to -4A chimera-infected marmosets exhibited consistent viremia and one showed transient viremia during the course of follow-up detection. All six infected animals with persistent circulating viremia presented characteristics typical of viral hepatitis, including viral RNA and proteins in hepatocytes and histopathological changes in liver tissue. Viremia was consistently detected for 5 to 54 weeks of follow-up. FK506 immunosuppression facilitated the establishment of persistent chimera infection in marmosets. An animal with chimera infection spontaneously cleared the virus in blood 7 weeks following the first inoculation, but viral-RNA persistence, low-level viral protein, and mild necroinflammation remained in liver tissue. The specific antibody and T-cell response to HCV NS3 in this viremia-resolved marmoset was boosted by rechallenging, but no viremia was detected during 57 weeks of follow-up. The chimera-infected marmosets described can be used as a suitable small-primate animal model for studying novel antiviral drugs and T-cell-based vaccines against HCV infection.IMPORTANCEHCV infection causes approximately 70% of chronic hepatitis and is frequently associated with primary liver cancer globally. Chimpanzees have been used as a reliable primate model for HCV infection, but ethical considerations have restricted their utility in biomedical research. GB virus B (GBV-B) is a flavivirus related to HCV. It can infect common marmosets, a New World small primate, and induces viral hepatitis similar to HCV infection in humans. To minimize differences between GBV-B and HCV, we generated HCV NS2 to -4A/GBV-B chimeric viruses and established a chimera-infected marmoset model. HCV NS2 to -4A chimera-infected marmosets provide a small-animal model for evaluating novel antiviral drugs targeting HCV NS3-NS4A protease and T-cell-based HCV vaccines.
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影响因子：
17.1
作者：
Swadling L;Capone S;Antrobus RD;Brown A;Richardson R;Newell EW;Halliday J;Kelly C;Bowen D;Fergusson J;Kurioka A;Ammendola V;Del Sorbo M;Grazioli F;Esposito ML;Siani L;Traboni C;Hill A;Colloca S;Davis M;Nicosia A;Cortese R;Folgori A;Klenerman P;Barnes E
通讯作者：
Barnes E
影响因子：
13.5
作者：
Rijnbrand, R;Yang, Y;Martin, A
通讯作者：
Martin, A
DOI：
10.1016/s0140-6736(78)90131-9
发表时间：
1978-03
期刊：
The Lancet
影响因子：
--
作者：
H. Alter;P. Holland;R. Purcell;H. Popper
通讯作者：
H. Alter;P. Holland;R. Purcell;H. Popper
影响因子：
3.7
作者：
Bukh, J;Apgar, CL;Yanagi, M
通讯作者：
Yanagi, M
影响因子：
82.9
作者：
Folgori, A;Capone, S;Nicosia, A
通讯作者：
Nicosia, A