Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge
Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge
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DOI：
10.1128/jvi.76.13.6586-6595.2002
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发表时间：
2002-07-01
影响因子：
5.4
通讯作者：
Feinstone, SM
中科院分区：
文献类型：
--
作者：
Major, ME;Mihalik, K;Feinstone, SM
比较了三只黑猩猩在接受感染RNA转录本的动物血浆中含有克隆丙型肝炎病毒(HCV)的攻击后的反应。其中两只黑猩猩(CH1552和CHX0186)已从先前感染丙型肝炎病毒的疾病中康复，而第三只(CH1605)是一只幼稚的动物。所有动物均经血浆稀释度递减的反向滴定激发，激发后血清RNA呈阳性。Ch1605显示了黑猩猩的典型疾病特征。我们观察到从接种后1周(P.I.)开始血清RNA水平升高，在P.I.第9周达到峰值10(6)拷贝/毫升，在P.I.第10周丙氨酸转氨酶(ALT)升高和向丙型肝炎病毒抗体的血清转换。相反，ChI552和ChX0186都表现出更短的病毒血症周期(4周)，低血清RNA水平(峰值，10(3)拷贝/毫升)，以及最低的ALT升高。ChI552和Ch1605的肝内细胞因子水平的比较显示，在先前感染的动物中，γ-干扰素(干扰素-γ)和肿瘤坏死因子α的反应更大和更早，在第4周P.I.的反应是基线反应的30倍。在第10周，CH1552的干扰素-γ是CH1605的12倍。这些数据表明：(I)由感染性RNA转录本产生的克隆丙型肝炎病毒将导致幼年黑猩猩感染典型的丙型肝炎病毒，(Ii)恢复的黑猩猩在再次攻击时存在控制丙型肝炎病毒感染的记忆免疫反应，以及(Iii)这些反应似乎是由T细胞介导的，因为这些动物都没有检测到针对丙型肝炎病毒包膜糖蛋白的抗体。这些观察结果对丙型肝炎疫苗的开发具有令人鼓舞的意义。
Responses in three chimpanzees were compared following challenge with a clonal hepatitis C virus (HCV) contained in plasma from an animal that had received infectious RNA transcripts. Two of the chimpanzees (Ch1552 and ChX0186) had recovered from a previous infection with HCV, while the third (Ch1605) was a naive animal. All animals were challenged by reverse titration with decreasing dilutions of plasma and became serum RNA positive following challenge. Ch1605 displayed a typical disease profile for a chimpanzee. We observed increasing levels of serum RNA from week 1 postinoculation (p.i.), reaching a peak of 10(6) copies/ml at week 9 p.i., and alanine aminotransferase (ALT) elevations and seroconversion to HCV antibodies at week 10 p.i. In contrast, both ChI552 and ChX0186 exhibited much shorter periods of viremia (4 weeks), low serum RNA levels (peak, 10(3) copies/ml), and minimal ALT elevations. A comparison of intrahepatic cytokine levels in ChI552 and Ch1605 showed greater and earlier gamma interferon (IFN-gamma) and tumor necrosis factor alpha responses in the previously infected animal, responses that were 30-fold greater than baseline responses at week 4 p.i. for IFN-gamma in Ch1552 compared to 12-fold in Ch1605 at week 10 p.i. These data indicate (i) that clonal HCV generated from an infectious RNA transcript will lead to a typical HCV infection in naive chimpanzees, (ii) that there are memory immune responses in recovered chimpanzees that control HCV infection upon rechallenge, and (iii) that these responses seem to be T-cell mediated, as none of the animals had detectable antibody against the HCV envelope glycoproteins. These observations have encouraging implications for the development of a vaccine for HCV.