Callendret Benoit, Eccleston Heather B, Hall Shelby, Satterfield William, Capone Stefania, Folgori Antonella, Cortese Riccardo, Nicosia Alfredo, Walker Christopher M
Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, OH.
Hepatology. 2014 Nov;60(5):1531-40. doi: 10.1002/hep.27278. Epub 2014 Sep 25.
Memory CD8+ T cells generated by spontaneous resolution of hepatitis C virus (HCV) infection rapidly control secondary infections and reduce the risk of virus persistence. Here, CD8+ T-cell immunity and response to reinfection were assessed in a chimpanzee cured of an earlier chronic infection with an interferon (IFN)-free antiviral regimen. CD8+ T cells expanded from liver immediately before and 2 years after cure of chronic infection with two direct-acting antivirals (DAAs) targeted epitopes in the E2, nonstructural (NS)5a, and NS5b proteins. A second infection to assess CD8+ T-cell responsiveness resulted in rapid suppression of HCV replication by week 2, but viremia rebounded 3 weeks later and the infection persisted. The E2, NS5a, and NS5b proteins remained dominant CD8+ T-cell targets after reinfection. Resurgent HCV replication was temporally associated with mutational escape of NS5a and NS5b class I epitopes that had also mutated during the first chronic infection. Two epitopes in E2 remained intact throughout both persistent infections. Intrahepatic CD8+ T cells targeting intact and escape-prone epitopes differed in expression of phenotypic markers of functional exhaustion 2 years after successful DAA therapy and in the capacity to expand in liver upon reinfection.
The intrahepatic HCV-specific CD8+ T-cell repertoire established during chronic infection was narrowly focused, but very stable, after cure with DAA. Existing intrahepatic CD8+ T cells targeting dominant epitopes of the challenge virus failed to prevent persistence. Vaccination after DAA cure may be necessary to broaden T-cell responses and reduce the risk of a second persistent infection.
丙型肝炎病毒（HCV）感染自然消退产生的记忆性CD8+T细胞能迅速控制二次感染并降低病毒持续存在的风险。在此，我们评估了一只通过无干扰素抗病毒方案治愈早期慢性感染的黑猩猩的CD8+T细胞免疫和对再次感染的反应。在用两种直接作用抗病毒药物（DAA）治愈慢性感染之前及之后2年，肝脏中扩增的CD8+T细胞靶向E2、非结构（NS）5a和NS5b蛋白中的表位。为评估CD8+T细胞反应性而进行的二次感染在第2周时导致HCV复制迅速受到抑制，但3周后病毒血症反弹且感染持续存在。再次感染后，E2、NS5a和NS5b蛋白仍是主要的CD8+T细胞靶点。HCV复制的复苏在时间上与NS5a和NS5b I类表位的突变逃逸相关，这些表位在第一次慢性感染期间也发生了突变。在两次持续感染过程中，E2中的两个表位始终保持完整。在成功的DAA治疗2年后，靶向完整和易逃逸表位的肝内CD8+T细胞在功能性耗竭的表型标志物表达以及再次感染时在肝脏中扩增的能力方面存在差异。
慢性感染期间建立的肝内HCV特异性CD8+T细胞库在DAA治愈后范围狭窄但非常稳定。现有的靶向攻击病毒主要表位的肝内CD8+T细胞未能阻止病毒持续存在。DAA治愈后进行疫苗接种可能有必要拓宽T细胞反应并降低二次持续感染的风险。
