T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee.
T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee.
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黑猩猩使用无干扰素抗病毒疗法治愈慢性丙型肝炎后的 T 细胞免疫和丙型肝炎病毒再感染。
DOI：
10.1002/hep.27278
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发表时间：
2014-11
期刊：
影响因子：
13.5
通讯作者：
Walker, Christopher M.
中科院分区：
文献类型：
--
作者：
Callendret, Benoit;Eccleston, Heather B.;Hall, Shelby;Satterfield, William;Capone, Stefania;Folgori, Antonella;Cortese, Riccardo;Nicosia, Alfredo;Walker, Christopher M.
记忆CD8+T细胞是由自发分解的丙型肝炎病毒感染产生的，可迅速控制继发感染，降低病毒持续感染的风险。在这里，CD8+T细胞免疫和对再次感染的反应在一只早期慢性感染的黑猩猩身上进行了评估，这些黑猩猩用不含干扰素的抗病毒方案治愈。在慢性感染治愈前和治愈两年后，CD8+T细胞通过E2、NS5A和NS5B蛋白中的两个直接作用抗病毒(DAA)靶位从肝脏中扩增。第二次感染以评估CD8+T细胞反应性导致在第二周迅速抑制了丙型肝炎病毒的复制，但病毒血症在三周后反弹，感染持续。在再次感染后，E2、NS5A和NS5B蛋白仍然是CD8+T细胞的主要靶点。丙型肝炎病毒复制的复苏与NS5A和NS5B I类表位的突变逃逸有关，这两个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中的两个表位保持不变。在DAA治疗成功两年后，针对完整表位和易逃逸表位的肝内CD8+T细胞在功能衰竭表型标志物的表达上存在差异，在再次感染时在肝脏中扩张的能力也不同。在慢性感染期间建立的肝内丙型肝炎病毒特异性CD8+T细胞谱系是狭窄的，但在DAA治愈后非常稳定。现有的针对挑战病毒优势表位的肝内CD8+T细胞未能阻止持久性。在DAA治愈后接种疫苗可能是必要的，以扩大T细胞反应并降低第二次持续感染的风险。
Memory CD8+ T cells generated by spontaneous resolution of HCV infection rapidly control secondary infections and reduce the risk of virus persistence. Here, CD8+ T cell immunity and the response to reinfection was assessed in a chimpanzee cured of an earlier chronic infection with an interferon-free antiviral regimen. CD8+ T cells expanded from liver immediately before and two years after cure of chronic infection with two direct acting antivirals (DAA) targeted epitopes in the E2, NS5a, 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 re-infection. 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 two 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 the T cell response and reduce the risk of a second persistent infection.
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影响因子：
20.3
作者：
Gil, MP;Salomon, R;Biron, CA
通讯作者：
Biron, CA
影响因子：
6.7
作者：
Fraietta JA;Mueller YM;Yang G;Boesteanu AC;Gracias DT;Do DH;Hope JL;Kathuria N;McGettigan SE;Lewis MG;Giavedoni LD;Jacobson JM;Katsikis PD
通讯作者：
Katsikis PD
影响因子：
15.9
作者：
KOZIEL, MJ;DUDLEY, D;WALKER, BD
通讯作者：
WALKER, BD
影响因子：
29.4
作者：
Seigel, Bianca;Bengsch, Bertram;Thimme, Robert
通讯作者：
Thimme, Robert
影响因子：
11.8
作者：
Grady, Bart P.;Schinkel, Janke;Dalgard, Olav
通讯作者：
Dalgard, Olav