Bertoletti A, Costanzo A, Chisari F V, Levrero M, Artini M, Sette A, Penna A, Giuberti T, Fiaccadori F, Ferrari C
Cattedra Malattie Infettive, Università di Parma, Italy.
J Exp Med. 1994 Sep 1;180(3):933-43. doi: 10.1084/jem.180.3.933.
Mutations that abrogate recognition of a viral epitope by class I-restricted cytotoxic T lymphocyte (CTL) can lead to viral escape if the CTL response against that epitope is crucial for viral clearance. The likelihood of this type of event is low when the CTL response is simultaneously directed against multiple viral epitopes, as has been recently reported for patients with acute self-limited hepatitis B virus (HBV) infection. The CTL response to HBV is usually quite weak, however, during chronic HBV infection, and it is generally acknowledged that this is a major determinant of viral persistence in this disease. If such individuals were to produce a mono- or oligospecific CTL response, however, negative selection of the corresponding mutant viruses might occur. We have recently studied two HLA-A2-positive patients with chronic hepatitis B who, atypically, developed a strong HLA-A2-restricted CTL response against an epitope (FLPSDFFPSV) that contains an HLA-A2-binding motif located between residues 18-27 of the viral nucleocapsid protein, hepatitis B core antigen (HBcAg). These patients failed, however, to respond to any of other HLA-A2-restricted HBV-derived peptides that are generally immunogenic in acutely infected patients who successfully clear the virus. Interestingly, DNA sequence analysis of HBV isolates from these two patients demonstrated alternative residues at position 27 (V --> A and V --> I) and position 21 (S --> N, S --> A, and S --> V) that reduced the HLA and T cell receptor-binding capacities of the variant sequences, respectively. Synthetic peptides containing these alternative sequences were poorly immunogenic compared to the prototype HBc18-27 sequence, and they could not be recognized by CTL clones specific for the prototype peptide. While we do not know if the two patients were originally infected by these variant viruses or if the variants emerged subsequent to infection because of immune selection, the results are most consistent with the latter hypothesis. If this is correct, the data suggest that negative selection of mutant viral genomes might contribute to viral persistence in a subset of patients with chronic HBV infection who express a narrow repertoire of anti-HBV CTL responses.
如果针对某一表位的细胞毒性T淋巴细胞（CTL）应答对于病毒清除至关重要，那么消除I类限制性CTL对病毒表位识别的突变可能导致病毒逃逸。正如最近针对急性自限性乙型肝炎病毒（HBV）感染患者所报道的那样，当CTL应答同时针对多个病毒表位时，这类事件发生的可能性较低。然而，在慢性HBV感染期间，CTL对HBV的应答通常相当微弱，并且人们普遍认为这是该疾病中病毒持续存在的主要决定因素。然而，如果此类个体产生单特异性或寡特异性CTL应答，那么相应突变病毒可能会发生阴性选择。我们最近研究了两名慢性乙型肝炎的HLA - A2阳性患者，他们非典型地产生了针对一个表位（FLPSDFFPSV）的强烈HLA - A2限制性CTL应答，该表位包含位于病毒核衣壳蛋白乙型肝炎核心抗原（HBcAg）第18 - 27位残基之间的HLA - A2结合基序。然而，这些患者对其他通常在成功清除病毒的急性感染患者中具有免疫原性的HLA - A2限制性HBV衍生肽均无应答。有趣的是，对这两名患者的HBV分离株进行DNA序列分析显示，第27位残基（V→A和V→I）以及第21位残基（S→N、S→A和S→V）存在替代残基，分别降低了变异序列与HLA和T细胞受体的结合能力。与原型HBc18 - 27序列相比，含有这些替代序列的合成肽免疫原性较差，并且不能被针对原型肽的CTL克隆识别。虽然我们不知道这两名患者最初是否被这些变异病毒感染，或者这些变异是否在感染后由于免疫选择而出现，但结果最符合后一种假设。如果这是正确的，数据表明突变病毒基因组的阴性选择可能导致一部分表达狭窄抗HBV CTL应答谱的慢性HBV感染患者的病毒持续存在。
