Price G E, Ou R, Jiang H, Huang L, Moskophidis D
Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta 30912, USA.
J Exp Med. 2000 Jun 5;191(11):1853-67. doi: 10.1084/jem.191.11.1853.
Antigenic variation is a strategy exploited by influenza viruses to promote survival in the face of the host adaptive immune response and constitutes a major obstacle to efficient vaccine development. Thus, variation in the surface glycoproteins hemagglutinin and neuraminidase is reflected by changes in susceptibility to antibody neutralization. This has led to the current view that antibody-mediated selection of influenza A viruses constitutes the basis for annual influenza epidemics and periodic pandemics. However, infection with this virus elicits a vigorous protective CD8(+) cytotoxic T lymphocyte (CTL) response, suggesting that CD8(+) CTLs might exert selection pressure on the virus. Studies with influenza A virus-infected transgenic mice bearing a T cell receptor (TCR) specific for viral nucleoprotein reveal that virus reemergence and persistence occurs weeks after the acute infection has apparently been controlled. The persisting virus is no longer recognized by CTLs, indicating that amino acid changes in the major viral nucleoprotein CTL epitope can be rapidly accumulated in vivo. These mutations lead to a total or partial loss of recognition by polyclonal CTLs by affecting presentation of viral peptide by class I major histocompatibility complex (MHC) molecules, or by interfering with TCR recognition of the mutant peptide-MHC complex. These data illustrate the distinct features of pulmonary immunity in selection of CTL escape variants. The likelihood of emergence and the biological impact of CTL escape variants on the clinical outcome of influenza pneumonia in an immunocompetent host, which is relevant for the design of preventive vaccines against this and other respiratory viral infections, are discussed.
抗原变异是流感病毒用来在宿主适应性免疫反应面前促进生存的一种策略，也是高效疫苗研发的主要障碍。因此，表面糖蛋白血凝素和神经氨酸酶的变异通过抗体中和敏感性的变化得以体现。这导致了目前的观点，即甲型流感病毒的抗体介导选择构成了年度流感流行和周期性大流行的基础。然而，感染这种病毒会引发强烈的保护性CD8(+)细胞毒性T淋巴细胞（CTL）反应，这表明CD8(+) CTL可能会对病毒施加选择压力。对携带针对病毒核蛋白具有特异性T细胞受体（TCR）的甲型流感病毒感染的转基因小鼠的研究表明，在急性感染明显得到控制数周后，病毒会再次出现并持续存在。持续存在的病毒不再被CTL识别，这表明主要病毒核蛋白CTL表位中的氨基酸变化可在体内迅速积累。这些突变通过影响I类主要组织相容性复合体（MHC）分子对病毒肽的呈递，或通过干扰TCR对突变肽-MHC复合体的识别，导致多克隆CTL的识别完全或部分丧失。这些数据说明了肺部免疫在选择CTL逃逸变体方面的独特特征。本文讨论了CTL逃逸变体出现的可能性及其对免疫功能正常宿主中流感肺炎临床结局的生物学影响，这与针对这种及其他呼吸道病毒感染的预防性疫苗设计相关。
