Zharikova Darya, Mozdzanowska Krystyna, Feng Jingqi, Zhang Manxin, Gerhard Walter
The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104-4268, USA.
J Virol. 2005 Jun;79(11):6644-54. doi: 10.1128/JVI.79.11.6644-6654.2005.
The ectodomain of matrix protein 2 (M2e) of human influenza type A virus strains has remained remarkably conserved since 1918. Because M2e-specific immunity has been shown to decrease morbidity and mortality associated with influenza virus infection in several animal models and because natural infection and current vaccines do not appear to induce a good M2e-specific antibody (Ab) response, M2e has been considered as potential vaccine for inducing cross-reactive protection against influenza type A viruses. The high degree of structural conservation of M2e could in part be the consequence of a poor M2e-specific Ab response and thus the absence of pressure for change. To assess this possibility, we studied the course of infection in SCID mice in the presence or absence of passive M2e-specific monoclonal Abs (MAbs). We found that virus mutants with antigenic changes in M2e emerged in 65% of virus-infected mice treated with M2e-specific but not control MAbs. However, the diversity of escape mutants was highly restricted since only two types were isolated from 22 mice, one with a proline-to-leucine and the other with a proline-to-histidine interchange at amino acid position 10 of M2e. The implications of these findings for the use of M2e as a broadly protective vaccine are discussed.
自1918年以来，甲型人流感病毒株基质蛋白2（M2e）的胞外域一直保持着显著的保守性。由于在多种动物模型中，M2e特异性免疫已被证明可降低与流感病毒感染相关的发病率和死亡率，且自然感染和现有疫苗似乎都不能诱导良好的M2e特异性抗体（Ab）反应，因此M2e被认为是诱导针对甲型流感病毒的交叉反应性保护的潜在疫苗。M2e高度的结构保守性可能部分是由于M2e特异性Ab反应较差，因此缺乏变异压力所致。为评估这种可能性，我们研究了在有无被动给予的M2e特异性单克隆抗体（MAb）情况下，SCID小鼠的感染过程。我们发现，在用M2e特异性而非对照MAb处理的65%的病毒感染小鼠中出现了M2e抗原性发生变化的病毒突变体。然而，逃逸突变体的多样性受到高度限制，因为从22只小鼠中仅分离出两种类型，一种是M2e第10位氨基酸处脯氨酸变为亮氨酸，另一种是脯氨酸变为组氨酸。本文讨论了这些发现对将M2e用作广泛保护性疫苗的意义。
