Hunziker Lukas, Ciurea Adrian, Recher Mike, Hengartner Hans, Zinkernagel Rolf M
Institute for Experimental Immunology, University Hospital, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.
Proc Natl Acad Sci U S A. 2003 May 13;100(10):6015-20. doi: 10.1073/pnas.1031671100. Epub 2003 May 2.
Noncytopathic RNA viruses persist in their natural hosts at various levels as highly mutating quasispecies. They exhibit only one known serotype. In most inbred DBA2 mice infected with 2 x 10(4) or 2 x 10(6) plaque-forming units (pfu) of lymphocytic choriomeningitis virus (LCMV), the virus is transiently controlled below detectable levels measured with conventional assays (<1.7 pfu), but reemerges despite a common neutralizing Ab (nAb) response. Wild-type virus and cloned mutant viruses that had escaped polyclonal nAb responses in vivo induced nAb titers in new hosts that were usually cross-reactive; some sera were highly specific for certain mutants. The few mice that controlled LCMV infection for >170 days produced not only nAb against wild-type but also variably against many other mutants isolated from other mice with reemerging viremia. When DBA2 mice were immunized and boosted with 200 pfu of a LCMV mutant, the neutralizing Ab response was limited to the immunizing "personal" clone. Thus, in contrast to classical serotype-defined cytopathic viruses (e.g., polio viruses) that induce strictly non-cross-reactive nAb titers, LCMV, a noncytopathic RNA virus, represents a dynamic multiplicity of personal serological submutants. Together, these mutants form a generally recognized "public" serotype. These findings may help to explain aspects of human infections and Ab responses against hepatitis B virus, hepatitis C virus, and HIV.
非细胞病变性RNA病毒以高度变异的准种形式在其天然宿主中以各种水平持续存在。它们仅表现出一种已知血清型。在大多数感染2×10⁴或2×10⁶个淋巴细胞性脉络丛脑膜炎病毒（LCMV）蚀斑形成单位（pfu）的近交系DBA2小鼠中，病毒被短暂控制在传统检测方法可检测水平以下（<1.7 pfu），但尽管有常见的中和抗体（nAb）反应仍会再次出现。在体内逃避多克隆nAb反应的野生型病毒和克隆突变病毒在新宿主中诱导的nAb滴度通常具有交叉反应性；一些血清对某些突变体具有高度特异性。少数控制LCMV感染超过170天的小鼠不仅产生了针对野生型的nAb，还不同程度地产生了针对从其他病毒血症复发小鼠中分离出的许多其他突变体的nAb。当用200 pfu的LCMV突变体对DBA2小鼠进行免疫和加强免疫时，中和抗体反应仅限于免疫的“个人”克隆。因此，与诱导严格非交叉反应性nAb滴度的经典血清型定义的细胞病变性病毒（如脊髓灰质炎病毒）不同，LCMV这种非细胞病变性RNA病毒代表了个人血清学亚突变体的动态多样性。这些突变体共同形成了一种普遍认可的“公共”血清型。这些发现可能有助于解释人类感染以及针对乙型肝炎病毒、丙型肝炎病毒和HIV的抗体反应的相关方面。
