Doherty P C, Christensen J P, Belz G T, Stevenson P G, Sangster M Y
Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Philos Trans R Soc Lond B Biol Sci. 2001 Apr 29;356(1408):581-93. doi: 10.1098/rstb.2000.0786.
The murine gamma-herpesvirus 68 (MHV-68) provides a unique experimental model for dissecting immunity to large DNA viruses that persist in B lymphocytes. The analysis is greatly facilitated by the availability of genetically disrupted (-/-) mice that lack key host-response elements, and by the fact that MHV-68 is a lytic virus that can readily be manipulated for mutational analysis. The mutant virus strategy is being used, for example, to characterize the part played in vivo by an MHV-68-encoded chemokine-binding protein that may ultimately find an application in human therapeutics. Experiments with various -/- mice and monoclonal antibody depletion protocols have shown very clearly that type I interferons (IFNs) are essential for the early control of MHV-68 replication, while CD4+ T cells producing IFN-gamma function to limit the consequences of viral persistence. Virus-specific CD8+ effectors acting in the absence of the CD4+ subset seem initially to control the lytic phase in the lung following respiratory challenge, but are then unable to prevent the reactivation of replicative infection in epithelia and the eventual death of CD4+ T-cell-deficient mice. This could reflect the fact that the interaction between the CD8+ T cells and the virus-infected targets is partially compromised by the MHV-68 K3 protein, which inhibits antigen presentation by MHC class I glycoproteins. Immunization strategies focusing on the CD8+ T-cell response to epitopes expressed during the lytic phase of MHV-68 infection can limit virus replication, but are unable to prevent the establishment of latency. Other experiments with mutant viruses also suggest that there is a disconnection between lytic MHV-68 infection and latency. The massive nonspecific immunoglobulin response and the dramatic expansion of Vbeta4+ CD8+ T cells, which is apparently MHC independent, could represent some sort of 'smoke screen' used by MHV-68 to subvert immunity. Although MHV-68 is neither Epstein-Barr virus nor human herpesvirus-8, the results generated from this system suggest possibilities that may usefully be addressed with these human pathogens. Perhaps the main lesson learned to date is that all the components of immunity are likely to be important for the control of these complex viruses.
小鼠γ-疱疹病毒68（MHV-68）为剖析针对持续存在于B淋巴细胞中的大型DNA病毒的免疫反应提供了一个独特的实验模型。缺乏关键宿主反应元件的基因敲除（-/-）小鼠的可用性，以及MHV-68是一种可轻易用于突变分析的裂解病毒这一事实，极大地促进了分析工作。例如，突变病毒策略正被用于表征MHV-68编码的趋化因子结合蛋白在体内所起的作用，该蛋白最终可能在人类治疗中得到应用。对各种-/-小鼠进行的实验以及单克隆抗体清除方案已经非常清楚地表明，I型干扰素（IFN）对于早期控制MHV-68复制至关重要，而产生IFN-γ的CD4+ T细胞则发挥作用以限制病毒持续存在的后果。在缺乏CD4+亚群的情况下起作用的病毒特异性CD8+效应细胞似乎最初能控制呼吸道感染后肺部的裂解阶段，但随后无法阻止上皮细胞中复制性感染的重新激活以及CD4+ T细胞缺陷小鼠的最终死亡。这可能反映了这样一个事实，即CD8+ T细胞与病毒感染靶标的相互作用因MHV-68 K3蛋白而部分受损，该蛋白抑制MHC I类糖蛋白的抗原呈递。专注于针对MHV-68感染裂解阶段表达的表位的CD8+ T细胞反应的免疫策略可以限制病毒复制，但无法阻止潜伏状态的建立。对突变病毒进行的其他实验还表明，MHV-68的裂解感染与潜伏状态之间存在脱节。大量非特异性免疫球蛋白反应以及Vbeta4+ CD8+ T细胞的显著扩增，这显然与MHC无关，可能代表了MHV-68用来颠覆免疫的某种“烟幕”。尽管MHV-68既不是爱泼斯坦-巴尔病毒也不是人类疱疹病毒8型，但从这个系统产生的结果提示了一些可能对这些人类病原体有用的研究方向。也许迄今为止学到的主要经验是，免疫的所有组成部分可能对控制这些复杂病毒都很重要。
