Evasion of Antigen Presentation by Rhesus CMV

描述(申请人提供)：人类巨细胞病毒(HCMV)的慢性感染和再感染不能被宿主的免疫系统消除，尽管T细胞反应非常强烈。病毒隐形策略防止免疫细胞的激活和识别病毒感染的细胞被认为是逃避免疫根除的关键。主要组织相容性复合体(MHC)分子抑制病毒抗原的提呈被认为是巨细胞病毒免疫逃逸的关键。然而，由于巨细胞病毒的感染是高度宿主限制性的，而且巨细胞病毒不感染免疫活性动物，因此抑制MHC提呈在巨细胞病毒致病和持续存在中的作用尚未确定。除了黑猩猩巨细胞病毒不是一种可行的动物模型外，与巨细胞病毒关系最近的是感染非人类灵长类动物的恒河猴巨细胞病毒(RhCMV)。与HCMV相似，我们观察到RhCMV能够再次感染血清阳性动物并建立持续感染。使用这个新的模型，我们将检验这样一个假设，即防止MHC I的表达对于建立和维持免疫活性宿主的持续感染是必不可少的。我们发现RhCMV编码MHC装配的抑制物，这些抑制物是HCMV US6家族糖蛋白US2、US3、US6和US11的功能和序列同源物。我们进一步证明，RhCMV在3kb的基因组片段Rh175-180中编码MHC I表达的额外调节子(S)，该片段编码RhCMV特异性基因，但也与HCMV US1的Rh181同源物的转录本重叠。这种新的机制被称为病毒干扰重链表达(VIHCE)，作用于转录后但在重链合成完成之前。因此，VIHCE先于US6相关蛋白抑制MHC I的组装和运输。本研究的目的是：1)确定编码在Rh175-181区域的哪些基因产物是VIHCE的致病基因；2)确定VIHCE的分子机制；3)确定在免疫活性动物持续感染的建立和维持过程中，阻止MHC I的表达、组装或转运以逃避CD8+淋巴细胞免疫检测的作用。

DESCRIPTION (provided by applicant): Chronic infections and re-infections by human cytomegalovirus (HCMV) cannot be eliminated by the host's immune system despite an extraordinary strong T cell response. Viral stealth strategies preventing the activation of immune cells and the recognition of virally infected cells are thought to be essential to escape immune eradication. Inhibiting the presentation of viral antigens by major histocompatibility complex (MHC) molecules is thought to play a key role in cytomegaloviral immune escape. However, the role of inhibiting MHC presentation for HCMV pathogenesis and persistence has not been established since infections by cytomegaloviruses are highly host-restricted and HCMV does not infect immunocompetent animals. Besides chimpanzee CMV, which is not a feasible animal model, the closest relative of HCMV is Rhesus CMV (RhCMV) which infects non-human primates. Similar to HCMV, we observed that RhCMV is capable of re-infecting seropositive animals and establishing a persistent infection. Using this new model, we will test the hypothesis that preventing expression of MHC I is essential for the establishment and maintenance of persistent infection in immunocompetent hosts. We show that RhCMV encodes inhibitors of MHC assembly that are functional and sequence homologues of the HCMV US6-family of glycoproteins US2, US3, US6 and US11. We further demonstrate RhCMV encodes additional modulator(s) of MHC I expression within a 3kb genomic fragment, Rh175-180 that encodes RhCMV-specific genes but also overlaps with the transcript of Rh181, the RhCMV homologue of HCMV US1. This novel mechanism, termed viral interference with heavy chain expression (VIHCE), acts post-transcriptionally but prior to completion of heavy chain synthesis. Thus, VIHCE precedes inhibition of MHC I assembly and transport by US6-related proteins. The goals of this proposal are i) to identify which of the gene products encoded in the Rh175-181 region are responsible for VIHCE, ii) to characterize the molecular mechanism of VIHCE, and iii) to determine the role of preventing MHC I expression, assembly or transport for escaping immune detection by CD8+ lymphocytes during establishment and maintenance of persistent infection of immunocompetent animals.