Evasion of Antigen Presentation by Rhesus Cytomegalovirus

描述（由申请人提供）：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，尽管有非常强的T细胞反应。防止免疫细胞激活和识别病毒感染细胞的病毒隐身策略被认为是逃避免疫根除的必要条件。通过主要组织相容性复合体（MHC）分子抑制病毒抗原的呈递被认为在巨细胞病毒免疫逃逸中起关键作用。然而，抑制MHC呈递在HCMV发病机制和持久性中的作用尚未确定，因为巨细胞病毒感染是高度受宿主限制的，而且HCMV不会感染免疫能力强的动物。除了黑猩猩巨细胞病毒不是可行的动物模型外，HCMV最近的亲戚是感染非人类灵长类动物的恒河猴巨细胞病毒（RhCMV）。与HCMV类似，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。利用这个新模型，我们将验证一个假设，即阻止MHC I的表达对于在免疫功能正常的宿主中建立和维持持续感染是必不可少的。我们发现，RhCMV编码MHC组装抑制剂，这些抑制剂是HCMV US6家族糖蛋白US2、US3、US6和US11的功能和序列同源物。我们进一步证明了RhCMV在一个3kb的基因组片段Rh175-180中编码MHC I表达的额外调节剂，该片段编码RhCMV特异性基因，但也与RhCMV US1的RhCMV同源物Rh181的转录物重叠。这种新机制被称为病毒干扰重链表达（VIHCE），在转录后但在重链合成完成之前起作用。因此，VIHCE先于us6相关蛋白对MHC I组装和运输的抑制。本研究的目的是：1)确定在Rh175-181区编码的哪些基因产物与VIHCE有关；2)表征VIHCE的分子机制；3)确定在免疫功能正常动物的持续感染建立和维持过程中，阻止MHC i的表达、组装或运输以逃避CD8+淋巴细胞的免疫检测的作用。

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.