Evasion of Antigen Presentation by Rhesus Cytomegalovirus

描述（由申请人提供）：尽管有非常强的T细胞应答，但人巨细胞病毒（HCMV）的慢性感染和再感染不能被宿主的免疫系统消除。防止免疫细胞活化和识别病毒感染细胞的病毒隐形策略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呈递对HCMV发病机制和持久性的作用尚未确定，因为巨细胞病毒感染是高度宿主限制性的，HCMV不感染免疫活性动物。 除了不是可行的动物模型的黑猩猩CMV之外，HCMV的最近亲属是感染非人灵长类动物的恒河猴CMV（RhCMV）。与HCMV类似，我们观察到RhCMV能够重新感染血清阳性动物并建立持续感染。使用这个新的模型，我们将测试的假设，防止表达的MHC I是必不可少的建立和维持免疫活性宿主的持续感染。我们表明，RhCMV编码抑制剂的MHC组装，是HCMV US 6-家庭的糖蛋白US 2，US 3，US 6和US 11的功能和序列同源物。我们进一步证明了RhCMV在3 kb基因组片段Rh 175 -180内编码MHC I表达的另外的调节剂，Rh 175 -180编码RhCMV特异性基因，但也与Rh 181的转录物重叠，RhCMV同源于HCMV US 1。这种新的机制，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US 6相关蛋白对MHC I组装和转运的抑制。本提案的目的是：i）鉴定Rh 175 -181区域编码的哪些基因产物负责VIHCE，ii）表征VIHCE的分子机制，以及iii）确定在免疫活性动物持续感染建立和维持期间防止MHC I表达、组装或转运以逃避CD 8+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.