HCMV US2 & US11 Inhibition of MHC Class II Presentation

描述（由申请人提供）：人类巨细胞病毒（HCMV）是一种普遍存在的病毒，感染了相当一部分美国人口，导致终身持续或潜伏感染。HCMV通常是良性的，但在免疫功能低下和免疫抑制的患者中会引起严重的疾病。目前更多移植的趋势将导致HCMV疾病的持续升级。在新生儿中，HCMV导致出生缺陷和神经功能障碍，并可能导致相当数量的残疾儿童。在艾滋病中，HCMV经常在疾病晚期引起视网膜炎，这严重降低了生活质量。HCMV视网膜炎在HAART治疗中发病率较低，尽管目前尚不清楚HAART治疗是否会使HIV下降，而视网膜炎可能会继续成为一个主要问题。细胞免疫反应对控制HCMV至关重要。然而，病毒可以持续存在，甚至再次感染先前存在和强大免疫力的血清阳性个体。在某种程度上，这可能与大量的HCMV免疫逃避或调节蛋白有关。了解这些蛋白质如何促进对免疫识别和效应策略的抵抗，将对生产疫苗具有重要意义，这是迫切需要的。我们描述了HCMV US2和US3对MHC II类抗原呈递到CD4+ T细胞的影响。US2引起MHC蛋白的降解，显然是通过触发一个称为er相关降解（ERAD）的基本和重要的细胞过程。我们将重点研究us2介导的降解和ERAD的分子机制。US2和相关蛋白US11是ERAD的最佳分子调控因子。我们最近的工作也为MHC II类途径如何通过内源性而不是外源性或细胞外途径正常发挥递呈HCMV抗原的功能提供了新的见解。我们将扩展这些HCMV II类抗原呈递的研究，并通过表征US2、US3和US11的恒河巨细胞病毒同源物来研究US2、US3和US11在HCMV感染细胞中的作用。

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is a ubiquitous virus that infects a substantial fraction of the U.S. population, leading to lifelong persistent or latent infections. HCMV is normally benign but causes serious disease in immunocompromised and immunosuppressed patients. The present trend toward more transplantation will cause continued escalation of HCMV disease. In newborn children, HCMV causes birth defects and neurological dysfunction and may account for a substantial number of children with disabilities. In AIDS, HCMV frequently causes retinitis seen in late stages of the disease and this seriously decreases the quality of life. HCMV retinitis is less frequent with HAART, although it is not clear whether HAART will keep HIV in decline and retinitis will likely continue to be a major problem. Cellular immune responses are critical to controlling HCMV. However, the virus can persist and even reinfect seropositive individuals that have preexisting and robust immunity. In part, this may relate to a substantial panel of HCMV immune evasion or modulation proteins. Understanding how these proteins promote resistance to immune recognition and effector strategies will have important implications for producing a vaccine, something that is critically needed. We described effects of HCMV US2 and US3 on MHC class II antigen presentation to CD4+ T cells. US2 causes degradation of MHC proteins, apparently by triggering a fundamental and important cellular process termed ER-associated degradation (ERAD). Our research will focus on the molecular mechanisms of US2-mediated degradation and ERAD. US2 and a related protein US11 are among the best molecular handles on ERAD. Our recent work has also provided new insights into how the MHC class II pathway normally functions to present HCMV antigens, by an endogenous, rather than exogenous or extra cellular, pathway. We will extend these studies of HCMV class II antigen presentation and grapple with how US2, US3 and US11 function in the context of HCMV-infected cells, in part by characterizing rhesus CMV homologues of US2, US3 and US11.