Immune evasion by KSHV

卡波西肉瘤相关疱疹病毒(KSHV)对移植受者和艾滋病患者等免疫功能低下的患者构成严重威胁。KSHV导致Kaposi肉瘤(KS)，这是艾滋病毒感染患者中最常见的癌症，以及其他淋巴增生性疾病。 该病毒已经进化出颠覆正常宿主免疫防御的方法，使其能够建立终身感染。我们的长期目标是充分了解KSHV是如何实现这一目标的。这些知识不仅对于了解KSHV的发病机制至关重要，而且对于设计抗病毒药物来治疗KS高危患者也是至关重要的。我们发现KSHV编码两种蛋白质MIR1和MIR2，它们诱导细胞表面的主要组织相容性复合体-I(MHC-I)分子的泛素化和随后的内在化。这会导致MHC-I分子的降解，从而阻止细胞毒性T淋巴细胞(C‘I-L)对感染细胞的识别。 在这项建议中，我们旨在表征MIRL诱导的MHC-I分子下调所涉及的分子机制(特定目标1和2)。我们最近发现，MIR1可以下调MHC-I分子，而不依赖其赖氨酸残基，赖氨酸残基是泛素化的已知目标。我们将测试假设，根据我们的初步结果，MIR1可以将泛素转移到半胱氨酸残基，这是一个全新的和意想不到的过程(特定目标1)。我们理解MIR1功能的重要一步是确定它的细胞辅助因子(特定目标2)。

Kaposi's Sarcoma associated Herpesvirus (KSHV) poses a serious threat to immunocompromised patients such as transplant recipients and AIDS patients. KSHV causes Kaposi's Sarcoma (KS), the most frequent cancer in HIV-infected patients, as well as other lymphoproliferative disorders. The virus has evolved means of subverting normal host immune defenses, allowing it to establish life-long infections. Our long-term goal is to fully understand how KSHV achieves this end. Such knowledge is not only critical to the understanding of KSHV pathogenesis, but also to the design of anti-viral drugs to treat patients at high risks for KS. We found that KSHV encodes two proteins, MIR1 and MIR2, that induce ubiquitination and subsequent internalization of the Major Histocompatibility Complex-I (MHC-I) molecules from the cell surface. This leads to the degradation of the MHC-I molecules thus preventing recognition of infected cells by the cytotoxic T lymphocytes (C'I-Ls). In this proposal, we aim at characterizing the molecular mechanisms implicated in the MIRl-induced downregulation of MHC-I molecules (specific aim 1 and 2). We recently discovered that MIR1 can downregulate MHC-I molecules independently of their lysine residues, the known targets of ubiquitination. We will test the hypothesis that, as suggested by our preliminary results, MIR1 can transfer ubiquitin to a cysteine residue, a completely novel and unexpected process (specific aim 1). An important step in our understanding of MIR1 functions will be to identify its cellular cofactors (specific aim 2).