Immune evasion by KSHV

卡波西肉瘤相关疱疹病毒（KSHV）对免疫功能低下的患者如移植受者和艾滋病患者构成严重威胁。KSHV引起卡波西肉瘤（KS），这是HIV感染患者中最常见的癌症，以及其他淋巴组织增生性疾病。 该病毒已经进化出破坏正常宿主免疫防御的手段，使其能够建立终身感染。我们的长期目标是充分了解KSHV如何实现这一目标。这些知识不仅对了解KSHV的发病机制至关重要，而且对设计抗病毒药物治疗KS高危患者也至关重要。我们发现，KSHV编码两种蛋白质，MIR 1和MIR 2，诱导泛素化和随后的内化的主要组织相容性复合物-I（MHC-I）分子从细胞表面。这导致MHC-I分子的降解，从而阻止细胞毒性T淋巴细胞（C 'I-Ls）识别感染的细胞。 在该提议中，我们旨在表征MIRl诱导的MHC-I分子下调中所涉及的分子机制（具体目标1和2）。我们最近发现MIR 1可以独立于其赖氨酸残基（已知的泛素化靶点）下调MHC-I分子。我们将测试假设，正如我们的初步结果所表明的那样，MIR 1可以将泛素转移到半胱氨酸残基上，这是一个全新的和意想不到的过程（具体目标1）。我们理解MIR 1功能的一个重要步骤是识别其细胞辅因子（具体目标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).