Characterization of a New Anti-HIV Immune Protein

摘要 在寻找介导先天性CD 8+细胞非细胞毒性抗HIV反应（CNAR）的蛋白质时，我们 发现CD 137（4-1BB）的外部部分是一种可溶性蛋白，可以诱导细胞抗病毒 防止艾滋病毒复制。全长膜结合的CD 137不触发这种活性。的 通过CD 137与其配体的相互作用，CD 137 L活化表达CD 137的细胞，特别是T淋巴细胞。 sCD 137的作用尚不清楚。sCD 137抑制所有测试的HIV分离株以及脊髓灰质炎的复制， 腺病毒、巨细胞病毒和VSV。它只在人类和灵长类动物细胞中有活性，并阻断病毒复制 在转录水平上。sCD 137可以在某些个体的血液中自然发现。计时实验 已经表明，sCD 137可以在人暴露后几小时内诱导这种抗病毒状态。 细胞初步研究表明，CD 137 L抗体阻断sCD 137诱导的抗病毒状态。 我们的假设是sCD 137与细胞表面的配体CD 137 L相互作用，诱导细胞内的CD 137受体。 抗病毒状态我们提出的研究旨在通过#1，使用RNA-Seq， 确定负责sCD 137诱导的抗病毒状态的细胞内途径，以及#2，使用CRISPR- Cas9，以证实sCD 137/CD 137 L相互作用参与诱导抗病毒状态。这些研究 为抗病毒免疫疗法提供了新的方向，这种疗法可以单独有效，也可以与 抗逆转录病毒疗法可溶性CD 137在“休克和杀死”治疗策略中也是有效的，其中， 可以控制活化病毒向未感染细胞的扩散。

Abstract In searching for the protein mediating the innate CD8+ cell non-cytotoxic anti-HIV response (CNAR) we have discovered that the external portion of CD137 (4-1BB) is a soluble protein that can induce a cellular antiviral state that prevents HIV replication. The full-length membrane-bound CD137 does not trigger this activity. The interaction of CD137 with its ligand, CD137L activates the cells expressing CD137, particularly T lymphocytes. The role of sCD137 is not known. sCD137 inhibits replication of all HIV isolates tested as well as polio, adenovirus, cytomegalovirus, and VSV. It is only active in human and primate cells and blocks virus replication at the transcription level. sCD137 can be found naturally in the blood of some individuals. Timing experiments have suggested that sCD137 can induce this antiviral state within a few hours after the exposure of human cells. Pilot studies have indicated that CD137L antibodies block the induction of the antiviral state by sCD137. Our hypothesis is that sCD137 interacts with the ligand CD137L on the cell surface to induce an intracellular antiviral state. Our proposed studies are aimed at confirming this hypothesis through #1, Using RNA-Seq, to determine the intracellular pathway responsible for the sCD137-induced antiviral state and #2, Using CRISPR- Cas9, to confirm that the sCD137/CD137L interaction is involved in inducing the antiviral state. These studies offer a new direction in antiviral immunotherapy that could be effective alone or in combination with antiretroviral therapy. Soluble CD137 could also be effective in "shock and kill" cure strategies in which the spread of the activated virus to uninfected cells could be controlled.