Characterization of a New Anti-HIV Immune Protein

摘要 在寻找介导先天CD8+细胞非细胞毒性抗HIV反应(CNAR)的蛋白质方面，我们有 发现CD137(4-1BB)的外部部分是一种可以诱导细胞抗病毒的可溶性蛋白质 防止艾滋病毒复制的州。全长的膜结合CD137不会触发这一活动。这个 CD137与其配体CD137L相互作用可激活表达CD137的细胞，尤其是T淋巴细胞。 目前尚不清楚sCD137的作用。SCD137抑制所有测试的艾滋病毒分离株和脊髓灰质炎病毒株的复制， 腺病毒、巨细胞病毒和VSV。它只在人类和灵长类细胞中有效，并阻止病毒复制。 在转录水平上。在一些人的血液中可以自然地发现sCD137。计时实验 已经表明，在人类接触病毒后的几个小时内，sCD137可以诱导这种抗病毒状态 细胞。初步研究表明，CD137L抗体阻断了sCD137诱导的抗病毒状态。 我们的假设是，sCD137与细胞表面的配体CD137L相互作用，诱导细胞内 抗病毒状态。我们建议的研究旨在通过使用RNA-Seq通过#1证实这一假设，以 使用CRISPR-确定负责sCD137诱导的抗病毒状态和#2的细胞内途径 Cas9，以证实sCD137/CD137L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一个新的方向，这种疗法可能单独有效，也可能与 抗逆转录病毒治疗。可溶性CD137也可以有效地用于“休克并杀死”治疗策略，在这种治疗策略中 激活的病毒向未感染细胞的传播可以得到控制。

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.