Novel Approaches to Innate Immunity Against HIV-1 and Other Co-infection Viruses

项目摘要 艾滋病毒-1领域的两个主要目标--免疫保护未感染者和治愈 -治愈目前更具想象力。当然是一种全球适用的灭菌疫苗 看起来很遥远。对于目前可用的策略将产生什么乐观情绪 针对未感染但处于危险中的HIV-1的有效适应性免疫系统保护 个人(患有成瘾症的人、有性接触的人)。这 NIDA Avant Garde项目将通过追求扎实的创新来与RFA目标保持一致 这一方向也与我们之前的工作有很大不同。它是与生俱来的，而不是 适应性免疫，它是基于我们最近公布的大量数据显示 病毒RNA依赖的RNA聚合酶(RdRP)在大肠杆菌中的转基因表达 没有其他病毒蛋白，因此不隔离在病毒内的细胞中 复制工厂，可以深刻地重新配置哺乳动物的先天抗病毒免疫。它 显著上调许多抗病毒因子，并提供广谱抗病毒 对老鼠的保护。这种反应对确诊的人类有很强的HIV-1保护作用 细胞模型。我们推测它可能也适用于混合感染。 折磨上瘾患者的病原体。在老鼠身上，先天基因发生了根本性的改变 免疫系统蛋白质组是终身稳定的，令人惊讶的是，它不会触发任何 炎性病理学。与深刻的抗病毒作用一起，后者具有挑衅性 而违反直觉的观察有多个下游发现机会。这里 我们将确定涉及的机制，并利用这些发现制定新的 在高危人群中实现预防艾滋病毒-1的战略。

Project Summary Of the two main goals of the HIV-1 field – immune protection of the uninfected, and cure – cure is more imaginable at present. Certainly a globally applicable sterilizing vaccine seems far away. There is little optimism that currently available strategies will produce effective adaptive immune system protection against HIV-1 for uninfected but at-risk individuals (people with the disease of addiction, people with sexual exposure). This NIDA Avant Garde project will align with RFA goals by pursuing a solidly innovative direction that also differs strongly from our previous work. It concerns innate rather than adaptive immunity, and it is based on our recently published body of data showing that transgenic expression of a viral RNA-dependent RNA polymerase (RdRP), in the absence of other viral proteins, and therefore unsequestered in the cell within viral replication factories, can profoundly reconfigure mammalian innate antiviral immunity. It dramatically upregulates many antiviral factors, and provides broad-spectrum antiviral protection to mice. This response is strongly HIV-1-protective in corroborative human cell models. We hypothesize that it may also have application to the co-infection pathogens that afflict people with addiction. In the mouse, the radically altered innate immune system proteome is stable life-long and, surprisingly, does not trigger any inflammatory pathology. Along with the profound antiviral effects, this latter provocative and counterintuitive observation has multiple downstream discovery opportunities. Here we will determine the mechanisms involved and use the discoveries to formulate new strategies to achieve protection against HIV-1 in at-risk populations.