Targeting the HIV-1 Reservoir in Myeloid Cells

摘要 艾滋病毒被逆转录并整合到宿主细胞的DNA中，导致持久的 难以清除的感染。到目前为止，还没有有效的疗法来清除艾滋病毒-- 被感染的病人。我们展示了一种通过选择性消除来根除艾滋病毒感染的方法 携带有复制能力的艾滋病毒(SECH)的宿主细胞。SECH治疗可以清除HIV-1 在用人类免疫系统重组的小鼠和HIV-1的血液样本中，超过50%的小鼠 被感染的病人。SECH不仅可以清除CD4T细胞中的HIV感染，还可以清除巨噬细胞中的HIV感染 和小胶质细胞。建议进行实验，以确定如何提高疗效和 SECH清除巨噬细胞系HIV感染的安全性：1)提高疗效 在杀死HIV-1感染的巨噬细胞方面具有特异性。我们发现，增加的病毒 重新激活可提高人源化小鼠的病毒清除能力。我们将识别那些显示出 病毒重新激活的更大潜力可能导致更好的艾滋病毒清除。我们将研究 巨噬细胞中IDB和替代LRA的炎症潜能，并确定什么 炎性细胞因子可能需要靶向；2)确定如何提高疗效 清除淋巴器官巨噬细胞系中HIV储存库的安全性和安全性 在人源化小鼠的大脑中。我们将评估替代代理是否可以改善 HIV-1在人源化小鼠体内的清除。我们还将确定最佳安全 治疗方案可以诱导有限和可控的炎症反应。我们提议的工作将 为靶向凋亡和自噬如何调节HIV清除提供了新的见解 巨噬细胞谱系中的感染。这些研究将促进Sech Clear的发展。 在淋巴器官和脑内感染HIV-1，实现HIV-1的彻底根除。

ABSTRACT HIV is reverse-transcribed and integrated into the DNA of host cells, resulting in persistent infections that are difficult to clear. To date, there is no effective cure to clear the virus from HIV- infected patients. We have shown an approach to eradicate HIV infections by selective elimination of host cells harboring replication-competent HIV (SECH). The SECH treatment can clear HIV-1 in over 50% mice reconstituted with a human immune system, and in blood samples from HIV-1- infected patients. SECH can clear HIV-infection not only in CD4 T cells, but also in macrophages and microglia cells. Experiments are proposed to determine how to improve the efficacy and safety for SECH in clearing HIV-infection in the macrophage lineage: 1) To improve the efficacy and specificity in the killing of HIV-1-infected macrophages. We have found that increased viral reactivation leads to improved viral clearance in humanized mice. We will identify drugs that show greater potentials in virus reactivation that could lead to better HIV clearance. We will examine the inflammatory potentials for IDB and alternative LRAs in macrophages, and determine what inflammatory cytokines may need to be targeted; 2) To determine how to improve the efficacy and safety in the clearance of HIV reservoir in the macrophage lineage in lymphoid organs and in the brain of humanized mice. We will evaluate whether alternative agents can improve the clearance of HIV-1 in humanized mice in vivo. We will also determine whether optimum SECH regimens can induce limited and controllable inflammatory responses. Our proposed work will provide novel insights into how targeting apoptosis and autophagy regulates the clearance of HIV infection in the macrophage lineage. The studies will facilitate the development of SECH clear HIV-1 infection in lymphoid organs and in the brain to achieve complete eradication of HIV-1.