Targeting the HIV-1 Reservoir in Myeloid Cells

摘要 HIV被逆转录并整合到宿主细胞的DNA中，导致持续的 难以清除的感染。到目前为止，还没有有效的治疗方法来清除艾滋病毒- 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HIV（SECH）的宿主细胞。SECH治疗可以清除HIV-1 在超过50%的人类免疫系统重建的小鼠中，以及在来自HIV-1- 感染的病人。SECH不仅可以清除CD 4 T细胞中的HIV感染，而且可以清除巨噬细胞中的HIV感染 和小胶质细胞。提出实验来确定如何提高功效， SECH清除巨噬细胞系HIV感染的安全性：1）提高疗效 和特异性杀死HIV-1感染的巨噬细胞。我们发现， 再活化导致人源化小鼠中病毒清除的改善。我们将找出药物， 更大的病毒再激活潜力，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的炎症潜力，并确定 可能需要靶向炎症细胞因子; 2）确定如何提高疗效 在淋巴器官巨噬细胞谱系中清除HIV储库的安全性， 在人源化小鼠的大脑中。我们将评估替代药物是否可以改善 体内人源化小鼠中HIV-1的清除。我们还将确定最佳SECH 治疗方案可以诱导有限的和可控的炎症反应。我们提出的工作将 为靶向细胞凋亡和自噬如何调节HIV的清除提供了新的见解 巨噬细胞系的感染。这些研究将促进SECH的发展， HIV-1在淋巴器官和大脑中的感染，以实现HIV-1的完全根除。

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.