HIV Infection of Hematopoietic Stem/Progenitor Cells (HSPC) in Bone Marrow

人类免疫缺陷病毒(HIV)治疗的主要目标是识别、靶向和消除病毒库。虽然在这一领域取得了重大进展，但在接受抗逆转录病毒治疗的患者中检测到的病毒RNA水平较低，以及停止这种治疗后病毒复制的反弹，这表明目前存在更多的艾滋病毒宿主。最近的研究表明，骨髓中的造血干/祖细胞(HSPC)可以被HIV感染并携带潜伏病毒。拟议研究的目标是充分描述体内骨髓中艾滋病毒感染的特征，并评估针对感染艾滋病毒的祖细胞的方法。由于基于干细胞的基因治疗被认为是根除艾滋病毒的潜在新途径，充分了解这个新的储存库如何影响新干细胞的植入和重建是至关重要的。为了解决这个问题，我们的目标是(I)使用人源化的小鼠和体外的人类组织(胎肝、脐带血)来充分描述HSPC中HIV感染的特征，(Ii)检测HIV感染对骨髓微环境的影响及其支持体内适当谱系发育的能力，以及(Iii)评估影响病毒库的基因治疗方法，包括开发保护转基因抗病毒效应细胞的方法。

The main objective in human immunodeficiency virus (HIV) therapy is the identification, targeting and elimination of viral reservoirs. While significant progress has been made in the field, the low levels of viral RNA detected in patients under antiretroviral therapy as well as the rebound of viral replication after cessation of such therapy suggest that there are additional HIV reservoirs present. Recent studies have suggested that hematopoietic stem/progenitor cells (HSPC) in the bone marrow can be infected by HIV and harbor latent virus. The goal of the proposed studies is to fully characterize HIV infection in the bone marrow in vivo and to assess the ways to target HIV infected progenitors. As stem cell based gene therapy is considered a potentially new avenue to eradicate HIV, it is essential to fully understand how this new reservoir impacts engraftment of and reconstitution by new stem cells. To address this question we aim to (i) fully characterize HIV infection in HSPC using both humanized mice and human tissues (fetal liver, cord blood) ex vivo, (ii) examine the effect HIV infection has on the bone marrow microenvironment and its ability to support proper lineage development in vivo, and (iii) evaluate gene therapy approaches to impact the viral reservoir, including the development of ways to protect genetically modified antiviral effector cells.