Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA.
Cell Host Microbe. 2011 Mar 17;9(3):223-234. doi: 10.1016/j.chom.2011.02.005.
HIV infection is characterized by gradual immune system collapse and hematopoietic dysfunction. We recently showed that HIV enters multipotent hematopoietic progenitor cells and establishes both active cytotoxic and latent infections that can be reactivated by myeloid differentiation. However, whether these multipotent progenitors include long-lived hematopoietic stem cells (HSCs) that could establish viral reservoirs for the life of the infected person remains unknown. Here we provide direct evidence that HIV targets long-lived HSCs and show that infected HSCs yield stable, multilineage engraftment in a xenograft model. Furthermore, we establish that the capacity to use the chemokine receptor CXCR4 for entry determines whether a virus will enter multipotent versus differentiated progenitor cells. Because HSCs live for the life span of the infected person and are crucial for hematopoietic health, these data may explain the poor prognosis associated with CXCR4-tropic HIV infection and suggest HSCs as long-lived cellular reservoirs of latent HIV.
HIV 感染的特征是免疫系统逐渐崩溃和造血功能障碍。我们最近表明，HIV 进入多能造血祖细胞，并建立既能进行活性细胞毒性感染又能建立潜伏感染的状态，这两种感染均可被髓系分化所激活。然而，这些多能祖细胞是否包括可建立感染个体终生病毒储存库的长寿造血干细胞（HSCs）仍不清楚。在这里，我们提供了 HIV 靶向长寿 HSCs 的直接证据，并表明感染的 HSCs 在异种移植模型中产生稳定的多谱系嵌合体。此外，我们确定了利用趋化因子受体 CXCR4 进行进入的能力决定了病毒将进入多能性还是分化祖细胞。由于 HSCs 的寿命与感染个体的寿命相同，并且对造血健康至关重要，这些数据可能解释了与 CXCR4 嗜性 HIV 感染相关的不良预后，并提示 HSCs 是潜伏 HIV 的长期细胞储存库。
