Koka P S, Fraser J K, Bryson Y, Bristol G C, Aldrovandi G M, Daar E S, Zack J A
Division of Hematology-Oncology, Department of Medicine, UCLA School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, California 90095, USA.
J Virol. 1998 Jun;72(6):5121-7. doi: 10.1128/JVI.72.6.5121-5127.1998.
Human immunodeficiency virus type 1 (HIV-1)-infected individuals often exhibit multiple hematopoietic abnormalities reaching far beyond loss of CD4(+) lymphocytes. We used the SCID-hu (Thy/Liv) mouse (severe combined immunodeficient mouse transplanted with human fetal thymus and liver tissues), which provides an in vivo system whereby human pluripotent hematopoietic progenitor cells can be maintained and undergo T-lymphoid differentiation and wherein HIV-1 infection causes severe depletion of CD4-bearing human thymocytes. Herein we show that HIV-1 infection rapidly and severely decreases the ex vivo recovery of human progenitor cells capable of differentiation into both erythroid and myeloid lineages. However, the total CD34+ cell population is not depleted. Combination antiretroviral therapy administered well after loss of multilineage progenitor activity reverses this inhibitory effect, establishing a causal role of viral replication. Taken together, our results suggest that pluripotent stem cells are not killed by HIV-1; rather, a later stage important in both myeloid and erythroid differentiation is affected. In addition, a primary virus isolated from a patient exhibiting multiple hematopoietic abnormalities preferentially depleted myeloid and erythroid colony-forming activity rather than CD4-bearing thymocytes in this system. Thus, HIV-1 infection perturbs multiple hematopoietic lineages in vivo, which may explain the many hematopoietic defects found in infected patients.
1型人类免疫缺陷病毒（HIV-1）感染的个体常常表现出多种造血异常，远远不止CD4(+)淋巴细胞的丧失。我们使用了SCID-hu（Thy/Liv）小鼠（移植了人类胎儿胸腺和肝脏组织的严重联合免疫缺陷小鼠），它提供了一个体内系统，人类多能造血祖细胞可以在其中维持并进行T淋巴细胞分化，并且HIV-1感染会导致携带CD4的人类胸腺细胞严重耗竭。在此我们表明，HIV-1感染迅速且严重地降低了能够分化为红细胞系和髓细胞系的人类祖细胞的体外恢复能力。然而，总的CD34+细胞群体并未耗竭。在多谱系祖细胞活性丧失后很久给予联合抗逆转录病毒疗法可逆转这种抑制作用，确立了病毒复制的因果作用。综上所述，我们的结果表明多能干细胞不会被HIV-1杀死；相反，在髓细胞和红细胞分化中重要的后期阶段受到了影响。此外，从一名表现出多种造血异常的患者分离出的一株原始病毒在该系统中优先耗尽了髓细胞和红细胞集落形成活性，而不是携带CD4的胸腺细胞。因此，HIV-1感染在体内扰乱了多个造血谱系，这可能解释了在感染患者中发现的许多造血缺陷。
