Zhang Jielin, Scadden David T, Crumpacker Clyde S
Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
J Clin Invest. 2007 Feb;117(2):473-81. doi: 10.1172/JCI28971.
Hematopoietic stem cells are resistant to HIV-1 infection. Here, we report a novel mechanism by which the cyclin-dependent kinase inhibitor (CKI) p21(Waf1/Cip1/Sdi1) (p21), a known regulator of stem cell pool size, restricts HIV-1 infection of primitive hematopoietic cells. Modifying p21 expression altered HIV-1 infection prior to changes in cell cycling and was selective for p21 since silencing the related CKIs, p27(Kip1) and p18(INK4C), had no effect on HIV-1. We show that p21 blocked viral infection by complexing with HIV-1 integrase and aborting chromosomal integration. A closely related lentivirus with a distinct integrase, SIVmac-251, and the other cell-intrinsic inhibitors of HIV-1, Trim5alpha, PML, Murr1, and IFN-alpha, were unaffected by p21. Therefore, p21 is an endogenous cellular component in stem cells that provides a unique molecular barrier to HIV-1 infection and may explain how these cells remain an uninfected "sanctuary" in HIV disease.
造血干细胞对HIV-1感染具有抗性。在此,我们报告了一种新机制,即细胞周期蛋白依赖性激酶抑制剂(CKI)p21(Waf1/Cip1/Sdi1)(p21),一种已知的干细胞池大小调节因子,可限制原始造血细胞的HIV-1感染。改变p21表达在细胞周期变化之前改变了HIV-1感染,并且对p21具有选择性,因为沉默相关的CKI p27(Kip1)和p18(INK4C)对HIV-1没有影响。我们表明p21通过与HIV-1整合酶复合并中止染色体整合来阻断病毒感染。一种具有独特整合酶的密切相关慢病毒SIVmac-251,以及HIV-1的其他细胞内在抑制剂Trim5α、PML、Murr1和IFN-α,不受p21影响。因此,p21是干细胞中的一种内源性细胞成分,为HIV-1感染提供了独特的分子屏障,并且可能解释了这些细胞在HIV疾病中如何保持未感染的“避难所”状态。