Primitive hematopoietic cells resist HIV-1 infection via p21.
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.
Zhang
Jielin
J
Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
Scadden
David T
DT
Crumpacker
Clyde S
CS
D048868:Adaptor Proteins, Signal Transducing; D000090103:Antiviral Restriction Factors; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D002453:Cell Cycle; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015658:HIV Infections / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology / Q000821:virology*; D006801:Humans; D066298:In Vitro Techniques; D016898:Interferon-alpha / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D000071156:Promyelocytic Leukemia Protein; D011506:Proteins / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D000070584:Tripartite Motif Proteins; D025521:Tumor Suppressor Proteins / Q000235:genetics; D044767:Ubiquitin-Protein Ligases; D016662:Virus Integration / Q000502:physiology; D014779:Virus Replication / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000090103:Antiviral Restriction Factors; C493956:CDKN1A protein, human; C480519:COMMD1 protein, human; D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016898:Interferon-alpha; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases