Primitive hematopoietic cells resist HIV-1 infection via p21.

Abstract

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.

• Authors: Jielin Zhang, David T Scadden, Clyde S Crumpacker
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 117 Issue 2 Pg. 473-81 (Feb 2007) ISSN: 0021-9738 [Print] United States
• PMID: 17273559 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antiviral Restriction Factors
• CDKN1A protein, human
• COMMD1 protein, human
• Carrier Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• Interferon-alpha
• Neoplasm Proteins
• Nuclear Proteins
• Promyelocytic Leukemia Protein
• Proteins
• RNA, Messenger
• RNA, Small Interfering
• Transcription Factors
• Tripartite Motif Proteins
• Tumor Suppressor Proteins
• PML protein, human
• TRIM5 protein, human
• Ubiquitin-Protein Ligases

Topics

• Adaptor Proteins, Signal Transducing
• Antiviral Restriction Factors
• Base Sequence
• Carrier Proteins (genetics)
• Cell Cycle
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p21 (antagonists & inhibitors, genetics, physiology)
• HIV Infections (genetics, physiopathology, prevention & control, virology)
• HIV-1 (pathogenicity, physiology)
• Hematopoietic Stem Cells (physiology, virology)
• Humans
• In Vitro Techniques
• Interferon-alpha (genetics)
• Neoplasm Proteins (genetics)
• Nuclear Proteins (genetics)
• Promyelocytic Leukemia Protein
• Proteins (genetics)
• RNA Interference
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Transcription Factors (genetics)
• Tripartite Motif Proteins
• Tumor Suppressor Proteins (genetics)
• Ubiquitin-Protein Ligases
• Virus Integration (physiology)
• Virus Replication (physiology)