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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Adaptor Proteins, Signal Transducing
-
Antiviral Restriction Factors
-
Base Sequence
-
Carrier Proteins / genetics
-
Cell Cycle
-
Cells, Cultured
-
Cyclin-Dependent Kinase Inhibitor p21 / antagonists & inhibitors
-
Cyclin-Dependent Kinase Inhibitor p21 / genetics
-
Cyclin-Dependent Kinase Inhibitor p21 / physiology*
-
HIV Infections / genetics
-
HIV Infections / physiopathology
-
HIV Infections / prevention & control*
-
HIV Infections / virology
-
HIV-1 / pathogenicity*
-
HIV-1 / physiology*
-
Hematopoietic Stem Cells / physiology
-
Hematopoietic Stem Cells / virology*
-
Humans
-
In Vitro Techniques
-
Interferon-alpha / genetics
-
Neoplasm Proteins / genetics
-
Nuclear Proteins / genetics
-
Promyelocytic Leukemia Protein
-
Proteins / genetics
-
RNA Interference
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
RNA, Small Interfering / genetics
-
Transcription Factors / genetics
-
Tripartite Motif Proteins
-
Tumor Suppressor Proteins / genetics
-
Ubiquitin-Protein Ligases
-
Virus Integration / physiology
-
Virus Replication / physiology*
Substances
-
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