Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 117, Issue 2, Pages 473-481Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI28971
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Funding
- NHLBI NIH HHS [R01 HL71859, R01 HL071859, R01 HL044851] Funding Source: Medline
- NIAID NIH HHS [K18 AI055313, K18 AI55313] Funding Source: Medline
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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, SlVmac-251, and the other cell-intrinsic inhibitors of HIV-1, Trim5 alpha, 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.
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