Primitive hematopoietic cells resist HIV-1 infection via p21Waf1/Cip1/Sdi1
Jielin Zhang, … , David T. Scadden, Clyde S. Crumpacker
Jielin Zhang, … , David T. Scadden, Clyde S. Crumpacker
Published February 1, 2007
Citation Information: J Clin Invest. 2007;117(2):473-481. https://doi.org/10.1172/JCI28971.
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Primitive hematopoietic cells resist HIV-1 infection via p21Waf1/Cip1/Sdi1

Abstract

Hematopoietic stem cells are resistant to HIV-1 infection. Here, we report a novel mechanism by which the cyclin-dependent kinase inhibitor (CKI) p21Waf1/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, p27Kip1 and p18INK4C, 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, Trim5α, PML, Murr1, and IFN-α, 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

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Figure 4

p21 was present in HIV-1 PIC.

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p21 was present in HIV-1 PIC. (A–C) Detection of p21 in HIV-1 PICs. CMK ...
(A–C) Detection of p21 in HIV-1 PICs. CMK (restrictive) and H9 (permissive) cells were infected with HIV-1IIIB and cytoplasmic PICs isolated at 7 hours after infection. Viral matrix protein is a component of PICs (22, 23). (A) Crude cytoplasmic PICs were isolated from CMK cells. Antibodies against p21 or HIV-1 Gag protein matrix (MA) (50) recovered similar levels of integrase (IN) (lanes 1 and 2). Purified integrase served as a marker (lane 3). Mock-infected cell control is shown in lane 4. (B) Analyses following PIC purification by spin column chromatography. Antibodies against p21 coimmunoprecipitated p21 with integrase in CMK cells (lane 4). Antibodies against p21 failed to recover IN when CMK cells were treated with p21 siRNA (lane 6) but not when cells were treated with mutated p21-siRNA (lane 7) (15). Isotype controls IgG3k (for MA) and IgG1 (for p21) failed to recover IN (lanes 2 and 8). Purified integrase served as a marker (lane 1). (C) Anti-MA antibodies coimmunoprecipitated p21 in PICs made from CMK cells (lane 1) but not from H9 cells (lane 2). p21-containing nuclear extract served as a marker (lane 5).