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Journal of Virology, December 2009, p. 12253-12265, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01395-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The CDK Inhibitor p21Cip1/WAF1 Is Induced by Fc{gamma}R Activation and Restricts the Replication of Human Immunodeficiency Virus Type 1 and Related Primate Lentiviruses in Human Macrophages {triangledown}

Anna Bergamaschi,1 Annie David,1 Erwann Le Rouzic,2,3 Sébastien Nisole,2,3 Françoise Barré-Sinoussi,1 and Gianfranco Pancino1*

Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France,1 Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Département des Maladies Infectieuses, Paris, France,2 INSERM, U567, 27 Rue du Faubourg St. Jacques, 75014 Paris, France3

Received 7 July 2009/ Accepted 10 September 2009

Macrophages are major targets of human immunodeficiency virus type 1 (HIV-1). We have previously shown that aggregation of activating immunoglobulin G Fc receptors (Fc{gamma}R) by immune complexes inhibits reverse transcript accumulation and integration of HIV-1 and related lentiviruses in monocyte-derived macrophages. Here, we show that Fc{gamma}R-mediated restriction of HIV-1 is not due to enhanced degradation of incoming viral proteins or cDNA and is associated to the induction of the cyclin-dependent kinase inhibitor p21Cip1/WAF1 (p21). Small interfering RNA-mediated p21 knockdown rescued viral replication in Fc{gamma}R-activated macrophages and enhanced HIV-1 infection in unstimulated macrophages by increasing reverse transcript and integrated DNA levels. p21 induction by other stimuli, such as phorbol myristate acetate and the histone deacetylase inhibitor MS-275, was also associated with preintegrative blocks of HIV-1 replication in macrophages. Binding of p21 to reverse transcription/preintegration complex-associated HIV-1 proteins was not detected in yeast two-hybrid, pulldown, or coimmunoprecipitation assays, suggesting that p21 may affect viral replication independently of a specific interaction with an HIV-1 component. Consistently, p21 silencing rescued viral replication from the Fc{gamma}R-mediated restriction also in simian immunodeficiency virus SIVmac- and HIV-2-infected macrophages. Our results point to a role of p21 as an inhibitory factor of lentiviral infection in macrophages and to its implication in Fc{gamma}R-mediated restriction.

* Corresponding author. Mailing address: Institut Pasteur, Unité de Régulation des Infections Rétrovirales, 25 Rue du Docteur Roux, Paris, France. Phone: 33-1-4568 8738. Fax: 33-1-4568 8957. E-mail: gianfranco.pancino{at}pasteur.fr

{triangledown} Published ahead of print on 16 September 2009.

Journal of Virology, December 2009, p. 12253-12265, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01395-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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