The CDK inhibitor p21Cip1/WAF1 is induced by FcgammaR activation and restricts the replication of human immunodeficiency virus type 1 and related primate lentiviruses in human macrophages.
Macrophages are major targets of human immunodeficiency virus type 1 (HIV-1). We have previously shown that aggregation of activating immunoglobulin G Fc receptors (FcgammaR) by immune complexes inhibits reverse transcript accumulation and integration of HIV-1 and related lentiviruses in monocyte-derived macrophages. Here, we show that FcgammaR-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 p21(Cip1/WAF1) (p21). Small interfering RNA-mediated p21 knockdown rescued viral replication in FcgammaR-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 FcgammaR-mediated restriction also in simian immunodeficiency virus SIV(mac)- 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 FcgammaR-mediated restriction.
Bergamaschi
Anna
A
Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France.
David
Annie
A
Le Rouzic
Erwann
E
Nisole
Sébastien
S
Barré-Sinoussi
Françoise
F
Pancino
Gianfranco
G
D000818:Animals; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D055785:Gene Knockdown Techniques; D015497:HIV-1 / Q000254:growth & development* / Q000276:immunology; D015498:HIV-2 / Q000254:growth & development / Q000276:immunology; D006801:Humans; D017958:Lentiviruses, Primate / Q000254:growth & development* / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D011323:Primates; D017452:Receptors, IgG / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000254:growth & development / Q000276:immunology; D016662:Virus Integration / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
D050759:Cyclin-Dependent Kinase Inhibitor p21; D017452:Receptors, IgG