Human immunodeficiency virus type 1 infection induces cyclin T1 expression in macrophages.
The Tat protein of human immunodeficiency virus type 1 (HIV-1) is essential for viral replication and activates RNA polymerase II transcriptional elongation through the association with a cellular protein kinase composed of Cdk9 and cyclin T1. Tat binds to this kinase complex through a direct protein-protein interaction with cyclin T1. Monocytes/macrophages are important targets of HIV-1 infection, and previous work has shown that cyclin T1 but not Cdk9 protein expression is low in monocytes isolated from blood. While Cdk9 expression is expressed at a high level during monocyte differentiation to macrophages in vitro, cyclin T1 expression is induced during the first few days of differentiation and is shut off after 1 to 2 weeks. We show here that the shutoff of cyclin T1 expression in late-differentiated macrophages involves proteasome-mediated proteolysis. We also show that cyclin T1 can be reinduced by a number of pathogen-associated molecular patterns that activate macrophages, indicating that up-regulation of cyclin T1 is part of an innate immune response. Furthermore, we found that HIV-1 infection early in macrophage differentiation results in sustained cyclin T1 expression, while infection at late times in differentiation results in the reinduction of cyclin T1. Expression of the viral Nef protein from an adenovirus vector suggests that Nef contributes to the HIV-1 induction of cyclin T1. These findings suggest that HIV-1 infection hijacks a component of the innate immune response in macrophages that results in enhancement rather than inhibition of viral replication.
Liou
Li-Ying
LY
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
Herrmann
Christine H
CH
Rice
Andrew P
AP
D000256:Adenoviridae / Q000235:genetics; D056906:Cyclin T; D016213:Cyclins / Q000096:biosynthesis*; D003546:Cysteine Endopeptidases / Q000502:physiology; D015693:Gene Products, nef / Q000502:physiology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D009097:Multienzyme Complexes / Q000502:physiology; D046988:Proteasome Endopeptidase Complex; D054311:nef Gene Products, Human Immunodeficiency Virus
C503684:CCNT1 protein, human; D056906:Cyclin T; D016213:Cyclins; D015693:Gene Products, nef; D009097:Multienzyme Complexes; D054311:nef Gene Products, Human Immunodeficiency Virus; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex