The role of the human immunodeficiency virus-1 in macrophage gene transcription

HIV-1 Tat is a potent trans-activator of HIV transcription after integration of the viral DNA into the host DNA. Tat increases HIV transcription, in part, by interacting with host cyclin T and CDK9. Tat has also been shown to alter host gene transcription that might compromise an immune response after opportunistic infection of the host. Macrophages play critical roles in the innate immune response and are targeted by HIV for productive infection. The mannose receptor is expressed on the surface of macrophages and immature dendritic cells, playing a critical role in the uptake and clearance of specific pathogens. Previous studies have demonstrated decreased mannose receptor function in macrophages during HIV infection. Studies described here using transient transfection assays of mannose receptor promoter constructs driving the luciferase reporter gene indicate that Tat represses transcription from the mannose receptor promoter and that repression is due to Tat interaction with cyclin T and CDK9. Another macrophage-expressed receptor that will be focused on is the bone morphogenetic protein receptor-2 (BMPR2), a member of the TGF-β superfamily. Mutations in the gene encoding BMPR2 lead to familial primary pulmonary hypertension, a disease that is clinically and histologically indistinguishable from HIV-related pulmonary hypertension (HRPH). The etiology of HRPH is unknown and there is no long-term therapy for patients suffering from HRPH. Data presented here will show that Tat represses BMPR2 transcription in macrophages, that alteration of BMPR2 transcription decreases BMPR2 signaling, and that Tat interaction with cyclin T contributes to the repression of BMPR2 transcription.