Urokinase–urokinase receptor interaction mediates an inhibitory signal for HIV-1 replication

Abstract

Elevated levels of soluble urokinase-type plasminogen activator (uPA) receptor, CD87͞u-PAR, predict survival in individuals infected with HIV-1. Here, we report that pro-uPA (or uPA) inhibits HIV-1 expression in U937-derived chronically infected promonocytic U1 cells stimulated with phorbol 12-myristate 13-acetate (PMA) or tumor necrosis factor-␣ (TNF-␣). However, pro-uPA did not inhibit PMA or TNF-␣-dependent activation of nuclear factor-kB or activation protein-1 in U1 cells. Cell-associated HIV protein synthesis also was not decreased by pro-uPA, although the release of virion-associated reverse transcriptase activity was substantially inhibited, suggesting a functional analogy between pro-uPA and the antiviral effects of IFNs. Indeed, cell disruption reversed the inhibitory effect of pro-uPA on activated U1 cells, and ultrastructural analysis confirmed that virions were preferentially retained within cell vacuoles in pro-uPA treated cells. Neither expression of endogenous IFNs nor activation of the IFN-inducible Janus kinase͞ signal transducer and activator of transcription pathway were induced by pro-uPA. Pro-uPA also inhibited acute HIV replication in monocyte-derived macrophages and activated peripheral blood mononuclear cells, although with great inter-donor variability. However, pro-uPA inhibited HIV replication in acutely infected promonocytic U937 cells and in ex vivo cultures of lymphoid tissue infected in vitro. Because these effects occurred at concentrations substantially lower than those affecting thrombolysis, pro-uPA may represent a previously uncharacterized class of antiviral agents mimicking IFNs in their inhibitory effects on HIV expression and replication.

Gene Expression Profiling of Host Response in Models of Acute HIV Infection

“…PLAUR is up-regulated during in vitro HIV-1 infection studies, but down-regulated on peripheral granulocytes from HIV-1-infected patients (22). Treatment with urokinase plasminogen activator, the natural ligand for PLAUR, can block viral replication in vitro (23). Opportunistic infection of the respiratory tract remains an important cause of mortality in HIVassociated disease, particularly in children of resource-poor countries (24).…”

Pertussis Toxin B-Oligomer Suppresses IL-6 Induced HIV-1 and Chemokine Expression in Chronically Infected U1 Cells via Inhibition of Activator Protein 1

“…For this reason, this cell line has served as a useful model to identify cytokines and other factors capable of modulating HIV expression and replication in primary cells in vitro and ex vivo (28,30,31). At the molecular level, in addition to Tat (32), several cellular transcription factors with binding sites in the HIV-1 long-terminal repeats (LTR) or present in the HIV genome (33) can be activated by chemical agents such as ionomycin (34) and PMA (35), superinfection by other viruses (36,37), or cytokine stimulation (28,29). Among these latter, IL-6 was early identified as a potent HIV-inductive cytokine acting by a mechanism different from that triggered by TNF-␣ or PMA (i.e., activation of NF-B and consequent HIV-1 LTRdriven transcription) (12).…”

A functional genomic study on NCI's anticancer drug screen

“…Interaction of urokinase receptor with urokinase mediates inhibitory signal for HIV-1 replication. 22 Polarization of PLAUR at the leading edge of the migrating Kaposi's sarcoma-like vascular cells is observed when stimulated by fibroblast growth factor-2. 23 To investigate how these genes correlate with MAP4, we first take X ¼ MAP4, Y ¼ CXCL12 and Z ¼ any gene.…”