A role for urokinase-type plasminogen activator in human immunodeficiency virus type 1 infection of macrophages

Abstract

Urokinase-type plasminogen activator (uPA), a proteinase which activates plasminogen by cleaving at-CPGR2V-, was shown to cleave the V3 loop in recombinant gp120 of human immunodeficiency virus type 1 (HIV-1) IIIB and MN strains, as well as a synthetic, cyclized peptide representing the clade B consensus sequence of V3. Proteolysis occurred at the homologous-GPGR2A-, an important neutralizing determinant of HIV-1. It required soluble CD4 and was prevented by inhibitors of uPA but not by inhibitors of likely contaminating plasma proteinases. It was accelerated by heparin, a known cofactor for plasminogen activation. In immune capture experiments, tight binding of uPA to viral particles, which did not depend on CD4, was also demonstrated. Active site-directed inhibitors of uPA diminished this binding, as did a neutralizing antibody to V3. Addition of exogenous uPA to the laboratory-adapted IIIB strain of HIV-1, the macrophage-tropic field strains JR-CSF and SF-162, or a fresh patient isolate of indeterminate tropism, followed by infection of macrophages with the various treated viruses, resulted in severalfold increases in subsequent viral replication, as judged by yields of reverse transcriptase activity and p24 antigen, as well as incorporation, as judged by PCR in situ. These responses were reversible by inhibitors or antibodies targeting the proteinase active site or the V3 loop. We propose that uPA, a transcriptionally regulated proteinase which is upregulated when macrophages are HIV infected, can be bound and utilized by the virus to aid in fusion and may be an endogenous component that is critical to the infection of macrophages by HIV-1.

Plasma Levels of Intact and Cleaved Urokinase Receptor Decrease in HIV‐1‐Infected Patients Initiating Highly Active Antiretroviral Therapy

“…As the uPAR–ligand uPA may either stimulate [69] or inhibit [70, 71] HIV‐1 replication, the decrease in plasma levels of especially suPAR(I–III) but also suPAR(II–III) and suPAR(I) in treatment‐naïve HIV‐1‐infected patients initiating HAART could have biological significance in these patients.…”

Plasmin-Coated Borrelia burgdorferi Degrades Soluble and Insoluble Components of the Mammalian Extracellular Matrix

“…It is now clear that bacteria utilize the PAS for a number of biological reasons (7), a phenomenon that has recently been extended to viruses (21,24). Specifically, streptococci, staphylococci, and yersiniae have endogenous mechanisms for activation of receptor-bound PLG (7).…”

Functional Interaction of Human Immunodeficiency Virus Type 1 Vpu and Gag with a Novel Member of the Tetratricopeptide Repeat Protein Family

“…Chemokine receptors are proteins involved in chemotaxis of immune system cells and have been co-opted by HIV-1 to allow entry into host cells in conjunction with CD4 (2,13). Urokinase-type plasminogen activator, a proteinase involved in tissue invasion by macrophages, binds to and cleaves the HIV-1 envelope glycoprotein gp120 and enhances the infectivity of HIV-1 in macrophages (24). Cyclophilins are proteins that bind to the immunosuppressive drug cyclosporin A (CsA) and are members of the immunophilin superfamily, which includes members that facilitate protein folding (18).…”