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

Abstract

Elevated blood levels of soluble urokinase receptor (suPAR) measured by ELISA decrease in human immunodeficiency virus-1

HIV-1 Infected Lymphoid Organs Upregulate Expression and Release of the Cleaved Form of uPAR That Modulates Chemotaxis and Virus Expression

“…Both R5 and X4 HIV-1 infection increased their release as detected 9 and 12 days post-infection (Figure 3F), when virus replication was also detected by either RT activity (Figure 3A) or p24 Gag accumulation in culture supernatants (Figure 3F). There was no preferential release of suPAR vs. c-suPAR as also observed in the plasma of HIV-1 + individuals [22], [23].…”

“…Therefore, uPAR might be present at the cell membrane as both full-length and cleaved form (uPAR and c-uPAR, respectively), and the two receptors are also shed as soluble molecules (suPAR and c-suPAR, respectively) by the action of phosphatidylinositol-specific phospholipase D acting at the GPI-anchor shared by both uPAR and c-uPAR [18], [19]. Plasma levels of suPAR, c-suPAR and D-dimer have been correlated with the severity of HIV-1 disease and state of immune activation even in individuals under cART [20], [21], [22], [23], [24], [25], [26], [27]. Of note is the fact that the plasma levels of suPAR and D-dimer in HIV-1 + individuals have been shown to represent predictors of disease progression, opportunistic diseases and mortality independently of viremia levels and of CD4 + T cells counts and that they were correlated with other inflammatory markers [20], [21], [22], [23], [24], [25], [26], [27].…”

“…Plasma levels of suPAR, c-suPAR and D-dimer have been correlated with the severity of HIV-1 disease and state of immune activation even in individuals under cART [20], [21], [22], [23], [24], [25], [26], [27]. Of note is the fact that the plasma levels of suPAR and D-dimer in HIV-1 + individuals have been shown to represent predictors of disease progression, opportunistic diseases and mortality independently of viremia levels and of CD4 + T cells counts and that they were correlated with other inflammatory markers [20], [21], [22], [23], [24], [25], [26], [27]. These observations support the hypothesis that these mediators might play an active role in inflammatory processes and inflammation-driven HIV-related comorbidities.…”

Ligand-engaged urokinase-type plasminogen activator receptor and activation of the CD11b/CD18 integrin inhibit late events of HIV expression in monocytic cells

“…This observation may account for the lack of correlation between circulating levels of uPA and suPAR and viremia. 11 In contrast, suPAR levels were found to be strictly correlated with the state of immune activation in HIV-infected individuals, as determined by the serum levels of TNF-␣, 43 sTNFrII, 12,44 CCL2, CCL4, and CCL5. 45 suPAR levels also correlate with lipid and glucose metabolism in HIV-infected individuals, 43,46 as was reflected in vitro by a trend of association among the levels of HIV-1 replication in acutely infected MDMs and the levels of suPAR and uPA-suPAR complexes (Figure 2).…”

“…5,6,9,10 High serum and cerebrospinal spinal fluid levels of soluble uPAR (suPAR) have been correlated with the severity of HIV-1 disease independent of CD4 ϩ T-cell counts or viremia levels. [11][12][13][14] Furthermore, uPA expression has been observed in the brains of HIV ϩ individuals whose brains stained negatively for both HIV-1 p24 Gag antigen and uPAR, 15 suggesting a potential role of uPA as a negative regulator of HIV-1 expression. In vitro, uPA inhibits HIV-1 replication in lymphoid histocultures, primary monocytederived macrophages (MDM), promonocytic U937 cells acutely infected with HIV, and chronically infected promonocytic U1 cells stimulated with the differentiating agent phorbol 12-myristate 13-acetate (PMA) or tumor necrosis factor-␣ (TNF-␣).…”