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Originally published online as doi:10.1189/jlb.0403176 on August 21, 2003

Published online before print August 21, 2003
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(Journal of Leukocyte Biology. 2003;74:750-756.)
© 2003 by Society for Leukocyte Biology

The role of urokinase-type plasminogen activator (uPA)/uPA receptor in HIV-1 infection

Massimo Alfano*, Nicolai Sidenius{dagger}, Francesco Blasi{ddagger},{dagger} and Guido Poli*,{ddagger},1

* AIDS Immunophatogenesis Unit, Department of Immunology and Infectious Diseases and
{dagger} Molecular Genetics Unit, Department of Molecular Biology and Functional Genomics, San Raffaele Scientific Institute, and
{ddagger} Vita-Salute University, School of Medicine, Via Olgettina n. 58, 20132 Milan, Italy

1 Correspondence: P2-P3 Laboratories, DIBIT, Via Olgettina 58, 20132, Milano, Italy. Tel.: 39-02-2643-4909; Fax: 39-02-2643-4905; E-mail: poli.guido{at}hsr.it


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ABSTRACT
 
The binding of urokinase-type plasminogen activator (uPA) to its glycosyl-phosphatidyl-inositol (GPI) anchored receptor (uPAR) mediates a variety of functions in terms of vascular homeostasis, inflammation and tissue repair. Both uPA and uPAR, as well as their soluble forms detectable in plasma and other body fluids, represent markers of cancer development and metastasis, and they have been recently described as predictors of human immunodeficiency virus (HIV) disease progression, independent of CD4+ T cell counts and viremia. A direct link between the uPA/uPAR system and HIV infection was earlier proposed in terms of cleavage of gp120 envelope by uPA. More recently, a negative regulatory effect on both acutely and chronically infected cells has been linked to the noncatalytic portion of uPA, also referred to as the amino-terminal fragment (ATF). ATF has also been described as a major CD8+ T cell soluble HIV suppressor factor. In chronically infected promonocytic U1 cells this inhibitory effect is exerted at the very late stages of the virus life cycle, involving virion budding and entrapment in intracytoplasmic vacuoles, whereas its mechanism of action in acutely infected cells remains to be defined. Since uPAR is a GPI-anchored receptor it requires association with a signaling-transducing component and different partners, which include CD11b/CD18 integrin and a G-protein coupled receptor homologous to that for the bacterial chemotactic peptide formyl-methionyl-leucyl-phenylalanine. Which signaling coreceptor(s) is(are) responsible for uPA-dependent anti-HIV effect remains currently undefined.

Key Words: macrophage • lymphocyte • interferon


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The urokinase-type plasminogen activator (uPA) and the uPA receptor (uPAR) system
 
UPA is a protein that has been first described as a protease regulating activation of plasminogen to the serine protease plasmin at the leading edge of cells, therefore influencing the rearrangement of extracellular matrix and cell migration (reviewed in [1 , 2 ]). UPA is produced as an inactive single chain precursor protein (pro-uPA), composed of two functionally independent regions: an amino-terminal fragment (ATF) responsible of the uPA binding to its own receptor (uPAR) and a carboxy-terminal catalytic domain (also named "low molecular weight fragment," LMWuPA). Binding of pro-uPA to uPAR allows activation of pro-uPA into the active enzymatic form (uPA) (Fig. 1 ), a process mediated by cell-bound plasminogen in a process referred to as reciprocal zymogen activation [3 ]. The receptor bound uPA is rapidly inactivated by specific PA inhibitors (PAI-1 and PAI-2) [4 5 6 ] that induce uPA internalization and degradation [7 , 8 ] via interaction with the {alpha}2-macroglobulin receptor [9 ], with uPAR ultimately recycling to the cell surface [10 ]. Thus, uPA biological effects can be subdivided into proteolytic and nonproteolytic functions mediated by the uPA/uPAR interaction and catalytic activity of uPA, respectively.



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  		Figure 1. uPA and uPAR. Enzymatically inactive single-chain pro-uPA is activated by membrane-bound plasmin into active uPA. Both pro-uPA and uPA are composed of two domains: a uPAR binding region (ATF) and the catalytic domain (LMW) responsible for the enzymatic activities of uPA (reviewed in [2 ]).

Proteolytic functions of uPA
UPA-mediated conversion of plasminogen to plasmin occurring at the leading edge of cells promotes cleavage of fibrinogen to fibrin and degradation of other extracellular membrane proteins [11 ], therefore regulating cell migration [12 ], physiological [13 , 14 ] and pathological tissue remodeling [15 ], and tumor invasion [16 ]. In addition, this catalytic process may affect cytokine or other inactive precursors involved in myelopoiesis sequestered in the extracellular matrix [17 , 18 ]. As discussed further, the enzymatic portion of uPA has been implicated in HIV interaction with target cells.

Nonproteolytic functions of uPA
Many different reports indicate that uPAR not only functions as a proteinase receptor, but also affects cell migration [19 ], adhesion [20 , 21 ], differentiation [20 , 22 , 23 ], and proliferation [24 , 25 ] through the formation of a trimeric uPA/uPAR complex [26 ] and generation of intracellular signaling (reviewed in [2 ]). UPAR is a three-domain (D1, D2, and D3) GPI-anchored protein [27 ] lacking a cytosolic domain and thus requiring a signaling partner. In this regard, different transmembrane proteins have been identified as mediators of a uPAR-regulated signal, including: (1) caveolin [21 , 28 ], (2) toll-like receptor-4 [29 ] (commonly associated with another GPI-anchored protein, i.e., CD14), (3) G-protein coupled receptors (GPCRs) [30 , 31 ], and (4) integrins [32 ].

Caveolin is a protein present in the small intracellular bodies, caveolae, present on the inner leaflet of the cellular membrane in which GPI-anchored proteins are concentrated (reviewed in [33 ]). Of note, uPAR also localizes in caveolae and it has been shown to coimmunoprecipitate with caveolin [21 , 28 , 34 ].

The observation that uPA/uPAR signaling and chemotaxis were inhibited by pertussis toxin, which blocks inhibitory GTP binding (Gi) receptor-associated proteins, has been interpreted as an indication that uPAR can be indeed associated with GPCRs [30 ]. In this regard, it has been recently demonstrated that FPRL1, a GPCR homologous to the high-affinity R for the bacterial chemotactic peptide formyl-methionyl-leucyl-phenylalanine (f-MLP), can transduce the chemotactic activity resulting from uPA/uPAR interaction [31 ].

UPAR has been shown to interact with many different integrins, including {alpha}3ß1, {alpha}5ß1, {alpha}Vß5, {alpha}Vß3, and CD11b/CD18 (Mac-1), as proven by coimmunoprecipitation of uPAR-{alpha}3ß1 [22 , 28 ] and uPAR-Mac-1 [32 ] or by anti-integrin antibodies (Abs) blocking uPA-dependent migration [30 , 35 , 36 ]. Two opposite models regarding uPAR/Mac-1 have been proposed: in the first model the two receptors are physically dissociated and ligand binding induces their association, thus inhibiting both integrin- and uPAR-mediated effects (Fig. 2 , Model A) [32 ]. In contrast, the second model foresees the two receptors as physically associated becoming uncoupled after formation of the uPA/uPAR complex [19 ] (Fig. 2 ).



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  		Figure 2. Opposite models of uPAR and Mac-1 interaction leading to an anti-HIV effect in U1 cells. In Model A, uPAR and Mac-1 are not physically associated and uPA binding to uPAR results in their association and signal transduction mediated by the integrin, as reported for other cell systems [19 ]. Alternatively (Model B) uPAR and Mac-1 are physically associated and binding of uPA to uPAR uncouples the two receptors [32 ]. Receptor dissociation induces either an inhibitory signal for HIV expression or it turns off a positive signal associated with cell stimulation by PMA or TNF-{alpha}. A variant of this model is the reassociation of uPAR with another signaling molecular partner.

UPA/uPAR-mediated signaling results in a wide variety of intracellular signals, characterized by activation of different kinases, including focal adhesion kinase [37 ], tyrosine kinases Src and Tyk2 [30 ], the Rho family GTPase Rac [35 , 38 ], and mitogen-activated protein kinase (MAPK), including ERK-1 and ERK-2 [30 , 37 , 39 ]. In addition, uPA/uPAR interaction has been linked to the activation of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway in epithelial kidney cells and smooth muscle cells with a pattern resembling that induced by class I interferons (IFNs) leading to activation of STAT1 and STAT2 [40 , 41 ].


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uPA/uPAR and HIV-related chemokines
 
The uPA/uPAR system has multiple and bidirectional interactions with chemokines and their receptors. Several chemokines, including CCL2, CCL3, CCL4, and CCL5, have been shown to decrease the secretion of uPA from microglial cells [42 ]. A transcriptome analysis of monocytes stimulated with CCL5 has shown up-regulation of uPAR expression [43 ]. uPA/uPAR has been reported to process CCL14 into an active form [44 ] and to modulate the chemotactic effect of CCL11 [45 ]. HIV infection of cell lines, peripheral blood mononuclear cells (PBMC) and/or monocyte-derived macrophages (MDM) has resulted in increased expression of uPAR [46 ], as well as of CCL2 [47 ], CCL3, and CCL4 [48 , 49 ] (Table 1 ).


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  		Table 1. Cross-Talk Among HIV, the uPA/uPAR System and Chemokines

Among other chemokines, a particular functional relationship seems to exist between uPA/uPAR and CCL2 in the context of HIV infection and its consequent acquired immunodeficiency syndrome (AIDS). Functionally, CCL2 inhibited uPA expression [42 ], and it counteracted the inhibitory effect of anti-uPAR Abs on the invasion of extracellular matrix by dendritic cells [50 ]. Both CCL2 and the uPA/uPAR system are up-regulated by HIV infection in vitro. In this regard, CCL2 has been shown to potentiate HIV replication in activated PBMC [51 , 52 ] and to promote the accumulation of intracellular virions in MDM by affecting the macrophage cytoskeleton [53 ] (Table 1) . In vivo, CCL2, but not other chemokines, was found up-regulated in the cerebrospinal fluid (CSF) of AIDS patients affected either by Cytomegalovirus (CMV) [54 ] or HIV [55 ] encephalitis, but not by other AIDS-associated diseases of the central nervous system (CNS). Similarly, elevated levels of suPAR have been recently observed in the CSF of HIV-infected individuals with AIDS-dementia complex or opportunistic infections of the CNS higher than in neurologically asymptomatic HIV-infected individuals (Nicolai Sidenius and P. Cinque, personal communication). Thus, a balance between uPA/uPAR and CCL2 is likely to play an important role in the regulation of the HIV life cycle, particularly in CNS infection.


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uPA/uPAR and HIV infection in vivo
 
In addition to their involvement in the pathogenesis and malignancy, high levels of uPA and/or uPAR have also been described in tissues or serum and represent major negative prognostic markers in several forms of human cancer [56 ]. Regarding susceptibility to infections uPA-deficient mice showed a reduced infiltration of CD4+/CD11b+/CD18+ cells in their lung and had an increased mortality by infection of Criptococcus neoformans [57 ]. Worthy of note, high serum levels of soluble uPAR (suPAR) were observed in a cohort of antiretroviral naïve HIV-1 infected individuals [58 ] (Table 1) . SuPAR levels were found to be highly correlated to the severity of HIV disease representing a negative prognosticator independent of and as indicative as low numbers of circulating CD4+ T cells or high levels of viremia [58 ], resembling the scenario previously observed with other markers of chronic inflammation, such as the IFN-{gamma}-related neopterin [59 ]. This observation suggests that the uPA/uPAR interaction may play an important role in the pathogenesis of HIV-1 infection and its progression toward AIDS. This hypothesis is also supported by the observation that increased levels of uPAR were found expressed on the surface of CD8+ T cells of AIDS patients [60 ] (Table 1) . Conversely, decreased expression of uPAR was demonstrated on the surface of granulocytes isolated from HIV-infected individuals (Table 1) , and its levels were significantly correlated to the number of their CD4+ T lymphocytes [61 ]. Finally, a decreased number of peripheral blood monocytes expressing uPA was found to be associated to increased levels of soluble uPA in children with AIDS [62 ] (Table 1) .


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UPA/uPAR interaction inhibits HIV replication
 
HIV enters target cells through binding of the viral envelope (Env) glycoprotein gp120 to CD4. This interaction leads to a conformational change of gp120 Env with exposure of cryptic sites, including sequences present in the hypervariable V3 loop region, resulting in the obligatory interaction with a chemokine R, either CCR5 or CXCR4, expressed on the plasma membrane of T lymphocytes and macrophages. In this regard, uPA has been shown to cleave in vitro gp120 Env in the GPGR sequence present in the V3 loop region of some HIV strains [63 ], resulting in an increase of infectivity and viral replication, although it is unclear whether this effect may also occur during conventional infection systems.

Following entry into host cells, HIV-1 RNA is retrotranscripted to DNA by the activity of the viral enzyme reverse transcriptase (RT). Thereafter, by interaction of viral and cellular proteins [64 ], one or more linear DNA molecules are integrated as provirus(es) into the host genome by action of the viral integrase. HIV transcription is mostly regulated by tandem repeat untranslated sequences present at the 5' and 3' ends of the genome and named long terminal repeats (LTRs) containing binding sites (once transcribed as RNA) for Tat and for several constitutive and inducible transcription factors, including Sp-1, AP-1, NF-kB, and NFAT [65 ]. The nuclear export of viral mRNAs is further regulated by the viral protein Rev, which interacts with several inhibitory RNA sequences dispersed in the HIV genome, as reviewed in [66 ]. Viral mRNAs are then translated by the cellular machinery; in particular, Gag is synthesized as a polyprotein precursor requiring cleavage in several functional fragments by the HIV-encoded protease [67 ]. Inhibitors of such a post-translational step represent a fundamental class of antiretroviral agents synergizing with that of RT inhibitors in various combinations of highly active antiretroviral therapy. Finally, assembly of viral proteins and genomic RNA occurs in the inner leaflet of the plasma membrane, particularly in plasma membrane compartments known as lipid rafts [68 , 69 ]. Lipid rafts are microdomains of the plasma membrane enriched in glycolipids and cholesterol that concentrate GPI-anchored proteins such as Thy-1, CD59, CD14, CD45, and uPAR. The process of new viral particle (virion) assembly, budding, and release from the plasma membrane has been very well characterized in T lymphocytes, whereas neither uPAR nor CD14 nor CD45 are taken up by the budding virions in macrophages. This observation suggests the possibility that virion budding in these cells occurs in regions of plasma membrane distinct from lipid rafts. In this regard, it has been recently reported that the Env composition of virions budding from macrophages contains proteins found in exosomes [70 ], subcellular organelles derived from the multivescicular endosome (J.E.K. Hildreth and S. J. Gould, personal communication).

Two converging lines of evidence support the hypothesis that uPA and its receptor may influence the capacity of HIV to infect and replicate in CD4+ T cells and macrophages. Searching for one or more soluble inhibitor(s) of HIV transcription and replication released by activated CD8+ T cells, as early described by J. Levy and recently referred to as CD8+ T cell antiviral factor (CAF) [71 ], M. Wada and colleagues have reported that one of the most potent antiviral activity among other candidates was associated with ATF, the receptor-binding moiety of uPA [72 ]. Of interest, Wada’s model system was based on the cocultivation of promonocytic U937 cells (bearing CD4 and CXCR4 on their cell surface) with a well-known chronically infected cell line (named U1) derived from acutely infected U937 cells following activation with phorbol 12, myristate-13, acetate (PMA). U1 is an infected cell line containing two integrated copies of HIV that is in a state of relative quiescence but in which virion production can be rapidly and potently induced by several extracellular stimuli, including proinflammatory cytokines and PMA [52 , 73 , 74 ]. CD8-supernatant derived ATF domain of uPA inhibited HIV infection of U937 cells cocultivated with activated U1 cell-derived HIV-1 line [72 ]. However, the analysis of the potential mechanism of action did not support a mechanism involved in repression of HIV transcription, typical of CAF, but rather it showed evidence of interference with a later, post-transcriptional step in the viral life cycle [72 ].

Independently, given the correlation observed between suPAR levels and HIV disease progression [58 ], we have investigated the potential effect of uPA in different models of in vitro infection. Inconsistent results were obtained in conventional systems of primary cell infection, that is, mitogen-activated PBMC (T cell blasts) and monocyte derived macrophages (MDM)-infected with viral strains differing for chemokine coreceptor usage. No effect of uPA was seen in T cell blasts, whereas a strong inhibition of viral replication was observed in MDM cultures established from a minority of donors. This variability was not justified by either uPA or uPAR levels on the donor’s cells [75 ] and remains today unexplained. However, a consistent inhibition of HIV replication was observed in ex vivo cultures of lymphoid tissue infected in vitro, a model system not requiring exogenous stimuli [76 ], as well as in acutely infected U937 cell clones [75 ]. Of interest, "minus" U937 cell clones, characterized by a poor capacity of supporting virus replication [77 78 79 ], showed higher levels of uPAR on their surface than "plus" clones. We further explored the potential anti-HIV activity of uPA and its derivatives in the U1 cell system, in analogy with the study of Wada and colleagues [72 ]. We indeed observed that either pro-uPA, uPA, or ATF (but not LMWuPA) exerted a potent inhibitory effect on HIV expression in these cells under either PMA or tumor necrosis factor-{alpha} (TNF-{alpha}) stimulation. In spite of the fact that both PMA and TNF-{alpha} are well-known transcriptional inducers of HIV expression acting via NF-kB activation, no evidence of interference with either de novo synthesis or steady-state accumulation of HIV RNA was observed in the presence of uPA. In addition, HIV protein synthesis was not found diminished whereas cell disruption restored control levels of HIV-associated RT activity [75 ]. At the ultrastructural level an increased vacuolization of the cells undergoing macrophage differentiation under PMA stimulation with features of enhanced budding and accumulation of virions in intracellular vacuoles was observed in the presence of uPA [75 ], resembling features associated with the mechanism of action of IFNs, particularly of IFN-{gamma} [80 ], and consistent with the mechanism proposed by Wada and colleagues [72 ]. However, in contrast to the described capacity of uPA/uPAR to activate the IFN-related JAK/STAT pathway in different cell types, no evidence of JAK/STAT activation was obtained in unstimulated or PMA-stimulated U1 cells [75 ]. This observation suggests that multiple signaling pathways may influence the virion maturation process.

Which signaling coreceptor is responsible for the anti-HIV effect exerted by uPA in either acutely or chronically infected cells? Although the question remains to be definitively answered we have found evidence pointing toward the integrin CD11b/CD18 (Mac-1) as a potential candidate, at least in U1 cells. In fact, only signals capable of up-regulating both uPAR and Mac-1, such as PMA or TNF-{alpha}, but not other HIV-inductive cytokines, are linked to the inhibitory effect of uPA. In addition, PMA stimulation of the ACH-2 T cell line chronically infected with HIV, like U1, resulted in the up-regulation of uPAR, but not of Mac-1 (Massimo Alfano, unpublished results), proved to be insensitive to the inhibitory action of pro-uPA, further reinforcing the hypothesis that the coexpression of uPAR and Mac-1 may be crucial for the anti-HIV effect of uPA.


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CONCLUSIONS
 
The up-regulation of uPA and uPAR observed in HIV-infected individuals may represent a mechanism of the innate immune system reacting to HIV infection and replication with an IFN-like mechanism. Yet, IFNs and uPA/uPAR appear to be nonredundant signals counteracting virus invasion, the former acting via the JAK/STAT transduction pathway [81 ], the latter via a JAK/STAT independent signaling system. The involvement of Mac-1 or other integrins appears to be counterintuitive given their ability to trigger a MAPK-dependent activation of NF-kB [82 ], although it is conceivable that ligand-induced association or dissociation of uPAR and the integrin may down-regulate this pathway or may lead to the reassociation of uPAR with a novel partner (Fig. 2) . Uncovering these basic modalities of uPA/uPAR interaction may not only lead to novel tools for preventing or curtailing HIV infection, but also for intervening in other major diseases such as cancer development and vascular pathology.

This manuscript was supported in part by grants of the IV° National Program of the ISS, Rome, Italy, for Research against AIDS, and by grants (to FB and to GP) from la Fundaciò La Maratò de TV3, Barcelona, Spain.

Received April 24, 2003; revised July 14, 2003; accepted July 17, 2003.


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