Matrix metalloproteinase dysregulation in HIV infection: implications for therapeutic strategies

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Vol.13 No.11

Matrix metalloproteinase dysregulation in HIV infection: implications for therapeutic strategies Claudio M. Mastroianni1 and Grazia M. Liuzzi2 1 2

Department of Infectious and Tropical Diseases, ‘Sapienza’ University of Rome, Ospedale S. Maria Goretti, 04100 Latina, Italy Department of Biochemistry and Molecular Biology ‘Ernesto Quagliariello’, University of Bari, Via Orabona 4, 70126 Bari, Italy

The emerging role of immune activation and inflammation in the pathogenesis of human immunodeficiency virus (HIV) disease has stimulated the search for new approaches for managing HIV infection. Recent evidence suggests that an imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs) might contribute to HIV-associated pathology by inducing remodelling of the extracellular matrix. Here, we discuss the evidence and the potential mechanisms for altered MMP or TIMP function in HIV infection and disease. Furthermore, we outline the possible medical implications for the use of compounds that target MMP activity, and we propose that antiretroviral drugs, particularly HIV protease inhibitors (PIs), and compounds with anti-inflammatory properties, such as statins, natural omega-3 fatty acids and tetracyclines, which inhibit MMP function, might represent useful therapeutic approaches to mitigate potential MMPrelated damage during HIV infection. Matrix metalloproteinases: links to HIV infection Matrix degrading metalloproteinases (MMPs) are a family of zinc-dependent, neutral endopeptidases the major targets of which include the components of the extracellular matrix (ECM), such as collagen, elastin, fibronectin and laminin [1,2]. The family of MMPs includes more than 20 members classified in six major subgroups based on substrate preferences and structural differences. The MMP family includes gelatinases, collagenases, stromelysins, matrilysins, membrane-type MMPs (MT-MMPs) and other MMPs (Table 1). Structurally, MMPs are multidomain enzymes. They all possess three common domains: the catalytic domain, the N-terminal predomain and the prodomain. The catalytic domain contains a zinc ion in the active site, which is essential for proteolytic activity. The pre-domain is a signal peptide that activates secretion and is clipped off as newly synthesized MMPs travel to the cell surface. The prodomain contains a single cysteine residue within a conserved inhibitory sequence, which is coordinated with the catalytic zinc ion and thus keeps the enzyme in a latent proform. Some additional domains are attached to the common structure in several MMPs. Corresponding author: Mastroianni, C.M. ([email protected]). Available online 29 October 2007. www.sciencedirect.com

By contrast to the other MMPs, the MT-MMPs are membrane proteins. Four MT-MMPs are characterized by a C-terminal transmembrane domain and two are glycosylphosphatidylinositol (GPI)-anchored MMPs. There are also several MMPs that do not fit into any of the above cited classes and, therefore, are classified as ‘other MMPs’. The expression and activity of MMPs are tightly regulated at several levels [3–5] (Box 1). MMPs are generally secreted as inactive precursors (pro-enzymes or zymogens) by a variety of cell types, including leukocytes, tumor cells and neural cells. MMPs are usually activated by removal of the pro-peptide in the extracellular or pericellular space in response to a variety of inducers such as cytokines, growth factors, chemical agents and physiological substances, for example metal ions, reactive oxygen species and hormones [3,4]. MMPs can be inhibited by aspecific inhibitors such as a2-macroglobulin or by a group of specific tissue inhibitors of MMPs (TIMPs) (Box 2), which bind to MMPs, forming 1:1 non-covalent complexes that inactivate the enzyme [6–8]. The balance between MMP and TIMP regulates enzyme activity in physiological conditions. An excessive or inappropriate expression of MMPs and/or a decrease in TIMP production might contribute to different pathological conditions, including inflammation, wounds, invasion of cancer cells and infectious diseases [9–11]. In particular, MMPs play an important role in the normal immune response to infection by degrading the ECM for leukocyte migration and by modulating the activity of cytokines, chemokines and defensins. Nevertheless, the imbalance between MMP and TIMP secretion after infection has been implicated in tissue damage, microbial dissemination and associated immunopathology. A pathogenetic involvement of MMPs has been described in several infectious diseases, including bacterial meningitis, endotoxic shock, mycobacterial infection, and hepatitis B and human immunodeficiency virus (HIV) infection [11]. The hallmark of HIV infection is the continuous depletion of CD4+ T cells, leading to progressive immunodeficiency, opportunistic diseases and death [12]. The introduction of potent antiretroviral treatment has produced substantial clinical benefits to individuals with HIV infection, reducing opportunistic infections, rate of hospitalization and HIV-associated mortality. Nevertheless, the toxic metabolic effects of the drugs and the persistence of a

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Table 1. The matrix metalloproteinase family Group

Enzyme

Name

Collagenases

MMP-1

Interstitial

Latent/active (kDa) 55/45

MMP-8

Neutrophil

75/58

MMP-13

Collagenase-3

60/48

Collagens I, II, III, IV, VII, IX, X, XIV; gelatin, Agg, FN, FG, proMMP-9

MMP-18

Collagenase-4

70/53

Collagen I

MMP-2

Gelatinase A

72/66

MMP-9

Gelatinase B

92/86

MMP-3

Stromelysin 1; transin

57/45/28

MMP-10

Stromelysin 2; transin-2

53/47

Collagens I, III, IV, V, VII, X, XI, XIV; gelatins, Agg, FN, PG, El, Pg, VN, LM, a1-proteinase inhibitor, proTNF-a, proMMP-1, 9, 13 Gelatins, collagens IV, V, VII, X, XIV; MBP, El, FN, Agg, Pg, proTNF-a, CXCL5, CXCL6, angiotensin-1, substance P, a1-proteinase inhibitor, VN Collagens III, IV, IX, X, XI; El, Agg, PG, FN, gelatin, LM, VN, a1-proteinase inhibitor, a2-M, proTNF-a, pro-MMP1, 7, 8, 9, 13 Collagens III, IV, V, IX, X; gelatins, FN, Agg, casein, El, PG, LM, pro-MMP1, 7, 8, 9

MMP-11

Stromelysin 3

51/44

a1-proteinase inhibitor, a2-M, casein

MMP-7

Matrilysin 1; Pump-1

28/21/19

MMP-26

Matrilysin 2

28/19

Collagens IV, X; Agg, PG, El, FN, gelatins, endactin, CD104, LM, VN, casein, Pg, MBP, proTNF-a, a1proteinase inhibitor, proMMP-1, 2, 9 Collagen IV, FN, VN, gelatins, a1proteinase inhibitor, FG, pro-MMP-9

Gelatinases

Stromelysins

Matrilysins

MT-MMPs

Other MMPs

Transmembrane MMP-14 MT1-MMP

66/56

MMP-15

MT2-MMP

72/60

MMP-16

MT3-MMP

64/52

MMP-24

MT5-MMP

GPI anchor MMP-17 MT4-MMP

57/53

MMP-25

MT6-MMP; leukolysin

56/38/45

MMP-12

Macrophage elastase

54/45/22

MMP-19

RASI 1

54/45

MMP-20 MMP-21 MMP-22 MMP-23

Enamelysin Xenopus MP Chick embryo MMP Femalysin

54/43/22 70/53 51/42

MMP-27 MMP-28

Epylysin

56/45

Main physiological substrate

Main cells producing the MMP

Collagens I, II, III, VI, VII, X; FN, gelatins, LM, activate procollagenase, a2-M, a1-proteinase inhibitor, proMMP-2,9 Collagens I, II, III, V, VI, VII, VIII, X; FN, gelatin, Agg, FG, CXCL5, CXCL6

Fibroblasts, endothelial cells, dendritic cells, keratinocytes, chondrocytes, leukocytes, odontoblast, osteoblast, tumor cells, brain cells Neutrophils, chondrocytes, fibroblasts, endothelial cells, keratinocytes, odontoblasts, osteoblasts, plasma cells Chondrocytes, endothelial cells, dendritic cells, fibroblasts, macrophages, osteoblasts, tumor cells, glial cells Endothelial cells, macrophages, cardiac myocytes, endometrial cells Fibroblasts, endothelial cells, chondrocytes, leukocytes, dendritic cells, keratinocytes, glial cells, osteoblasts, odontoblasts, tumor cells Mononuclear cells, neutrophils, chondrocytes, glial cells, fibroblasts, endothelial cells, osteoclasts, dendritic cells, endometrial cells, keratinocytes, odontoblasts, tumor cells Fibroblasts, leukocytes, keratinocytes, glial cells, endothelial cells, chondrocytes, dendritic cells, endometrial cells, odontoblasts, tumor cells Fibroblasts, tumor cells, keratinocytes, T lymphocytes, chondrocytes, osteoblasts, glial cells, endothelial cells, monocytes, odontoblasts Carcinoma cells, fibroblasts, macrophages, osteoblasts, glial cells, chondrocytes, odontoblasts Tumor cells, endothelial cells, chondrocytes, keratinocytes, glial cells, odontoblasts, mononuclear cells, osteoblasts, osteoclasts Tumor cells, endothelial cells, endometrial cells, enterocytes, keratinocytes

Collagens I, II, III; FN, Agg, El, gelatin, fibrin, LM, a2-M, proTNF-a, FG, a1proteinase inhibitor, PG, VN, proMMP-2, 13; tenascin C Agg, FN, LM, gelatin, fibrin, proTNF-a, proMMP-2 tenascin C Pro-MMP-2, collagen III, gelatin, FN, a-2M, PG, a1-proteinase inhibitor Pro-MMP-2, gelatin

Endothelial cells, fibroblasts, keratinocytes, glial cells, chondrocytes, endometrial cells, mononuclear cells, osteoblasts, osteoclasts, tumor cells Hepatocytes, myocytes, microglia, odontoblasts, osteoblasts Endothelial cells, myocytes, microglia, macrophages, odontoblasts, osteoblasts Osteoblasts, odontoblasts, astrocytomas, glioblastomas

ProMMP-2, FG, fibrin, gelatin, proTNF-a Collagen IV, gelatin, FN, TACE substrate, a1-proteinase inhibitor, fibrin, casein, proMMP-2 Collagens I, IV; Agg, El, PG, casein, FN, gelatin, FG, a1-proteinase inhibitor, VN Collagen IV, gelatin, LM, casein, El, FN, tenascin C Amelogenin, Agg Unknown Casein, gelatin Gelatin

Leukocytes, endothelial cells, osteoblasts, odontoblasts, tumor cells Leukocytes, osteoblasts, odontoblasts, tumor cells

Collagen I, gelatin, casein Casein

Endothelial cells, macrophages, astrocytes, chondrocytes, osteoclasts, dendritic cells Endothelial cells, mononuclear cells, fibroblasts, keratinocytes Chondrocytes, odontoblasts, osteoblasts Epithelial cells, tumor cells Chondrocytes, fibroblasts, odontoblasts, osteoblasts Keratinocytes

Abbreviations: a2-M, a2-macroglobulin; Agg, aggrecans; CXCL5, CXC chemokine ligand 5; CXCL6, CXC chemokine ligand 6; El, elastin; FG, fibrinogen; FN, fibronectin; LM, laminin; MBP, myelin basic protein; Pg, plasminogen; PG, proteoglycans; TACE, tumor necrosis factor-a converting enzyme; TNF-a, tumor necrosis factor-a; VN, vitronectin. The information in this table has been collected from Refs [1,4,16] and from the ExPASY Proteomics Server (http://expasy.org) which provides a catalogue of MMPs including primary literature.

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Box 1. Physiological functions and regulation of matrix metalloproteinases Matrix metalloproteinases (MMPs) are a growing family of metalloendopeptidases that cleave the protein components of the extracellular matrix (ECM) and thereby play a central role in processes that involve ECM remodelling, such as embryonic development, bone remodelling and tissue repair [1]. Although the main function of MMPs is removal of ECM during tissue resorption, it is becoming increasingly clear that MMPs, through their ability to process several bioactive molecules, are implicated in the functional regulation of non-ECM molecules, including growth factors and their receptors, cytokines and chemokines, adhesion receptors and cell-surface proteoglycans, and a variety of enzymes [9]. The overexpression of MMPs by various cell types has been implicated in the pathogenesis of many diseases and diverse invasive processes, including tissue destruction during inflammatory reactions, arthritis, periodontitis, glomerulonephritis, atherosclerosis, tissue ulceration, cancer, multiple sclerosis and infectious diseases. Among the MMP family, the gelatinases MMP-2 and MMP9 have been shown to be dysregulated in HIV infection and disease [11,16]. Given their destructive potential, the expression and activity of MMPs are tightly regulated. Most MMPs are not constitutively expressed in vivo, but can be induced in response to exogenous signals, such as cytokines, chemokines, growth factors, LPS, physiological substances and cell–cell or cell–ECM interactions (reviewed in Refs [3,4]). MMP inducers mainly act at the level of transcription through a mechanism of signal transduction that involves the phosphorylation of different serine–threonine kinases related to the mitogen-activated protein kinase (MAPK) superfamily. Different signaling cascades are involved in MMP regulation, depending on the stimulus, cell type and MMP. For example, MMP-9 transcription is driven by three different MAPK signaling cascades and is mediated by activation of the transcription factors activating protein-1 (AP-1) and nuclear factor-kappa B (NF-kB), via the c-Jun N-terminal kinases/stress-activated protein kinases (JNK/ SAPK), the extracellular signal-regulated kinases (ERK1/2) or the p38 MAPK pathways [3]. Post-transcriptional regulation of MMPs involves secretion as inactive enzymes, in which the cysteine residue present in the propeptide region binds the catalytic zinc ion. Activation of MMPs is achieved by disruption of the cystein–Zn2+ interaction, the so-called ’cystein switch’ mechanism, and enzymatic removal of the propeptide [4]. The latter is a stepwise process that involves other MMPs and different proteinases, including the endogenous plasmin that is generated from plasminogen by the action of plasminogen activators. The plasminogen–plasmin system and MMPs act in concert in several normal processes, such as angiogenesis as well as in different pathological conditions [5]. Most MMPs are secreted from cells as zymogens and are activated extracellularly. Other MMPs, such as the MT-MMPs, are activated during secretion and appear on the cell surface in the active form. A third level of MMP regulation is governed by the interaction of MMPs with tissue inhibitors of matrix metalloproteinases (TIMPs) (Box 2), which results in the formation of stable, 1:1 non-covalent enzyme–inhibitor complexes.

chronic state of immune activation, cytokine dysregulation and immune dysfunction might contribute to the development of a variety of diseases that adversely affect the clinical outcome of HIV-infected patients [13,14]. Several lines of evidence indicate that HIV infection is associated with an altered production and secretion of MMPs and TIMPs, which contribute to immunopathology, dysregulation in T-cell, monocyte/macrophage and dendritic cell (DC) trafficking and viral dissemination [15,16]. Here, we highlight the pathogenic role of MMPs and TIMPs in the development and progression of HIV-associated diseases. The excessive MMP activity related to www.sciencedirect.com

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Box 2. Tissue inhibitors of matrix metalloproteinases Tissue inhibitors of matrix metalloproteinases (TIMPs) are small (21–20 kDa) multifunctional glycoproteins that regulate MMP functions both at the level of their activation and by their ability to hydrolyze a particular substrate (see Ref. [6] for a review). Four human TIMPs have been characterized so far, and these TIMPs exihibit distinctive features with respect to structure, tissue distribution, regulation and function. TIMPs are dimers consisting of an N-terminal domain, which is largely responsible for MMP inhibition, and a smaller C-terminal domain that can bind to proMMPs and might control their autocatalytic activation. TIMPs are active as dimers. TIMP-1, TIMP-2 and TIMP-4 are present in a soluble form, whereas TIMP-3 is insoluble and bound to the ECM [7]. TIMPs are expressed by a variety of cells and are present in most tissues and body fluids. TIMPs show little differences in their specificity for MMPs, and TIMP-1 and TIMP-2 can inhibit the activity of almost all MMPs. Among the family of TIMPs, TIMP-1 is the inducible TIMP and is regulated by a network of different signaling molecules, such as cytokines and growth factors and by chemical agents [6]. Unlike TIMP-1, both TIMP-2 and -3 are effective inhibitors of MT-MMPs. The inhibition of MMPs by TIMPs is achieved through noncovalent binding between residues within the N-terminal sequence of TIMP and the MMP catalytic Zn2+ binding site. TIMPs play a major role in maintaining balance between ECM deposition and formation in different physiological processes. Numerous studies have indicated that TIMPs inhibit cellular invasion, tumorigenesis, metastasis and angiogenesis. These activities of TIMPs could be attributed to the inhibition of MMPs, but TIMPs also exhibit important regulatory activities independent of MMP inhibition. It has been demonstrated that TIMP-1 and TIMP-2 promote growth and alter cell morphology in a variety of cultured cell lines and that they possess anti-apoptotic, anti-angiogenic and erythroid potentiating activity [6]. By contrast, overexpression of TIMP-3 gene in cells increases apoptotic cell death [8]. Interestingly, TIMP-3 is also the only TIMP that can inhibit TNF-a-converting enzyme (TACE), which indicates that TIMP-3 plays a role in the modulation of inflammation. The dysregulation of TIMP expression, in particular of the inducible TIMP-1, with the consequent imbalance between TIMPs and MMPs, might lead to excessive degradation of matrix or to matrix apposition and, therefore, contribute to the pathogenesis of different diseases in which MMPs might play an important role. In the context of HIV infection, there are few studies and these have mainly investigated the role of TIMP-1. The downregulation of TIMP-1 observed in brain and CSF samples from individuals with HIV-associated dementia might contribute to pathogenesis of neural tissue damage [28]. However, the increase of TIMP-1 could play a pathogenetic role in other HIV-associated pathologies, such as HCV infection and kidney disease [56,57].

HIV-associated immune activation could be involved in the viral dissemination and the development of HIVrelated illnesses. In addition, we discuss the possible medical implications of therapeutic approaches targeting MMP activity seen in HIV-infected patients. Both macromolecular inhibitors (natural TIMPs and monoclonal antibodies) and small molecules (synthetic and natural products) have been investigated as potential therapies to counteract the excessive MMP activity in cancer and in vascular and inflammatory diseases [17]. However, technical difficulties with the biotechnological production, side effects and reduced patient compliance because of parenteral administration have greatly limited their development. To combat the MMP-related damage during HIV infection, we propose the use of compounds that inhibit MMP function and have been widely used in clinical practice. These agents include antiretroviral drugs,

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particularly HIV protease inhibitors (PIs), which represent the gold standard for the management of HIV infection, and statins, omega-3 polyunsaturated fatty acids (v-3 PUFAs) and tetracyclines, well-known compounds with anti-inflammatory properties that are capable of inhibiting MMP activity. This potential approach could have a double therapeutic effect: blocking viral replication and dissemination and counteracting the downstream consequences of chronic HIV-associated immune activation and inflammation. Dysregulation of MMPs in HIV infection Several studies have shown that MMP expression or secretion, particularly of MMP-9 (gelatinase B), is increased during HIV infection [15,16]. The abnormal MMP expression and secretion could play a pathogenetic role in HIV dissemination and associated pathology by altering cellular trafficking and by inducing remodelling of the ECM. HIV productive infection of lymphocytes and monocytes leads to increased adhesion of these cells to vascular endothelium and ECM molecules [18]. The treatment of monocytes with recombinant HIV Tat protein is also associated with the formation of large aggregates of monocytes and increased adhesion to endothelial monolayers [19]. The ability of HIV-infected mononuclear cells to traverse artificial basement membrane barriers is dependent on enhanced secretion and expression of MMP-9 [20,21]. In addition, HIV infection of human macrophage cultures in vitro promotes MMP-9 secretion and intracellular retention of TIMP-1 and TIMP-2 [22]. A recent study, which assessed virus-induced gene transcription in HIVinfected human macrophages by using cDNA expression arrays, showed that MMP-9 is one of the immediate early genes expressed after monocyte/macrophage infection in vitro [23]. HIV Tat and gp120 proteins can upregulate MMP-9 secretion from monocytes and T cells, whereas MMP-2 production can be stimulated by gp41-derived peptides [24,25]. By contrast, one study reported that MMP-9 secretion is downregulated after HIV infection of mononuclear phagocytes, but these findings could be related to different experimental conditions, such as the time of infection and the different degree of monocyte/ macrophage maturation [26]. Our group demonstrated for the first time that there is an in vivo cellular upregulation of MMP-9 in patients with HIV infection who were not receiving antiretroviral treatment [27]. HIV infection is also associated with the impairment of mechanisms that balance the enhanced MMP production and protect the tissue from ECM breakdown. Indeed, the expression of TIMPs is generally downregulated and might drive HIV-associated pathology, especially in brain tissues [28]. The mechanisms involved in the dysregulation of MMP9 production, expression and function during the course of HIV infection are not well established (Box 3). Various studies in vitro suggest a direct effect of HIV virions or viral products on MMP-9 expression [19,24,25]. The treatment of primary T cells with the viral protein gp120 induced activation of the p38/MAPK pathway, leading to increased MMP-9 transcription; conversely, the inhibition of p38 mitogen-activated protein kinase (MAPK) activation abolished MMP-9 expression [25]. However, no correlation between HIV load and MMP-9 activity has been found www.sciencedirect.com

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Box 3. Outstanding questions  What are the mechanisms involved in the dysregulation of MMP production, expression and function during the course of HIV infection?  What is the link between MMP dysregulation and chronic immune activation?  Do TIMPs contribute to HIV-associated pathology with mechanisms that are independent from MMP inhibition?  Could targeting MMPs with HIV PIs and compounds with antiinflammatory properties, such as statins, natural omega-3 (v-3) polyunsaturated fatty acids (PUFA) and tetracyclines, be used to counteract the downstream consequences of HIV-associated chronic immune activation?  Can the MMP inhibition interfere with HIV dissemination and establishment of the viral reservoir?  What are the possible detrimental effects of the long-term use of MMP inhibitors in a chronic disease such as HIV infection?

in vivo in either antiretroviral-treated or -untreated patients [27]. Therefore, possible indirect mechanisms could be involved in the increased production and expression of MMPs in HIV-infected patients. It is conceivable that the chronic immune activation and inflammation might be the main factor involved in MMP/TIMP dysregulation during HIV infection. Chronic immune activation and HIV infection It has long been recognized that HIV infection is characterized not only by the development of profound immunodeficiency but also by a marked and persistent cellular immune activation. The central role of immune activation in the pathogenesis of HIV infection has been highlighted both in animal and human studies [14]. Sooty mangabeys and African green monkeys infected with simian immunodeficiency virus (SIV), a naturally occurring lentivirus related to HIV, exhibit no or minimal T-cell activation and despite sustained high levels of viremia rarely progress to AIDS [29]. Conversely, when SIV is experimentally transferred to rhesus macaques, a massive immune activation and CD4 depletion occurs and the animals progress rapidly to AIDS and death. These findings suggest that heightened immune activation has the paradoxical effect of accelerating viral replication, CD4 depletion and disease progression. In humans, the level of immune activation is an important predictive marker of disease progression during acute and chronic HIV infection, regardless of CD4+ T-cell count and/or viral load [30–32]. This state of chronic immune activation is manifested not only in enhanced expression of phenotypic activation markers on peripheral blood T cells and B cells, but also by increased plasma levels of proinflammatory cytokines and chemokines that could be responsible for MMP overexpression [33,34]. In addition, it has been suggested that HIVassociated systemic immune activation is due to increased circulating levels of lipopolysaccharide (LPS), as a consequence of microbial translocation from a damaged gastrointestinal tract [35]. Translocated LPS, which directly correlates with several independent aspects of innate and adaptive immune activation, might also be involved in the upregulation of MMP secretion by monocytes/macrophages, DCs and neutrophils.

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The generalized immune activation can induce failure of CD4+ T-cell homeostasis by rendering CD4+ T cells more susceptible to direct HIV infection, and it might also impair the regenerative capacity of the immune system. Chronic inflammation might also be involved in the pathogenesis of some organ and metabolic disorders associated with HIV infection, including liver and kidney diseases, atherosclerosis and diabetes. Dysregulation of MMPs and HIV dissemination Increased MMP activity after HIV infection might contribute to disease progression, by inducing degradation and breakdown of matrix barriers. The tissue damage might favor the migration and spreading of HIV-infected mononuclear cells across the vascular endothelium, facilitating HIV dissemination or its persistence in immunoprivileged sanctuaries that are poorly accessible to host immune cells or antiretroviral drugs. The role of mononuclear phagocytic cells, including monocytes/macrophages and DCs, in both transmitting HIV infection and acting as reservoirs of actively replicating virus has been widely investigated [36]. In particular, DCs residing within epithelial and subepithelial surfaces (dermal DCs) are the initial targets for HIV after mucosal exposure to the virus. DCs express the CD4 receptor and co-receptors such as CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4), which are required for fusion and entry of HIV into a cell; however, the capture and uptake of HIV by DCs can occur via cell-surface interactions that are distinct from the classical infectious process. DC-specific intercellular adhesion-molecule-grabbing non-integrin (DC-SIGN) has been found to be the main C-type lectin receptor expressed on DCs that mediates binding of gp120 to HIV. [37]. In a similar manner to monocytes/macrophages, DCs are actively involved in the initiation and dissemination of infection in human tissue and viral reservoirs. Proposed potential reservoirs of infection include sites within the genitourinary tract and certain populations of monocytes and tissue macrophages, particularly those in the central nervous system (CNS) [38]. HIV enters the CNS early after primary infection, and this is believed to be attributable mainly to the transmigration of infected monocytes/macrophages into the brain, providing a source of virus that can then infect CNS resident cells, such as microglia and perivascular macrophages. Alterations of the endothelial cells of the brain microvasculature and increased permeability of the blood–brain barrier (BBB) facilitate the entry of activated and infected mononuclear cells into the CNS [39]. One mechanism by which BBB permeability might be altered is through increased activity of selected MMPs, which might also mediate both maturation and transmigration of DCs through brain microvessel endothelium [40]. The transmigration of DCs across brain endothelial cell monolayers could contribute to the maintenance of DC antigen-presenting function as well as to the dissemination of HIV infection in brain tissue. Dysregulation of MMPs and HIV-associated diseases HIV-associated neurological diseases Imbalance between MMPs and TIMPs during HIV infection might contribute to the development and progression www.sciencedirect.com

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of various HIV-associated pathological disorders (Figure 1). There is evidence that MMPs are involved in the development of HIV-associated brain injury by three main mechanisms: (i) breakdown of the BBB; (ii) degradation of myelin; (iii) induction of neuronal death [41]. MMP-9 is involved in all of these mechanisms. Pathological studies indicate that structural and functional alterations of the BBB might occur in HIV-infected patients [39]. Brain macrophages, microglia and astrocytes can not only replicate the virus actively but also play an important role in HIV-associated neural injury through the production of inflammatory mediators and various neurotoxins, including viral proteins Nef, Rev and Tat, eicosanoids (arachidonic acid and its metabolites), quinolinic acid, tumor necrosis factor-a (TNF-a), plateletactivating factor, nitric oxide and MMPs [42]. MMPs are involved in the induction of neural damage, both by their ability to degrade myelin and by toxic effects on neurons [43,44] MMP-9 in the cerebrospinal fluid (CSF) might be a marker of the presence of neurotropic viruses and of neuroinflammation [45]. The CSF of HIV-infected patients with neurological diseases exhibits myelindegrading proteolytic activity, which correlates with demyelination and with the presence of MMP-9 [43]. MMPs might also be involved in neural damage through the cleavage of proteins, releasing products with neurotoxic effects. In particular, MMP-2 secreted by HIVinfected macrophages has been reported to cleave stromal-cell-derived factor-1 (SDF-1, CXCL12), a chemokine overexpressed by astrocytes, which stimulates neuronal death both in vitro and in vivo. MMPs also interact with integrin receptors on neurons, causing apoptosis and neuronal death by a non-proteolytic mechanism that involves changes in integrin signaling [44]. HIV-associated dementia (HAD) is the main neurological disorder in which the pathogenic role of MMPs has been widely investigated. Despite the introduction of potent antiretroviral treatment, HAD still represents an important cause of morbidity in HIV-infected patients. The pathogenesis of HAD is complex and multifactorial. Studies both in animal models and humans with HAD reported the presence of increased levels of MMPs in CSF samples. Indeed, intracisternal injection of the HIV Nef protein in an experimental rat model of HIV causes a disruption of the BBB that correlates with the changes in CSF MMP-9 levels and development of neural damage [46]. In a macaque model of neuroAIDS, increased expression of MMP-9 in microglia was associated with development of cognitive and motor deficits, alterations in evoked potentials and rapid disease progression [47]. Increased levels of MMP-9 have been reported in patients with HIV infection, especially in association with HAD [48,49]. We also detected MMP-9 in 77–100% of CSF samples from HIV-infected patients with different disease manifestations, including those with HAD and CNS opportunistic infections and those who were neurologically asymptomatic [50]. A correlation between CSF MMP-9 activity and CSF cell count was found only in patients with HAD. MMP mRNA and protein levels are also increased in infected brain tissue from patients with HAD. HIV clones containing brainderived envelope fragments from patients with HAD induce more MMP-2 and -9 secretion from macrophages

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Figure 1. The possible role of MMPs in the pathogenesis of HIV-associated diseases and the potential effect of treatment. The replication of HIV leads to immune activation and altered production and secretion of MMPs and TIMPs. The enhanced secretion of MMPs after HIV-associated immune activation induces ECM degradation and hence promotes the migration and spreading of HIV through the vascular endothelium. The imbalance between MMPs and TIMPs can facilitate HIV dissemination and tissue disruption contributing to the development and progression of various HIV-associated pathologies. The use of compounds that block HIV replication and counteract both the exaggerated immune activation and the MMP activity could be useful to combat viral dissemination and HIV-associated diseases. Abbreviations: CVD, cardiovascular disease; ECM, extracellular matrix; KS, Kaposi’s sarcoma; MMPs, matrix metalloproteinases; TIMPs, tissue inhibitors of MMPs.

than do clones from nondemented patients [51]. The chronic activation of immune cells and astrocytes could downregulate the production of TIMPs that do not counteract the excessive MMP production. Indeed, CSF and brain tissue samples from HAD patients showed reduced TIMP-1 levels compared with samples from seronegative controls [28]. The increased production and expression of MMPs and the concomitant decrease in TIMPs are involved in HIV neuropathology by causing a breakdown in the BBB, by increasing inflammatory cell influx within the brain and also by generating neurotoxic products. Other HIV-associated diseases Kaposi’s sarcoma (KS), the most frequent tumor in AIDS patients, is characterized by a process of angiogenesis, which involves the breakdown of ECM by MMPs [52]. In particular, MMP-2 has been detected in plasma samples from KS patients, and it is overexpressed in cells from KS lesions [53]. Possible medical implications of these findings www.sciencedirect.com

include the use of MMP inhibitors to counteract angiogenesis and endothelial cell invasion and to promote the regression of KS lesions. MMPs have also been implicated in the development of periodontal diseases, which are usually more aggressive during HIV infection. MMPs can induce rapid ECM degradation and destruction of periodontal tissue. Indeed, increased amounts of different molecular forms of MMPs and TIMPs were reported in both salivary and gingival tissue from HIV-infected subjects and were a predictive marker of disease severity [54,55]. HIV-associated nephropathy (HIVAN) is a unique clinical and histopathological entity, and it is thought to be caused by HIV gene expression in renal tissue, resulting in injury of glomerular and tubular epithelial cells. The overexpression of MMP-9 and TIMP-1 has been reported in the glomeruli of renal biopsies of patients with HIVAN. In our opinion, these findings suggest that MMP–TIMP dysregulation could contribute to the development of pathologic process of the kidney [56].

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Recent evidence indicates that the altered balance between MMPs and TIMPs could play an important role in the development of fibrosis during chronic hepatitis C virus (HCV) infection [57]. Liver fibrosis is a process of tissue remodelling characterized by a pathological accumulation of the ECM, which reflects the imbalance between enhanced matrix synthesis and decreased breakdown of connective tissue proteins. HIV–HCV co-infected patients exhibit a striking increase in circulating TIMP-1 levels that is more evident in patients with more advanced CD4 depletion. By contrast, there is no increase in the plasma concentrations of MMP-9, suggesting an imbalance between TIMP-1 and MMP-9 [57]. These findings indicate that the altered balance between circulating MMP-9 and TIMP-1 during HIV infection might play a potential role in exacerbating progression of liver fibrosis in patients coinfected with HCV. Cytokines, such as TNF-a, and transforming growth factor-b (TGF-b), are important mediators in fibrogenesis, favoring activation of hepatic stellate cells (HSC) and stimulating ECM production [58]. In particular, TGF-b is a potent inducer of TIMP-1. It is conceivable that the HIV-associated cytokine dysregulation contributes to the activation of HSC and the upregulation of TIMPs, which, in turn, promote the progression of hepatic fibrosis through inhibition of matrix degradation [59]. Cardiovascular diseases are an increasing cause of morbidity in HIV-infected patients. Both HIV infection itself and current antiretroviral therapies can increase the cardiovascular risk in HIV-infected individuals. Antiretroviral drugs, particularly HIV PIs, adversely affect lipid and glucose metabolism, and there is a strong correlation between the risk of myocardial infarction and the duration of antiretroviral treatment [60]. Paradoxically, patients who interrupt antiretroviral drugs after years of treatment and exhibit a rebound of both HIV viral load and markers of immune activation have a short-term increase in cardiovascular events [61]. These findings suggest that HIV itself and the associated immune activation might contribute to the development of atherosclerosis and the control of HIV replication and that chronic immune activation might reduce the risk of cardiovascular disease. Interactions between circulating mononuclear cells and the vascular endothelium are key events in the pathogenesis of cardiovascular diseases such as atherosclerosis. Leukocyte adhesion to endothelial cells or to components of the endothelial basement membrane can trigger the synthesis and secretion from inflammatory and endothelial cells of MMPs, which are overexpressed in the atherosclerotic lesion and contribute to weakening of the vascular wall by degrading the extracellular matrix [62]. Both animal experiments and clinical sample analysis have shown that imbalance in expression and activation of MMPs and inhibition by TIMPs could be crucial for progression of atherosclerotic lesions and plaque rupture [63,64]. On the basis of these observations, the pathogenic link between MMP dysregulation, HIV-associated immune activation and development of atherosclerotic lesions is an important issue that needs to be thoroughly investigated. In summary, an MMP–TIMP imbalance might play a pathogenetic role in tumor, inflammatory and degenerative HIV-associated pathologies. The HIV-associated dyswww.sciencedirect.com

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regulation of MMPs can induce host tissue damage at several levels, for example by promoting angiogenesis and endothelial cell invasion in KS, by inducing tissue destruction and ECM degradation in periodontal and kidney diseases, and by contributing to the development of atherosclerosis and fibrosis in cardiovascular and liver diseases. Finally, the potential involvement of MMPs in other metabolic disorders associated with HIV infection, such as diabetes, osteoporosis and lipodystrophy, might represent a relevant issue for investigation [65]. MMPs as therapeutic targets in HIV infection The data outlined above suggest that MMP dysregulation contributes to host tissue damage in HIV disease; thus the potential for therapeutic targeting of excess MMP activity is now considered. The introduction of potent antiretroviral therapy has produced substantial clinical benefits to individuals with HIV infection, but the cost of regimens, drug toxicity, emergence of drug-resistant HIV variants and incomplete immune reconstitution are limitations of current antiretroviral drugs. As noted previously, despite complete virological suppression under treatment, many HIV-infected patients have a persistent state of immune activation, which accelerates the progression of HIVrelated disease and impairs the qualitative and quantitative restoration of the immune response. In recent years, the administration of immunosuppressive and/or antiinflammatory agents, such as prednisone, mycophenolic acid, hydroxyurea and cyclosporin A, has been investigated to counteract the chronic state of immune activation seen in AIDS patients [66]. However, the administration of these drugs in chronic HIV infection has provided limited benefits and in some cases has caused harm [67–70]. One potential reason for the failure of immunosuppressive therapy is that the immunopathological consequences of chronic immune activation are irreversible. Thus, potential therapeutic strategies should be designed not only to suppress generalized immune activation but also to counteract and possibly reverse the downstream consequences of immune activation. The use of compounds that can target MMP activity might represent an attractive challenge for the development of an adjunctive approach to treat HIV infection (Figure 1). Different synthetic, low molecular weight inhibitors of MMPs have been developed and used in clinical trials for the treatment of diseases in which matrix remodelling plays a major role [71]. Most of these inhibitors were developed by structure-based design to fit stereospecifically into the active site of MMPs. Clinical trials involving these MMP inhibitors for treatment of cancer have shown limited benefit (or even harm), which has dampened enthusiasm for this approach (Table 2). Recent findings, however, indicate that the use of selective inhibitors might lead to the development of new therapies for acute and chronic inflammatory and vascular diseases [17]. To date, clinical trials investigating the potential use of MMP inhibitors during HIV infection have been conducted only for the therapy of KS. The MMP inhibitor COL-3, a chemically modified tetracycline, was reported to be active and well tolerated in patients with AIDS-related KS in both Phase I and II trials [72]. The regression of KS lesions

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Table 2. The matrix metalloproteinase inhibitors in clinical developmenta Type

Class

Agent

Specifity

Synthetic MMP inhibitors

Peptidomimetic inhibitor

Marimastat (BB2516) Batimast (BB-94)

Nonpeptidomimetic inhibitor

Modified tetracycline

Prinomastat (AG3340) BMS-275291 CP-471 RO 32–3555 CGS 27023A Tanomastat (BAY 12–9566) Metastat (COL-3)

Diseases

Broad spectrum

Clinical trials Phase III

Broad spectrum

Phase II

Cancer Arthritis

MMP-2, -3, -9,-13, -14 MMP-2, -9 MMP-2, -3, -8, -9, -12, -13, -14 MMP-1 Broad spectrum MMP-2, -3, -9 MMP-2, -9

Tetracycline

Statins

Antiretroviral drugs

Compounds from natural sources

HIV reverse transcriptase inhibitors HIV protease inhibitors Shark cartilage extract Fatty acid

Doxycycline

Cancer

Refs [71,89]

Animal experimental studies

[71,89] [17]

Phase III

Cancer

[71,89]

Phase III Phase I, II

Cancer Cancer

[89] [89]

Phase Phase Phase Phase Phase

Arthritis Cancer, arthritis Cancer Arthritis AIDS-related Kaposi’s sarcoma Cancer Chronic periodontitis Meningitis

[89] [71] [71,89] [89] [72]

III I III II I, II

Phase I Antiinflammatory drugs

Remarks

MMP-1, -8, -9; ProMMP-9; TIMP-1

Brain diseases and HIV dementia Atherosclerosis; cardiovascular diseases Acute myocardial infarction

Human experimental studies Animal experimental studies Animal experimental studies Animal and human experimental studies

[71] [73] [74]

Minocycline

MMP-9

Cerivastatin, lovastatin, simvastatin Pravastatin

MMP-1, -2 -3, -9

Zidovudine (AZT)

MMP-2, -9

[83]

Indinavir; saquinavir; nelfinavir Neovastat (AE-941) Omega-3 PUFA

MMP-2, -9

[83,84]

a-lipoic acid

MMP-9

MMP-2, -9

MMP-1, -2, -7, -9, -12, -13 MMP-2, -9

Phase III

Human experimental studies

Cancer Multiple sclerosis Multiple sclerosis

[76,77] [78]

[80]

[89] in vitro study; human experimental studies Human experimental studies

[82] [90]

a The list of MMP inhibitors is not exhaustive; it refers to the main synthetic inhibitors used in clinical trials and in human and animal studies and to those cited in the paper. For more detailed information see Refs [17,87–89]. Abbreviation: PUFA, polyunsaturated fatty acid.

induced by COL-3 correlated with a parallel decline in serum MMP-2 levels. Tetracycline and its derivatives are naturally occurring or semi-synthetic bacteriostatic agents with a well-known broad-spectrum antibacterial activity. In addition to their antimicrobial activity, tetracyclinetype compounds, such as doxycycline and minocycline, exert anti-inflammatory effects by downregulating the release of proinflammatory chemokines and cytokines and by inhibiting the secretion of MMPs. Experimental and clinical studies have indicated that treatment with doxycycline and minocycline might be beneficial in inflammatory diseases associated with excessive MMP activity [73,74]. These findings suggest that the use of tetracycline and its derivatives could be a promising approach for targeting MMPs in HIV infection. It was reported that minocycline, a semi-synthetic tetracycline derivative, is a potent inhibitor of gelatinases [75]. Minocycline crosses the BBB easily, and it is being investigated for the treatment of multiple sclerosis (MS) and vascular neurological disorders [76]. In the experimental SIV model of HIV-associated CNS disease, minocycline has been reported to have a neuroprotective effect by reducing the severity of encephawww.sciencedirect.com

litis and decreasing the expression of CNS inflammatory markers [77]. Statins are a structurally related group of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are widely used for the management of dyslipidemia and the prevention of cardiovascular diseases. The beneficial effects of statins might also extend to mechanisms beyond lipid-lowering activity and include the improvement of endothelial function, the maintenance of atherosclerotic plaque stability and the modulation of inflammatory response by reducing proinflammatory cytokines. Recent studies indicate that these drugs also inhibit the secretion of MMP-1, MMP-3 and MMP-9 from macrophages and both human vascular endothelial and smooth muscle cells [78–80]. Inhibition of MMP secretion could contribute to the plaque-stabilizing potential of statins. The potential usefulness of statins in HIV-associated immune activation and inflammation awaits investigation. In addition, we believe that statins could display great benefits in modifying the progression of HIV-related atherosclerosis via anti-inflammatory and matrix-stabilizing mechanisms.

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TRENDS in Molecular Medicine

Omega-3 (v-3) PUFAs are natural compounds that are commonly used as lipid-lowering agents. Animal experiments and clinical intervention studies indicate that v-3 PUFAs have immunomodulatory anti-inflammatory properties and, therefore, they have also been proposed for the management of acute and chronic inflammation and for diseases involving an inappropriately activated immune response, such as MS and other autoimmune processes [81]. Recently, it has been demonstrated that the treatment with both v-3 PUFA and fish oil dose-dependently inhibits the LPS-induced expression of MMP-9 from microglial cells [82]. Although there are no data in HIV disease, we believe that the long-term administration of v-3 PUFAs in HIV-infected individuals might be useful not only for the management of metabolic disorders, but also to combat the host detrimental effect of chronic inflammation and exaggerated MMP activity. The antiretroviral drugs, particularly HIV PIs, have also been shown to inhibit MMP-2 and MMP-9 secretion and expression in LPS-stimulated astrocytes and microglia [83]. More recent data indicate that antiretroviral compounds can also significantly downregulate the expression of MMP-9 in mononuclear cells naturally infected with HIV [27]. These findings could have great therapeutic implications, suggesting that antiretroviral drugs might mitigate MMP-mediated damage by mechanisms that are independent from their ability to block HIV replication. Recent studies have indicated that part of the efficacy of PI-based therapy in controlling HIV infection and progression might be due to extravirologic properties of PIs leading to immune system modulation, blocking of inflammation, T-cell activation and cell apoptosis, and inhibition of MMP activity [84,85]. Nevertheless, the modulation of MMP production by HIV PIs could also have some detrimental effects. Indeed, a link between HIV PI-related lipodystrophic syndrome and downregulation of MMP-9 has been suggested. Chronic treatment with HIV PIs, by reducing the expression of MMP-9, might promote human adipose tissue atrophy by preventing the replacement of adipocytes [86]. At present, several findings indicate that MMPs could be a potential target for the development of adjunctive strategies for the management of HIV infection (Table 2). Preclinical evidence supports the hypothesis that the combination of antiretroviral drugs with compounds exhibiting anti-inflammatory and anti-MMP activity, such as statins, tetracyclines and v-3 PUFAs, is a promising approach, but we also acknowledge that there are important issues that should be addressed (Box 3). Concluding remarks Studies have assessed the association of MMPs and TIMPs in the process of immune dysregulation and activation seen in HIV infection. The overproduction of these enzymes and the failure to control their activity and expression might be involved in the pathogenesis of many HIV-related diseases (Figure 1). A first objective of future research should be to study the association between HIV-related diseases and a broad array of MMPs to elucidate the complexity in the interrelations of the different MMPs involved in HIV infection. In addition, the mechanisms by which TIMPs www.sciencedirect.com

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contribute to HIV-associated pathology should be elucidated further (Box 3). Because of the potential role of MMP in HIV-associated immunopathology, targeting MMP enzyme activity might constitute a novel therapeutic approach for HIV infection. In this respect, different therapeutic approaches could be considered. The first approach includes the use of synthetic inhibitors of MMPs. In the past decade, different synthetic MMP inhibitors have entered clinical trials for cancer and other diseases [17,71], but the results have been equivocal in terms of efficacy and limited selectivity [87–90]. Therefore, future directions should focus on designing more selective MMP inhibitors, considering the important role of MMPs in normal physiological processes. This goal might be achieved by a more detailed structural and functional analysis of MMPs, as well as increased knowledge of the molecular mechanisms regulating MMP gene expression. A second more practical approach concerns the development of therapeutic strategies, based on anti-MMP compounds currently used in clinical practice, which can be administered orally and have favorable pharmacokinetic and safety profiles. The antiretroviral drugs (e.g. HIV PIs) in combination with other nonspecific anti-inflammatory drugs (e.g. statins, natural fatty acids and tetracyclines) could be potential candidates for the experimental treatment of HIV-related disorders in which inhibition of MMP expression could have clinical benefits. Studies examining the impact of such therapeutic strategies on HIV disease should be strongly encouraged. Acknowledgements The authors thank Pasqua Gramegna and Tiziana Latronico for their technical assistance in the elaboration of figure and tables and for the critical reading of the manuscript.

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