Chemokine Proteolytic Processing in HIV Infection: Neurotoxic and Neuroimmune Consequences

  • David Vergote
  • Christopher M. Overall
  • Christopher Power


Together with transcriptional and translational regulation, posttranslational modification is a pivotal mechanism regulating protein abundance and function. Proteolysis has been suggested to be the most important posttranslational modification of proteins – it affects every protein and can result in marked changes in activity and eventual clearance (Doucet et al. 2008). Not only do protein degradation and processing modulate protein stability, permitting extra- or misfolded protein recycling, but they are also important evolutionary strategies for generating bioactive molecules that affect cell function and survival. Two major enzymatic mechanisms are known to be involved in protein degradation and processing: (1) ubiquitin-dependent degradation of proteins by the proteasome and (2) protease-dependent maturation and processing of proteins with ensuing effects on their biological functions. Indeed, the maturation of numerous neuropeptides involves sequential proteolytic cleavages of a precursor protein by different proteases leading to peptide products with pleiotropic effects (see (Hallberg and Nyberg 2003) for review). Requisite maturation by proteolysis has also been reported for molecules involved in immune response including inflammatory proteins (pro-IL-1β by caspase-1/ICE and MMP-9 (Cerretti et al. 1992; Schonbeck et al. 1998), pro-TNF-α by ADAM17/TACE (Moss et al. 1997), TGFβ by plasmin (Yee et al. 1993), receptors (protease-activated receptors by their ligands) (Noorbakhsh et al. 2003), or elements of the complement cascade (Gasque 2004) to reveal their full activity. Several proteins acquire neuropathogenic properties following a proteolytic processing; one of the best examples occurs in Alzheimer’s disease in which the pathogenicity of amyloid peptides depends on proteases, namely secretases, involved in amyloid precursor protein (APP) maturation. This chapter will describe how the proteolysis of chemokines might participate in the neuropathogenesis of HIV infection, thus contributing to the development of the central nervous system disorder termed HIV-associated dementia (HAD).


Feline Immunodeficiency Virus Dipeptidyl Peptidase Antiviral Property CXCR3 Antagonist CXCR3 Ligand 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank Leah DeBlock for assistance with manuscript preparation. D.V. was supported by a Toupin Chair Fellowship. C.P. and C.M.O. hold Canada Research Chairs (T1) in Neurological Infection and Immunity, and Metalloproteinase Proteomics and Systems Biology, respectively. This research was supported by the Canadian Institutes for Health Research (CIHR), the Canadian Foundation for AIDS Research (CANFAR), National Institutes of Health (NIMH), and an Infrastructure Grant from the Michael Smith Research Foundation (University of British Columbia Centre for Blood Research). The authors have no conflicting financial interests.


  1. Ajami K, Pitman MR, Wilson CH et al (2008) Stromal cell-derived factors 1alpha and 1beta, inflammatory protein-10 and interferon-inducible T cell chemo-attractant are novel substrates of dipeptidyl peptidase 8. FEBS Lett 582:819–825PubMedCrossRefGoogle Scholar
  2. Albright AV, Shieh JT, O’Connor MJ et al (2000) Characterization of cultured microglia that can be infected by HIV-1. J Neurovirol 6(Suppl 1):S53–S60PubMedGoogle Scholar
  3. Allen SJ, Crown SE, Handel TM (2007) Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol 25:787–820PubMedCrossRefGoogle Scholar
  4. Aytac U, Dang NH (2004) CD26/dipeptidyl peptidase IV: a regulator of immune function and a potential molecular target for therapy. Curr Drug Targets Immune Endocr Metabol Disord 4:11–18PubMedCrossRefGoogle Scholar
  5. Balabanian K, Lagane B, Infantino S et al (2005) The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem 280:35760–35766PubMedCrossRefGoogle Scholar
  6. Berahovich RD, Miao Z, Wang Y et al (2005) Proteolytic activation of alternative CCR1 ligands in inflammation. J Immunol 174:7341–7351PubMedGoogle Scholar
  7. Berman NE, Marcario JK, Yong C et al (1999) Microglial activation and neurological symptoms in the SIV model of NeuroAIDS: association of MHC-II and MMP-9 expression with behavioral deficits and evoked potential changes. Neurobiol Dis 6:486–498PubMedCrossRefGoogle Scholar
  8. Biber K, Zuurman MW, Dijkstra IM et al (2002) Chemokines in the brain: neuroimmunology and beyond. Curr Opin Pharmacol 2:63–68PubMedCrossRefGoogle Scholar
  9. Booth V, Keizer DW, Kamphuis MB et al (2002) The CXCR3 binding chemokine IP-10/CXCL10: structure and receptor interactions. Biochemistry 41:10418–10425PubMedCrossRefGoogle Scholar
  10. Burns JM, Summers BC, Wang Y et al (2006) A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med 203:2201–2213PubMedCrossRefGoogle Scholar
  11. Callebaut C, Krust B, Jacotot E et al (1993) T cell activation antigen, CD26, as a cofactor for entry of HIV in CD4+ cells. Science 262:2045–2050PubMedCrossRefGoogle Scholar
  12. Callebaut C, Jacotot E, Blanco J et al (1998) Increased rate of HIV-1 entry and its cytopathic effect in CD4+/CXCR4+ T cells expressing relatively high levels of CD26. Exp Cell Res 241:352–362PubMedCrossRefGoogle Scholar
  13. Campbell JJ, Qin S, Unutmaz D et al (2001) Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire. J Immunol 166:6477–6482PubMedGoogle Scholar
  14. Cerretti DP, Kozlosky CJ, Mosley B et al (1992) Molecular cloning of the interleukin-1 beta converting enzyme. Science 256:97–100PubMedCrossRefGoogle Scholar
  15. Chandran K, Sullivan NJ, Felbor U et al (2005) Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 308:1643–1645PubMedCrossRefGoogle Scholar
  16. Chen Y, Zhang Y, Yang B et al (2007) Seroprevalence of Entamoeba histolytica infection in HIV-infected patients in China. Am J Trop Med Hyg 77:825–828PubMedGoogle Scholar
  17. Christopherson KW 2nd, Hangoc G, Broxmeyer HE (2002) Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells. J Immunol 169:7000–7008PubMedGoogle Scholar
  18. Conant K, McArthur JC, Griffin DE et al (1999) Cerebrospinal fluid levels of MMP-2, 7, and 9 are elevated in association with human immunodeficiency virus dementia. Ann Neurol 46:391–398PubMedCrossRefGoogle Scholar
  19. Conant K, St Hillaire C, Nagase H et al (2004) Matrix metalloproteinase 1 interacts with neuronal integrins and stimulates dephosphorylation of Akt. J Biol Chem 279:8056–8062PubMedCrossRefGoogle Scholar
  20. Cox JH, Overall CM (2008) Cytokine substrates: MMP regulation of inflammatory mediator signalling. In: Edwards D, Hoyer-Hansen G, Blasi F, Sloane BF (eds) The Cancer Degradome” Springer New York 519–539Google Scholar
  21. Cox JH, Dean RA, Roberts CR et al (2008) Matrix metalloproteinase processing of CXCL11/I-TAC results in loss of chemoattractant activity and altered glycosaminoglycan binding. J Biol Chem 283(28):19389–19399PubMedCrossRefGoogle Scholar
  22. Crump MP, Gong JH, Loetscher P et al (1997) Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. EMBO J 16:6996–7007PubMedCrossRefGoogle Scholar
  23. Culley FJ, Brown A, Conroy DM et al (2000) Eotaxin is specifically cleaved by hookworm metalloproteases preventing its action in vitro and in vivo. J Immunol 165:6447–6453PubMedGoogle Scholar
  24. Davis DA, Singer KE, De La Luz Sierra M et al (2005) Identification of carboxypeptidase N as an enzyme responsible for C-terminal cleavage of stromal cell-derived factor-1alpha in the circulation. Blood 105:4561–4568PubMedCrossRefGoogle Scholar
  25. De Pasquale A, Ginaldi L, Limoncelli P et al (1989) Dipeptidyl amino peptidase IV cytochemistry in circulating lymphocytes from HIV-I-seropositive subjects. Acta Haematol 81:19–21PubMedCrossRefGoogle Scholar
  26. Dean RA, Cox JH, Bellac CL et al (2008) Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, 7, 8, and 13 antagonists: potential role of the macrophage in terminating PMN influx. Blood 112(8):3455–3464PubMedCrossRefGoogle Scholar
  27. Delgado MB, Clark-Lewis I, Loetscher P et al (2001) Rapid inactivation of stromal cell-derived factor-1 by cathepsin G associated with lymphocytes. Eur J Immunol 31:699–707PubMedCrossRefGoogle Scholar
  28. Deshane J, Chen S, Caballero S et al (2007) Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism. J Exp Med 204:605–618PubMedCrossRefGoogle Scholar
  29. Detheux M, Standker L, Vakili J et al (2000) Natural proteolytic processing of hemofiltrate CC chemokine 1 generates a potent CC chemokine receptor (CCR)1 and CCR5 agonist with anti-HIV properties. J Exp Med 192:1501–1508PubMedCrossRefGoogle Scholar
  30. Dhawan S, Toro LA, Jones BE et al (1992) Interactions between HIV-infected monocytes and the extracellular matrix: HIV-infected monocytes secrete neutral metalloproteases that degrade basement membrane protein matrices. J Leukoc Biol 52:244–248PubMedGoogle Scholar
  31. Doucet A, Butler GS, Rodriguez D et al (2008) Quantitative degradomics analysis of proteolytic post-translational modifications of the cancer proteome. Mol Cell Proteomics 7(10):1925–1951PubMedCrossRefGoogle Scholar
  32. Dragic T, Litwin V, Allaway GP et al (1996) HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381:667–673PubMedCrossRefGoogle Scholar
  33. Ehlert JE, Petersen F, Kubbutat MH et al (1995) Limited and defined truncation at the C terminus enhances receptor binding and degranulation activity of the neutrophil-activating peptide 2 (NAP-2). Comparison of native and recombinant NAP-2 variants. J Biol Chem 270:6338–6344PubMedCrossRefGoogle Scholar
  34. El Messaoudi K, Thiry L, Van Tieghem N et al (1999) HIV-1 infectivity and host range modification by cathepsin D present in human vaginal secretions. AIDS 13:333–339PubMedCrossRefGoogle Scholar
  35. Ellyard JI, Simson L, Bezos A et al (2007) Eotaxin selectively binds heparin. An interaction that protects eotaxin from proteolysis and potentiates chemotactic activity in vivo. J Biol Chem 282:15238–15247PubMedCrossRefGoogle Scholar
  36. Gasque P (2004) Complement: a unique innate immune sensor for danger signals. Mol Immunol 41:1089–1098PubMedCrossRefGoogle Scholar
  37. Gelman BB, Wolf DA, Rodriguez-Wolf M et al (1997) Mononuclear phagocyte hydrolytic enzyme activity associated with cerebral HIV-1 infection. Am J Pathol 151:1437–1446PubMedGoogle Scholar
  38. Giraudon P, Buart S, Bernard A et al (1997) Cytokines secreted by glial cells infected with HTLV-I modulate the expression of matrix metalloproteinases (MMPs) and their natural inhibitor (TIMPs): possible involvement in neurodegenerative processes. Mol Psychiatry 2(107–10):84Google Scholar
  39. Gong JH, Clark-Lewis I (1995) Antagonists of monocyte chemoattractant protein 1 identified by modification of functionally critical NH2-terminal residues. J Exp Med 181:631–640PubMedCrossRefGoogle Scholar
  40. Gonzalez-Scarano F, Martin-Garcia J (2005) The neuropathogenesis of AIDS. Nat Rev Immunol 5:69–81PubMedCrossRefGoogle Scholar
  41. Gorry PR, Bristol G, Zack JA et al (2001) Macrophage tropism of human immunodeficiency virus type 1 isolates from brain and lymphoid tissues predicts neurotropism independent of coreceptor specificity. J Virol 75:10073–10089PubMedCrossRefGoogle Scholar
  42. Guan E, Wang J, Roderiquez G et al (2002) Natural truncation of the chemokine MIP-1 beta /CCL4 affects receptor specificity but not anti-HIV-1 activity. J Biol Chem 277:32348–32352PubMedCrossRefGoogle Scholar
  43. Guan E, Wang J, Norcross MA (2004) Amino-terminal processing of MIP-1beta/CCL4 by CD26/dipeptidyl-peptidase IV. J Cell Biochem 92:53–64PubMedCrossRefGoogle Scholar
  44. Hallberg M, Nyberg F (2003) Neuropeptide conversion to bioactive fragments – an important pathway in neuromodulation. Curr Protein Pept Sci 4:31–44PubMedCrossRefGoogle Scholar
  45. Hasan L, Mazzucchelli L, Liebi M et al (2006) Function of liver activation-regulated chemokine/CC chemokine ligand 20 is differently affected by cathepsin B and cathepsin D processing. J Immunol 176:6512–6522PubMedGoogle Scholar
  46. Hauser AE, Debes GF, Arce S et al (2002) Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response. J Immunol 169:1277–1282PubMedGoogle Scholar
  47. Hosono O, Homma T, Kobayashi H et al (1999) Decreased dipeptidyl peptidase IV enzyme activity of plasma soluble CD26 and its inverse correlation with HIV-1 RNA in HIV-1 infected individuals. Clin Immunol 91:283–295PubMedCrossRefGoogle Scholar
  48. Iwata S, Yamaguchi N, Munakata Y et al (1999) CD26/dipeptidyl peptidase IV differentially regulates the chemotaxis of T cells and monocytes toward RANTES: possible mechanism for the switch from innate to acquired immune response. Int Immunol 11:417–426PubMedCrossRefGoogle Scholar
  49. Jacotot E, Callebaut C, Blanco J et al (1996) HIV envelope glycoprotein-induced cell killing by apoptosis is enhanced with increased expression of CD26 in CD4+ T cells. Virology 223:318–330PubMedCrossRefGoogle Scholar
  50. Jassar BS, Harris KH, Ostashewski PM et al (1999) Ionic mechanisms of action of neurotensin in acutely dissociated neurons from the diagonal band of Broca of the rat. J Neurophysiol 81:234–246PubMedGoogle Scholar
  51. Johnston JB, Jiang Y, van Marle G et al (2000) Lentivirus infection in the brain induces matrix metalloproteinase expression: role of envelope diversity. J Virol 74:7211–7220PubMedCrossRefGoogle Scholar
  52. Johnston JB, Zhang K, Silva C et al (2001) HIV-1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors. Ann Neurol 49:230–241PubMedCrossRefGoogle Scholar
  53. Johnston JB, Silva C, Power C (2002) Envelope gene-mediated neurovirulence in feline immunodeficiency virus infection: induction of matrix metalloproteinases and neuronal injury. J Virol 76:2622–2633PubMedCrossRefGoogle Scholar
  54. Jones G, Power C (2006) Regulation of neural cell survival by HIV-1 infection. Neurobiol Dis 21:1–17PubMedCrossRefGoogle Scholar
  55. Jones GJ, Barsby NL, Cohen EA et al (2007) HIV-1 Vpr causes neuronal apoptosis and in vivo neurodegeneration. J Neurosci 27:3703–3711PubMedCrossRefGoogle Scholar
  56. Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410:988–994PubMedCrossRefGoogle Scholar
  57. Keane NM, Price P, Lee S et al (2001) An evaluation of serum soluble CD30 levels and serum CD26 (DPPIV) enzyme activity as markers of type 2 and type 1 cytokines in HIV patients receiving highly active antiretroviral therapy. Clin Exp Immunol 126:111–116PubMedCrossRefGoogle Scholar
  58. Khan MZ, Brandimarti R, Shimizu S et al (2008) The chemokine CXCL12 promotes survival of postmitotic neurons by regulating Rb protein. Cell Death Differ 15(10):1663–1672PubMedCrossRefGoogle Scholar
  59. Krijgsveld J, Zaat SA, Meeldijk J et al (2000) Thrombocidins, microbicidal proteins from human blood platelets, are C-terminal deletion products of CXC chemokines. J Biol Chem 275:20374–20381PubMedCrossRefGoogle Scholar
  60. Langford D, Sanders VJ, Mallory M et al (2002) Expression of stromal cell-derived factor 1alpha protein in HIV encephalitis. J Neuroimmunol 127:115–126PubMedCrossRefGoogle Scholar
  61. Latronico T, Liuzzi GM, Riccio P et al (2007) Antiretroviral therapy inhibits matrix metalloproteinase-9 from blood mononuclear cells of HIV-infected patients. AIDS 21:677–684PubMedCrossRefGoogle Scholar
  62. Lim JK, Burns JM, Lu W et al (2005) Multiple pathways of amino terminal processing produce two truncated variants of RANTES/CCL5. J Leukoc Biol 78:442–452PubMedCrossRefGoogle Scholar
  63. Lim JK, Lu W, Hartley O et al (2006) N-terminal proteolytic processing by cathepsin G converts RANTES/CCL5 and related analogs into a truncated 4-68 variant. J Leukoc Biol 80:1395–1404PubMedCrossRefGoogle Scholar
  64. Liuzzi GM, Mastroianni CM, Fanelli M et al (1994) Myelin degrading activity in the CSF of HIV-1-infected patients with neurological diseases. Neuroreport 6:157–160PubMedCrossRefGoogle Scholar
  65. Lopez-Herrera A, Liu Y, Rugeles MT et al (2005) HIV-1 interaction with human mannose receptor (hMR) induces production of matrix metalloproteinase 2 (MMP-2) through hMR-mediated intracellular signaling in astrocytes. Biochim Biophys Acta 1741:55–64PubMedCrossRefGoogle Scholar
  66. Mastroianni CM, Liuzzi GM (2007) Matrix metalloproteinase dysregulation in HIV infection: implications for therapeutic strategies. Trends Mol Med 13:449–459PubMedCrossRefGoogle Scholar
  67. McQuibban GA, Gong JH, Tam EM et al (2000) Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science 289:1202–1206PubMedCrossRefGoogle Scholar
  68. McQuibban GA, Butler GS, Gong JH et al (2001) Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem 276:43503–43508PubMedCrossRefGoogle Scholar
  69. McQuibban GA, Gong JH, Wong JP et al (2002) Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 100:1160–1167PubMedGoogle Scholar
  70. Moran P, Ramos F, Ramiro M et al (2005) Infection by human immunodeficiency virus-1 is not a risk factor for amebiasis. Am J Trop Med Hyg 73:296–300PubMedGoogle Scholar
  71. Moriuchi H, Moriuchi M, Fauci AS (2000) Cathepsin G, a neutrophil-derived serine protease, increases susceptibility of macrophages to acute human immunodeficiency virus type 1 infection. J Virol 74:6849–6855PubMedCrossRefGoogle Scholar
  72. Moss ML, Jin SL, Milla ME et al (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385:733–736PubMedCrossRefGoogle Scholar
  73. Nixon RA, Cataldo AM (2006) Lysosomal system pathways: genes to neurodegeneration in Alzheimer’s disease. J Alzheimers Dis 9:277–289PubMedGoogle Scholar
  74. Noorbakhsh F, Vergnolle N, Hollenberg MD et al (2003) Proteinase-activated receptors in the nervous system. Nat Rev Neurosci 4:981–990PubMedCrossRefGoogle Scholar
  75. Noorbakhsh F, Vergnolle N, McArthur JC et al (2005) Proteinase-activated receptor-2 induction by neuroinflammation prevents neuronal death during HIV infection. J Immunol 174:7320–7329PubMedGoogle Scholar
  76. Noso N, Sticherling M, Bartels J et al (1996) Identification of an N-terminally truncated form of the chemokine RANTES and granulocyte-macrophage colony-stimulating factor as major eosinophil attractants released by cytokine-stimulated dermal fibroblasts. J Immunol 156:1946–1953PubMedGoogle Scholar
  77. Nufer O, Corbett M, Walz A (1999) Amino-terminal processing of chemokine ENA-78 regulates biological activity. Biochemistry 38:636–642PubMedCrossRefGoogle Scholar
  78. Oberlin E, Amara A, Bachelerie F et al (1996) The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382:833–835PubMedCrossRefGoogle Scholar
  79. Ogilvie P, Thelen S, Moepps B et al (2004) Unusual chemokine receptor antagonism involving a mitogen-activated protein kinase pathway. J Immunol 172:6715–6722PubMedGoogle Scholar
  80. Ohtsuki T, Hosono O, Kobayashi H et al (1998) Negative regulation of the anti-human immunodeficiency virus and chemotactic activity of human stromal cell-derived factor 1alpha by CD26/dipeptidyl peptidase IV. FEBS Lett 431:236–240PubMedCrossRefGoogle Scholar
  81. Ohtsuki T, Tsuda H, Morimoto C (2000) Good or evil: CD26 and HIV infection. J Dermatol Sci 22:152–160PubMedCrossRefGoogle Scholar
  82. Okamoto T, Akaike T, Sawa T et al (2001) Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation. J Biol Chem 276:29596–29602PubMedCrossRefGoogle Scholar
  83. Okamoto M, Wang X, Baba M (2005) HIV-1-infected macrophages induce astrogliosis by SDF-1alpha and matrix metalloproteinases. Biochem Biophys Res Commun 336:1214–1220PubMedCrossRefGoogle Scholar
  84. Oravecz T, Pall M, Roderiquez G et al (1997) Regulation of the receptor specificity and function of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted) by dipeptidyl peptidase IV (CD26)-mediated cleavage. J Exp Med 186:1865–1872PubMedCrossRefGoogle Scholar
  85. Overall CM, McQuibban GA, Clark-Lewis I (2002) Discovery of chemokine substrates for matrix metalloproteinases by exosite scanning: a new tool for degradomics. Biol Chem 383:1059–1066PubMedCrossRefGoogle Scholar
  86. Palermo C, Joyce JA (2008) Cysteine cathepsin proteases as pharmacological targets in cancer. Trends Pharmacol Sci 29:22–28PubMedCrossRefGoogle Scholar
  87. Patrick MK, Johnston JB, Power C (2002) Lentiviral neuropathogenesis: comparative neuroinvasion, neurotropism, neurovirulence, and host neurosusceptibility. J Virol 76:7923–7931PubMedCrossRefGoogle Scholar
  88. Pertuz Belloso S, Ostoa Saloma P, Benitez I et al (2004) Entamoeba histolytica cysteine protease 2 (EhCP2) modulates leucocyte migration by proteolytic cleavage of chemokines. Parasite Immunol 26:237–241PubMedCrossRefGoogle Scholar
  89. Pham CT (2006) Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol 6:541–550PubMedCrossRefGoogle Scholar
  90. Poggi A, Carosio R, Fenoglio D et al (2004) Migration of V delta 1 and V delta 2 T cells in response to CXCR3 and CXCR4 ligands in healthy donors and HIV-1-infected patients: competition by HIV-1 Tat. Blood 103:2205–2213PubMedCrossRefGoogle Scholar
  91. Power C, McArthur JC, Nath A et al (1998) Neuronal death induced by brain-derived human immunodeficiency virus type 1 envelope genes differs between demented and nondemented AIDS patients. J Virol 72:9045–9053PubMedGoogle Scholar
  92. Prin-Mathieu C, Baty V, Faure G et al (2001) Assessment by flow cytometry of peripheral blood leukocyte enzymatic activities in HIV patients. J Immunol Methods 252:139–146PubMedCrossRefGoogle Scholar
  93. Proost P, Struyf S, Couvreur M et al (1998a) Posttranslational modifications affect the activity of the human monocyte chemotactic proteins MCP-1 and MCP-2: identification of MCP-2(6-76) as a natural chemokine inhibitor. J Immunol 160:4034–4041PubMedGoogle Scholar
  94. Proost P, Struyf S, Schols D et al (1998b) Processing by CD26/dipeptidyl-peptidase IV reduces the chemotactic and anti-HIV-1 activity of stromal-cell-derived factor-1alpha. FEBS Lett 432:73–76PubMedCrossRefGoogle Scholar
  95. Proost P, De Meester I, Schols D et al (1998c) Amino-terminal truncation of chemokines by CD26/dipeptidyl-peptidase IV. Conversion of RANTES into a potent inhibitor of monocyte chemotaxis and HIV-1-infection. J Biol Chem 273:7222–7227PubMedCrossRefGoogle Scholar
  96. Proost P, Menten P, Struyf S et al (2000) Cleavage by CD26/dipeptidyl peptidase IV converts the chemokine LD78beta into a most efficient monocyte attractant and CCR1 agonist. Blood 96:1674–1680PubMedGoogle Scholar
  97. Proudfoot AE, Buser R, Borlat F et al (1999) Amino-terminally modified RANTES analogues demonstrate differential effects on RANTES receptors. J Biol Chem 274:32478–32485PubMedCrossRefGoogle Scholar
  98. Qin AP, Zhang HL, Qin ZH (2008) Mechanisms of lysosomal proteases participating in cerebral ischemia-induced neuronal death. Neurosci Bull 24:117–123PubMedCrossRefGoogle Scholar
  99. Richter R, Bistrian R, Escher S et al (2005) Quantum proteolytic activation of chemokine CCL15 by neutrophil granulocytes modulates mononuclear cell adhesiveness. J Immunol 175:1599–1608PubMedGoogle Scholar
  100. Russo R, Siviglia E, Gliozzi M et al (2007) Evidence implicating matrix metalloproteinases in the mechanism underlying accumulation of IL-1beta and neuronal apoptosis in the neocortex of HIV/gp120-exposed rats. Int Rev Neurobiol 82:407–421PubMedCrossRefGoogle Scholar
  101. Ryu OH, Choi SJ, Firatli E et al (2005) Proteolysis of macrophage inflammatory protein-1alpha isoforms LD78beta and LD78alpha by neutrophil-derived serine proteases. J Biol Chem 280:17415–17421PubMedCrossRefGoogle Scholar
  102. Schols D, Proost P, Struyf S et al (1998) CD26-processed RANTES(3-68), but not intact RANTES, has potent anti-HIV-1 activity. Antiviral Res 39:175–187PubMedCrossRefGoogle Scholar
  103. Schonbeck U, Mach F, Libby P (1998) Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. J Immunol 161:3340–3346PubMedGoogle Scholar
  104. Shimizu N, Kobayashi M, Liu HY et al (1995) Detection of tryptase TL2 and CD26 antigen in brain-derived cells non-permissive to T-cell line-tropic human immunodeficiency virus type 1. FEBS Lett 358:48–52PubMedCrossRefGoogle Scholar
  105. Shioda T, Kato H, Ohnishi Y et al (1998) Anti-HIV-1 and chemotactic activities of human stromal cell-derived factor 1alpha (SDF-1alpha) and SDF-1beta are abolished by CD26/dipeptidyl peptidase IV-mediated cleavage. Proc Natl Acad Sci USA 95:6331–6336PubMedCrossRefGoogle Scholar
  106. Smith RE, Talhouk JW, Brown EE et al (1998) The significance of hypersialylation of dipeptidyl peptidase IV (CD26) in the inhibition of its activity by Tat and other cationic peptides. CD26: a subverted adhesion molecule for HIV peptide binding. AIDS Res Hum Retroviruses 14:851–868PubMedCrossRefGoogle Scholar
  107. Soejima K, Rollins BJ (2001) A functional IFN-gamma-inducible protein-10/CXCL10-specific receptor expressed by epithelial and endothelial cells that is neither CXCR3 nor glycosaminoglycan. J Immunol 167:6576–6582PubMedGoogle Scholar
  108. Sporer B, Paul R, Koedel U et al (1998) Presence of matrix metalloproteinase-9 activity in the cerebrospinal fluid of human immunodeficiency virus-infected patients. J Infect Dis 178:854–857PubMedCrossRefGoogle Scholar
  109. Struyf S, De Meester I, Scharpe S et al (1998) Natural truncation of RANTES abolishes signaling through the CC chemokine receptors CCR1 and CCR3, impairs its chemotactic potency and generates a CC chemokine inhibitor. Eur J Immunol 28:1262–1271PubMedCrossRefGoogle Scholar
  110. Struyf S, Proost P, Schols D et al (1999) CD26/dipeptidyl-peptidase IV down-regulates the eosinophil chemotactic potency, but not the anti-HIV activity of human eotaxin by affecting its interaction with CC chemokine receptor 3. J Immunol 162:4903–4909PubMedGoogle Scholar
  111. Sui Y, Stehno-Bittel L, Li S et al (2006) CXCL10-induced cell death in neurons: role of calcium dysregulation. Eur J Neurosci 23:957–964PubMedCrossRefGoogle Scholar
  112. Suryadevara R, Holter S, Borgmann K et al (2003) Regulation of tissue inhibitor of metalloproteinase-1 by astrocytes: links to HIV-1 dementia. Glia 44:47–56PubMedCrossRefGoogle Scholar
  113. Tester AM, Cox JH, Connor AR et al (2007) LPS responsiveness and neutrophil chemotaxis in vivo require PMN MMP-8 activity. PLoS One 2:e312PubMedCrossRefGoogle Scholar
  114. Vakili J, Standker L, Detheux M et al (2001) Urokinase plasminogen activator and plasmin efficiently convert hemofiltrate CC chemokine 1 into its active. J Immunol 167:3406–3413PubMedGoogle Scholar
  115. Valenzuela-Fernandez A, Planchenault T, Baleux F et al (2002) Leukocyte elastase negatively regulates Stromal cell-derived factor-1 (SDF-1)/CXCR4 binding and functions by amino-terminal processing of SDF-1 and CXCR4. J Biol Chem 277:15677–15689PubMedCrossRefGoogle Scholar
  116. Van Coillie E, Proost P, Van Aelst I et al (1998) Functional comparison of two human monocyte chemotactic protein-2 isoforms, role of the amino-terminal pyroglutamic acid and processing by CD26/dipeptidyl peptidase IV. Biochemistry 37:12672–12680PubMedCrossRefGoogle Scholar
  117. Van Damme J, Struyf S, Wuyts A et al (1999) The role of CD26/DPP IV in chemokine processing. Chem Immunol 72:42–56PubMedCrossRefGoogle Scholar
  118. van Marle G, Henry S, Todoruk T et al (2004) Human immunodeficiency virus type 1 Nef protein mediates neural cell death: a neurotoxic role for IP-10. Virology 329:302–318PubMedCrossRefGoogle Scholar
  119. Vergote D, Butler GS, Ooms M et al (2006) Proteolytic processing of SDF-1alpha reveals a change in receptor specificity mediating HIV-associated neurodegeneration. Proc Natl Acad Sci USA 103:19182–19187PubMedCrossRefGoogle Scholar
  120. Wang W, Schulze CJ, Suarez-Pinzon WL et al (2002) Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury. Circulation 106:1543–1549PubMedCrossRefGoogle Scholar
  121. Webster NL, Crowe SM (2006) Matrix metalloproteinases, their production by monocytes and macrophages and their potential role in HIV-related diseases. J Leukoc Biol 80:1052–1066PubMedCrossRefGoogle Scholar
  122. Weng Y, Siciliano SJ, Waldburger KE et al (1998) Binding and functional properties of recombinant and endogenous CXCR3 chemokine receptors. J Biol Chem 273:18288–18291PubMedCrossRefGoogle Scholar
  123. Witherden IR, Vanden Bon EJ, Goldstraw P et al (2004) Primary human alveolar type II epithelial cell chemokine release: effects of cigarette smoke and neutrophil elastase. Am J Respir Cell Mol Biol 30:500–509PubMedCrossRefGoogle Scholar
  124. Wolf M, Clark-Lewis I, Buri C et al (2003) Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer. Am J Pathol 162:1183–1190PubMedCrossRefGoogle Scholar
  125. Yee JA, Yan L, Dominguez JC et al (1993) Plasminogen-dependent activation of latent transforming growth factor beta (TGF beta) by growing cultures of osteoblast-like cells. J Cell Physiol 157:528–534PubMedCrossRefGoogle Scholar
  126. Yong VW, Power C, Forsyth P et al (2001) Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 2:502–511PubMedCrossRefGoogle Scholar
  127. Zhang K, McQuibban GA, Silva C et al (2003) HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nat Neurosci 6:1064–1071PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • David Vergote
    • 1
  • Christopher M. Overall
    • 2
  • Christopher Power
    • 1
  1. 1.Department of Medicine (Neurology), 6-11 Heritage Medical Research CentreUniversity of AlbertaEdmontonCanada
  2. 2.Molecular Biology and Biochemistry and Oral Biological and Medical SciencesUniversity of British ColumbiaVancouverCanada

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