Key Points
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Cytokines initiate and orchestrate the immune response and have a crucial role in anti-viral defence. Some cytokines have a direct anti-viral effect by inducing an anti-viral state in the cell, activating apoptosis or mediating the killing of infected cells by activated immune cells. Chemokines are a class of cytokines that control the migration of immune cells to sites of infection and inflammation.
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Large DNA viruses (poxviruses and herpesviruses) encode homologues of cytokines, chemokines and their receptors as a strategy to evade the host immune response.
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Viral cytokines have immunomodulatory activity that downregulates specific anti-viral responses, or they promote viral replication by inducing the proliferation of immune cells that are good targets for the virus.
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Soluble cytokine-receptor homologues, identified mainly in the poxvirus family, are secreted from infected cells and neutralize the activity of cytokines. Viruses also encode secreted proteins that bind cytokines but are unrelated to the cytokine receptors that are expressed at the cell surface.
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Viral homologues of chemokines might be agonists or antagonists of chemokine activity. Chemokine agonists might induce the migration of specific lymphoid cells that are good targets for viral replication, whereas chemokine antagonists might downregulate specific anti-viral immune responses.
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The chemokine-receptor homologues, which are encoded mainly by herpesviruses, are expressed by infected cells and might reduce the chemokine concentration in the vicinity of the infected cell, transmit signals inside the cell that promote viral replication or confer on the infected cell the ability to migrate to other tissues.
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A third class of anti-chemokine strategy involves the secretion from infected cells of proteins that bind chemokines with broad specificity and are unrelated to the seven-transmembrane-domain chemokine receptors, and so are new protein structures that bind chemokines. These proteins block the interaction of chemokines with their receptors and/or the presentation of chemokines to leukocytes on the surface of glycosaminoglycans, resulting in efficient neutralization of the activity of chemokines.
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Viral proteins that mimic cytokines, chemokines or their receptors might contribute directly to the pathology that is associated with viral infection, and their characterization will uncover entirely new mechanisms of viral pathogenesis that will lead to new treatment or prevention strategies for virus-associated diseases. Moreover, viral immunomodulatory proteins might help us to uncover new human genes that control immunity and new strategies of immune modulation with therapeutic potential.
Abstract
Viruses have evolved elegant mechanisms to evade detection and destruction by the host immune system. One of the evasion strategies that have been adopted by large DNA viruses is to encode homologues of cytokines, chemokines and their receptors — molecules that have a crucial role in control of the immune response. Viruses have captured host genes or evolved genes to target specific immune pathways, and so viral genomes can be regarded as repositories of important information about immune processes, offering us a viral view of the host immune system. The study of viral immunomodulatory proteins might help us to uncover new human genes that control immunity, and their characterization will increase our understanding of not only viral pathogenesis, but also normal immune mechanisms. Moreover, viral proteins indicate strategies of immune modulation that might have therapeutic potential.
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References
Tortorella, D., Gewurz, B. E., Furman, M. H., Schust, D. J. & Ploegh, H. L. Viral subversion of the immune system. Annu. Rev. Immunol. 18, 861–926 (2000).
Alcami, A. & Koszinowski, U. H. Viral mechanisms of immune evasion. Immunol. Today 21, 447–455 (2000).
McFadden, G. & Murphy, P. M. Host-related immunomodulators encoded by poxviruses and herpesviruses. Curr. Opin. Microbiol. 3, 371–378 (2000).
Nash, P. et al. Immunomodulation by viruses: the myxoma virus story. Immunol. Rev. 168, 103–120 (1999).
Smith, G. L., Symons, J. A., Khanna, A., Vanderplasschen, A. & Alcami, A. Vaccinia virus immune evasion. Immunol. Rev. 159, 137–154 (1997).
Murphy, P. M. Molecular mimicry and the generation of host defense protein diversity. Cell 72, 823–826 (1993).
Biron, C. A. Interferons α and β as immune regulators — a new look. Immunity 14, 661–664 (2001).
Redpath, S., Angulo, A., Gascoigne, N. R. & Ghazal, P. Immune checkpoints in viral latency. Annu. Rev. Microbiol. 55, 531–560 (2001).
Guidotti, L. G. & Chisari, F. V. Cytokine-mediated control of viral infections. Virology 273, 221–227 (2000).
Albini, A. et al. HIV-1 Tat protein mimicry of chemokines. Proc. Natl Acad. Sci. USA 95, 13153–13158 (1998). This study reports the chemokine-like activity of HIV Tat and its ability to induce monocyte migration, which might facilitate viral replication.
Tripp, R. A. et al. CX3C chemokine mimicry by respiratory syncytial virus G glycoprotein. Nature Immunol. 2, 732–738 (2001).
McFadden, G., Graham, K. & Opgenorth, A. in Viroceptors, Virokines and Related Immune Modulators Encoded by DNA Viruses (ed. McFadden, G.) 1–15 (R. G. Landes Company, Georgetown, Texas, 1994).
Imlach, W., McCaughan, C. A., Mercer, A. A., Haig, D. & Fleming, S. B. Orf virus-encoded interleukin-10 stimulates the proliferation of murine mast cells and inhibits cytokine synthesis in murine peritoneal macrophages. J. Gen. Virol. 83, 1049–1058 (2002).
Kotenko, S. V., Saccani, S., Izotova, L. S., Mirochnitchenko, O. V. & Pestka, S. Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc. Natl Acad. Sci. USA 97, 1695–1700 (2000).
Spencer, J. V. et al. Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10. J. Virol. 76, 1285–1292 (2002).
Spriggs, M. K. Shared resources between the neural and immune systems: semaphorins join the ranks. Curr. Opin. Immunol. 11, 387–391 (1999). This paper reviews the identification of semaphorin homologues in viral genomes and discusses their potential functions.
Gardner, J. D., Tscharke, D. C., Reading, P. C. & Smith, G. L. Vaccinia virus semaphorin A39R is a 50–55 kDa secreted glycoprotein that affects the outcome of infection in a murine intradermal model. J. Gen. Virol. 82, 2083–2093 (2001).
Smith, C. A. et al. T2 open reading frame from Shope fibroma virus encodes a soluble form of the TNF receptor. Biochem. Biophys. Res. Commun. 176, 335–342 (1991).
Alcami, A. & Smith, G. L. A soluble receptor for interleukin-1β encoded by vaccinia virus: a novel mechanism of virus modulation of the host response to infection. Cell 71, 153–167 (1992).
Spriggs, M. K. et al. Vaccinia and cowpox viruses encode a novel secreted interleukin-1-binding protein. Cell 71, 145–152 (1992).
Upton, C., Mossman, K. & McFadden, G. Encoding of a homolog of IFN-γ receptor by myxoma virus. Science 258, 1369–1372 (1992). References 18–21 report the first identification of soluble cytokine receptors encoded by viruses.
Alcami, A. & Smith, G. L. Vaccinia, cowpox and camelpox viruses encode soluble γ-interferon receptors with novel broad species specificity. J. Virol. 69, 4633–4639 (1995).
Mossman, K., Upton, C., Buller, R. M. L. & McFadden, G. Species specificity of ectromelia virus and vaccinia virus interferon-γ binding proteins. Virology 208, 762–769 (1995).
Smith, V. P. & Alcami, A. Inhibition of interferons by ectromelia virus. J. Virol. 76, 1124–1134 (2002).
Mossman, K., Upton, C. & McFadden, G. The myxoma virus soluble interferon-γ receptor homolog, M-T7, inhibits interferon-γ in a species-specific manner. J. Biol. Chem. 270, 3031–3038 (1995).
Schreiber, M., Rajarathnam, K. & McFadden, G. Myxoma virus T2 protein, a tumor-necrosis factor (TNF) receptor homolog, is secreted as a monomer and dimer that each bind rabbit TNFα, but the dimer is a more potent TNF inhibitor. J. Biol. Chem. 271, 13333–13341 (1996).
Alcami, A. & Smith, G. L. The vaccinia virus soluble interferon-γ receptor is a homodimer. J. Gen. Virol. 83, 545–549 (2002).
Lalani, A. S. et al. The purified myxoma virus γ-interferon receptor homolog M-T7 interacts with the heparin-binding domains of chemokines. J. Virol. 71, 4356–4363 (1997). This study describes the first viral chemokine-binding protein (vCKBP) to be identified in viruses, which is encoded by myxoma virus and binds a broad range of chemokines through their heparin-binding sites.
Loparev, V. N. et al. A third distinct tumor-necrosis factor receptor of orthopoxviruses. Proc. Natl Acad. Sci. USA 95, 3786–3791 (1998).
Hu, F., Smith, C. A. & Pickup, D. J. Cowpox virus contains two copies of an early gene encoding a soluble secreted form of the type II TNF receptor. Virology 204, 343–356 (1994).
Smith, C. A. et al. Cowpox virus genome encodes a second soluble homologue of cellular TNF receptors, distinct from CrmB, that binds TNF but not LTα. Virology 223, 132–147 (1996).
Saraiva, M. & Alcami, A. CrmE, a novel soluble tumor-necrosis factor receptor encoded by poxviruses. J. Virol. 75, 226–233 (2001).
Massung, R. F. et al. Potential virulence determinants in terminal regions of variola smallpox virus genome. Nature 366, 748–751 (1993).
Alcami, A., Khanna, A., Paul, N. L. & Smith, G. L. Vaccinia virus strains Lister, USSR and Evans express soluble and cell-surface tumour-necrosis factor receptors. J. Gen. Virol. 80, 949–959 (1999).
Reading, P. C., Khanna, A. & Smith, G. L. Vaccinia virus CrmE encodes a soluble and cell-surface tumor-necrosis factor receptor that contributes to virus virulence. Virology 292, 285–298 (2002).
Schreiber, M., Sedger, L. & McFadden, G. Distinct domains of M-T2, the myxoma virus TNF-receptor homolog, mediate extracellular TNF binding and intracellular apoptosis inhibition. J. Virol. 71, 2171–2181 (1997).
Benedict, C. A. et al. Cutting edge: a novel viral TNF receptor superfamily member in virulent strains of human cytomegalovirus. J. Immunol. 162, 6967–6970 (1999).
Panus, J. F. et al. Cowpox virus encodes a fifth member of the tumor-necrosis factor receptor family: a soluble, secreted CD30 homologue. Proc. Natl Acad. Sci. USA 99, 8348–8353 (2002).
Saraiva, M., Smith, P., Fallon, P. G. & Alcami, A. Inhibition of type 1 cytokine-mediated inflammation by a soluble CD30 homologue encoded by ectromelia (mousepox) virus. J. Exp. Med. 196, 829–839 (2002). References 38 and 39 report the identification of a CD30 homologue encoded by poxviruses. Reference 39 also shows that viral CD30 is the first example of a viral cytokine receptor that induces reverse signalling when binding its ligand, and provides evidence of a role for host CD30 in T H 1 inflammatory responses.
Colamonici, O. R., Domanski, P., Sweitzer, S. M., Larner, A. & Buller, R. M. L. Vaccinia virus B18R gene encodes a type I interferon-binding protein that blocks interferon-α transmembrane signaling. J. Biol. Chem. 270, 15974–15978 (1995).
Symons, J. A., Alcami, A. & Smith, G. L. Vaccinia virus encodes a soluble type I interferon receptor of novel structure and broad species specificity. Cell 81, 551–560 (1995). References 40 and 41 provide the first description of a viral secreted protein that binds cytokines, in this case IFN-α/β, and has an amino-acid sequence that is unrelated to that of the host receptor.
Xiang, Y. & Moss, B. IL-18 binding and inhibition of interferon-γ induction by human poxvirus-encoded proteins. Proc. Natl Acad. Sci. USA 96, 11537–11542 (1999).
Born, T. L. et al. A poxvirus protein that binds to and inactivates IL-18, and inhibits NK-cell response. J. Immunol. 164, 3246–3254 (2000).
Smith, V. P., Bryant, N. A. & Alcami, A. Ectromelia, vaccinia and cowpox viruses encode secreted interleukin-18-binding proteins. J. Gen. Virol. 81, 1223–1230 (2000).
Novick, D. et al. Interleukin-18 binding protein: a novel modulator of the TH1 cytokine response. Immunity 10, 127–136 (1999).
Aizawa, Y. et al. Cloning and expression of interleukin-18 binding protein. FEBS Lett. 445, 338–342 (1999).
Deane, D. et al. Orf virus encodes a novel secreted protein inhibitor of granulocyte–macrophage colony-stimulating factor and interleukin-2. J. Virol. 74, 1313–1320 (2000).
Strockbine, L. D. et al. The Epstein–Barr virus BARF1 gene encodes a novel, soluble colony-stimulating factor-1 receptor. J. Virol. 72, 4015–4021 (1998).
Alcami, A., Symons, J. A. & Smith, G. L. The vaccinia virus soluble α/β-interferon (IFN) receptor binds to the cell surface and protects cells from the antiviral effects of IFN. J. Virol. 74, 11230–11239 (2000). A new mechanism by which a soluble IFN-binding protein binds to cell surfaces to enhance its ability to prevent IFN-mediated anti-viral effects.
Baggiolini, M. Chemokines and leukocyte traffic. Nature 392, 565–568 (1998).
Schall, T. J. & Bacon, K. B. Chemokines, leukocyte trafficking and inflammation. Curr. Opin. Immunol. 6, 865–873 (1994).
Middleton, J. et al. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91, 385–395 (1997).
Cinamon, G., Shinder, V. & Alon, R. Shear forces promote lymphocyte migration across vascular endothelium bearing apical chemokines. Nature Immunol. 2, 515–522 (2001).
Lalani, A. S., Barrett, J. W. & McFadden, G. Modulating chemokines: more lessons from viruses. Immunol. Today 21, 100–106 (2000).
Murphy, P. M. Viral exploitation and subversion of the immune system through chemokine mimicry. Nature Immunol. 2, 116–122 (2001).
Locati, M. & Murphy, P. M. Chemokines and chemokine receptors: biology and clinical relevance in inflammation and AIDS. Annu. Rev. Med. 50, 425–440 (1999).
Zlotnik, A. & Yoshie, O. Chemokines: a new classification system and their role in immunity. Immunity 12, 121–127 (2000).
Lalani, A. S. et al. Use of chemokine receptors by poxviruses. Science 286, 1968–1971 (1999).
Masters, J. et al. Poxvirus infection rapidly activates tyrosine kinase signal transduction. J. Biol. Chem. 276, 48371–48375 (2001).
Kledal, T. N. et al. A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science 277, 1656–1659 (1997).
Krathwohl, M. D., Hromas, R., Brown, D. R., Broxmeyer, H. E. & Fife, K. H. Functional characterization of the CC-chemokine-like molecules encoded by molluscum contagiosum virus types 1 and 2. Proc. Natl Acad. Sci. USA 94, 9875–9880 (1997).
Damon, I., Murphy, P. M. & Moss, B. Broad-spectrum chemokine antagonistic activity of a human poxvirus chemokine homolog. Proc. Natl Acad. Sci. USA 95, 6403–6407 (1998).
Luttichau, H. R. et al. A highly selective CC-chemokine receptor (CCR)8 antagonist encoded by the poxvirus molluscum contagiosum. J. Exp. Med. 191, 171–180 (2000).
Zou, P. et al. Human herpesvirus 6 open reading frame U83 encodes a functional chemokine. J. Virol. 73, 5926–5933 (1999).
Penfold, M. E. et al. Cytomegalovirus encodes a potent α-chemokine. Proc. Natl Acad. Sci. USA 96, 9839–9844 (1999).
Boshoff, C. et al. Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science 278, 290–294 (1997). This study reports the angiogenic properties of KSHV-encoded viral macrophage inflammatory proteins (vMIPs) and their potential contribution to virus-induced pathology.
Sozzani, S. et al. The viral chemokine macrophage inflammatory protein-II is a selective TH2 chemoattractant. Blood 92, 4036–4039 (1998).
Endres, M. J., Garlisi, C. G., Xiao, H., Shan, L. & Hedrick, J. A. The Kaposi's sarcoma-related herpesvirus (KSHV)-encoded chemokine vMIP-I is a specific agonist for the CC-chemokine receptor (CCR)8. J. Exp. Med. 189, 1993–1998 (1999).
Dairaghi, D. J., Fan, R. A., McMaster, B. E., Hanley, M. R. & Schall, T. J. HHV8-encoded vMIP-I selectively engages chemokine receptor CCR8. Agonist and antagonist profiles of viral chemokines. J. Biol. Chem. 274, 21569–21574 (1999).
Stine, J. T. et al. KSHV-encoded CC-chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells. Blood 95, 1151–1157 (2000).
Weber, K. S. et al. Selective recruitment of TH2-type cells and evasion from a cytotoxic immune response mediated by viral macrophage inhibitory protein-II. Eur. J. Immunol. 31, 2458–2466 (2001). References 67–71 show the ability of KSHV-encoded vMIPs to induce the migration of T H 2 cells and to influence the type of immune response.
Arvanitakis, L., Geras-Raaka, E., Varma, A., Gershengorn, M. C. & Cesarman, E. Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 385, 347–350 (1997).
Pati, S. et al. Activation of NF-κB by the human herpesvirus 8 chemokine receptor ORF74: evidence for a paracrine model of Kaposi's sarcoma pathogenesis. J. Virol. 75, 8660–8673 (2001).
Waldhoer, M., Kledal, T. N., Farrell, H. & Schwartz, T. W. Murine cytomegalovirus (CMV) M33 and human CMV US28 receptors exhibit similar constitutive signaling activities. J. Virol. 76, 8161–8168 (2002).
Gruijthuijsen, Y. K. et al. The rat cytomegalovirus R33-encoded G-protein-coupled receptor signals in a constitutive fashion. J. Virol. 76, 1328–1338 (2002).
Bodaghi, B. et al. Chemokine sequestration by viral chemoreceptors as a novel viral escape strategy: withdrawal of chemokines from the environment of cytomegalovirus-infected cells. J. Exp. Med. 188, 855–866 (1998).
Milne, R. S. et al. RANTES binding and down-regulation by a novel human herpesvirus-6 β-chemokine receptor. J. Immunol. 164, 2396–2404 (2000).
Fraile-Ramos, A. et al. The human cytomegalovirus US28 protein is located in endocytic vesicles and undergoes constitutive endocytosis and recycling. Mol. Biol. Cell 12, 1737–1749 (2001).
Fraile-Ramos, A. et al. Localization of HCMV UL33 and US27 in endocytic compartments and viral membranes. Traffic 3, 218–232 (2002).
Martin, W. J. Chemokine receptor-related genetic sequences in an african green monkey simian cytomegalovirus-derived stealth virus. Exp. Mol. Pathol. 69, 10–16 (2000).
Alcami, A., Symons, J. A., Collins, P. D., Williams, T. J. & Smith, G. L. Blockade of chemokine activity by a soluble chemokine binding protein from vaccinia virus. J. Immunol. 160, 624–633 (1998).
Graham, K. A. et al. The T1/35kDa family of poxvirus-secreted proteins bind chemokines and modulate leukocyte influx into virus-infected tissues. Virology 229, 12–24 (1997).
Smith, C. A. et al. Poxvirus genomes encode a secreted, soluble protein that preferentially inhibits β-chemokine activity yet lacks sequence homology to known chemokine receptors. Virology 236, 316–327 (1997). References 81–83 describe the second vCKBP to be discovered, which is encoded by various poxviruses, and the first one found to bind CC-chemokines with high affinity and to block their interaction with cellular chemokine receptors.
Smith, V. P. & Alcami, A. Expression of secreted cytokine and chemokine inhibitors by ectromelia virus. J. Virol. 74, 8460–8471 (2000).
Burns, J. M., Dairaghi, D. J., Deitz, M., Tsang, M. & Schall, T. J. Comprehensive mapping of poxvirus vCCI chemokine-binding protein. Expanded range of ligand interactions and unusual dissociation kinetics. J. Biol. Chem. 277, 2785–2789 (2002).
Carfi, A., Smith, C. A., Smolak, P. J., McGrew, J. & Wiley, D. C. Structure of a soluble secreted chemokine inhibitor vCCI (p35) from cowpox virus. Proc. Natl Acad. Sci. USA 96, 12379–12383 (1999). This paper reports the first crystal structure of a vCKBP, showing that poxvirus vCKBP2 has a new type of protein fold with the ability to bind chemokines.
Seet, B. T. et al. Molecular determinants for CC-chemokine recognition by a poxvirus CC-chemokine inhibitor. Proc. Natl Acad. Sci. USA 98, 9008–9013 (2001).
Beck, C. G. et al. The viral CC-chemokine-binding protein vCCI inhibits monocyte chemoattractant protein-1 activity by masking its CCR2B-binding site. J. Biol. Chem. 276, 43270–43276 (2001).
Seet, B. T. et al. Glycosaminoglycan-binding properties of the myxoma virus CC-chemokine inhibitor, M-T1. J. Biol. Chem. 276, 30504 30513 (2001).
Parry, C. M. et al. A broad spectrum secreted chemokine-binding protein encoded by a herpesvirus. J. Exp. Med. 191, 573–578 (2000).
van Berkel, V. et al. Identification of a γ-herpesvirus selective chemokine-binding protein that inhibits chemokine action. J. Virol. 74, 6741–6747 (2000). References 90 and 91 describe the first vCKBP to be identified in herpesviruses, which binds a broad spectrum of chemokines and blocks their interaction with cellular chemokine receptors.
Alexander, J. M. et al. Structural basis of chemokine sequestration by a herpesvirus decoy receptor. Cell 111, 343–356 (2002). This study reports the crystal structure of herpesvirus CKBP3 complexed with CCL2, and provides the structural basis for chemokine recognition by secreted proteins that lack sequence similarity to seven-transmembrane-domain chemokine receptors.
Upton, C., Macen, J. L., Schreiber, M. & McFadden, G. Myxoma virus expresses a secreted protein with homology to the tumor-necrosis factor receptor gene family that contributes to viral virulence. Virology 184, 370–382 (1991).
Mossman, K. et al. Myxoma virus M-T7, a secreted homolog of the interferon-γ receptor, is a critical virulence factor for the development of myxomatosis in European rabbits. Virology 215, 17–30 (1996).
Lalani, A. S. et al. Role of the myxoma virus soluble CC-chemokine inhibitor glycoprotein, M-T1, during myxoma virus pathogenesis. Virology 256, 233–245 (1999).
Bridgeman, A., Stevenson, P. G., Simas, J. P. & Efstathiou, S. A secreted chemokine-binding protein encoded by murine γ-herpesvirus-68 is necessary for the establishment of a normal latent load. J. Exp. Med. 194, 301–312 (2001).
van Berkel, V. et al. Critical role for a high-affinity chemokine-binding protein in γ-herpesvirus-induced lethal meningitis. J. Clin. Invest. 109, 905–914 (2002).
Jensen, K. K. et al. Disruption of CCL21-induced chemotaxis in vitro and in vivo by M3, a chemokine-binding protein encoded by murine γ-herpesvirus 68. J. Virol. (in the press).
Alcami, A. & Smith, G. L. A mechanism for the inhibition of fever by a virus. Proc. Natl Acad. Sci. USA 93, 11029–11034 (1996). This article describes the ability of vaccinia virus IL-1β receptor to block the fever response and adverse effects in the infected host, and illustrates how viral cytokine receptors can provide new insights into the function of cytokines in vivo.
Miller, C. G., Shchelkunov, S. N. & Kotwal, G. J. The cowpox virus-encoded homolog of the vaccinia virus complement control protein is an inflammation modulatory protein. Virology 229, 126–133 (1997).
Aguado, B., Selmes, I. P. & Smith, G. L. Nucleotide sequence of 21.8 kbp of variola major virus strain Harvey and comparison with vaccinia virus. J. Gen. Virol. 73, 2887–2902 (1992).
Shchelkunov, S. N. et al. The genomic sequence analysis of the left and right species-specific terminal region of a cowpox virus strain reveals unique sequences and a cluster of intact ORFs for immunomodulatory and host-range proteins. Virology 243, 432–460 (1998).
Moss, B., Shisler, J. L., Xiang, Y. & Senkevich, T. G. Immune-defense molecules of molluscum contagiosum virus, a human poxvirus. Trends Microbiol. 8, 473–477 (2000).
Wise, L. M. et al. Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1. Proc. Natl Acad. Sci. USA 96, 3071–3076 (1999).
Meyer, M. et al. A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. EMBO J. 18, 363–374 (1999).
Savory, L. J., Stacker, S. A., Fleming, S. B., Niven, B. E. & Mercer, A. A. Viral vascular endothelial growth factor plays a critical role in orf virus infection. J. Virol. 74, 10699–10706 (2000).
Fleming, P. et al. The murine cytomegalovirus chemokine homolog, m131/129, is a determinant of viral pathogenicity. J. Virol. 73, 6800–6809 (1999).
Saederup, N., Lin, Y. C., Dairaghi, D. J., Schall, T. J. & Mocarski, E. S. Cytomegalovirus-encoded β-chemokine promotes monocyte-associated viremia in the host. Proc. Natl Acad. Sci. USA 96, 10881–10886 (1999).
Davis-Poynter, N. J. et al. Identification and characterization of a G-protein-coupled receptor homolog encoded by murine cytomegalovirus. J. Virol. 71, 1521–1529 (1997). The first report to provide evidence that viral chemokine receptors (vCKRs) have a role in the infected host.
Yang, T. Y. et al. Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi's sarcoma. J. Exp. Med. 191, 445–454 (2000). This study shows that expression of KSHV ORF74 by transgenic mice is sufficient to induce Kaposi's sarcomas associated with KSHV, providing evidence of a direct role for vCKRs in mediating pathology.
Cesarman, E., Mesri, E. A. & Gershengorn, M. C. Viral G-protein-coupled receptor and Kaposi's sarcoma: a model of paracrine neoplasia? J. Exp. Med. 191, 417–422 (2000).
Rosenkilde, M. M., Kledal, T. N., Brauner-Osborne, H. & Schwartz, T. W. Agonists and inverse agonists for the herpesvirus-8-encoded constitutively active seven-transmembrane oncogene product, ORF-74. J. Biol. Chem. 274, 956–961 (1999).
Holst, P. J. et al. Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity. J. Clin. Invest. 108, 1789–1796 (2001).
Kirshner, J. R., Staskus, K., Haase, A., Lagunoff, M. & Ganem, D. Expression of the open reading frame 74 (G-protein-coupled receptor) gene of Kaposi's sarcoma (KS)-associated herpesvirus: implications for KS pathogenesis. J. Virol. 73, 6006–6014 (1999).
Aoki, Y. et al. Angiogenesis and hematopoiesis induced by Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6. Blood 93, 4034–4043 (1999).
Jones, K. D. et al. Involvement of interleukin-10 (IL-10) and viral IL-6 in the spontaneous growth of Kaposi's sarcoma herpesvirus-associated infected primary effusion lymphoma cells. Blood 94, 2871–2879 (1999).
Streblow, D. N. et al. The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration. Cell 99, 511–520 (1999). This study provides evidence that HCMV US28 confers on muscle cells the ability to migrate, and provides the molecular basis that links HCMV to vascular disease.
Pleskoff, O. et al. Identification of a chemokine receptor encoded by human cytomegalovirus as a cofactor for HIV-1 entry. Science 276, 1874–1878 (1997).
Yao, Z. et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3, 811–821 (1995).
Xiang, Y. & Moss, B. Identification of human and mouse homologs of the MC51L-53L-54L family of secreted glycoproteins encoded by the Molluscum contagiosum poxvirus. Virology 257, 297–302 (1999).
Ishikawa-Mochizuki, I. et al. Molecular cloning of a novel CC-chemokine, interleukin-11 receptor α-locus chemokine (ILC), which is located on chromosome 9p13 and a potential homologue of a CC-chemokine encoded by molluscum contagiosum virus. FEBS Lett. 460, 544–548 (1999).
Tidona, C. A. & Darai, G. The complete DNA sequence of lymphocystis disease virus. Virology 230, 207–216 (1997).
Ng, A., Tscharke, D. C., Reading, P. C. & Smith, G. L. The vaccinia virus A41L protein is a soluble 30 kDa glycoprotein that affects virus virulence. J. Gen. Virol. 82, 2095–2105 (2001).
Murphy, P. M. Viral antichemokines: from pathogenesis to drug discovery. J. Clin. Invest. 105, 1515–1517 (2000).
Dabbagh, K. et al. Local blockade of allergic airway hyperreactivity and inflammation by the poxvirus-derived pan-CC-chemokine inhibitor vCCI. J. Immunol. 165, 3418–3422 (2000).
Liu, L. et al. The viral anti-inflammatory chemokine-binding protein M-T7 reduces intimal hyperplasia after vascular injury. J. Clin. Invest. 105, 1613–1621 (2000).
DeBruyne, L. A., Li, K., Bishop, D. K. & Bromberg, J. S. Gene transfer of virally encoded chemokine antagonists vMIP-II and MC148 prolongs cardiac allograft survival and inhibits donor-specific immunity. Gene Ther. 7, 575–582 (2000).
Chen, S. et al. In vivo inhibition of CC and CX3C chemokine-induced leukocyte infiltration and attenuation of glomerulonephritis in Wistar-Kyoto (WKY) rats by vMIP-II. J. Exp. Med. 188, 193–198 (1998).
Lechman, E. R. et al. Direct adenoviral gene transfer of viral IL-10 to rabbit knees with experimental arthritis ameliorates disease in both injected and contralateral control knees. J. Immunol. 163, 2202–2208 (1999).
Henke, P. K. et al. Viral IL-10 gene transfer decreases inflammation and cell adhesion molecule expression in a rat model of venous thrombosis. J. Immunol. 164, 2131–2141 (2000).
Gavin, A. C. et al. Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415, 141–147 (2002).
Moss, B. in Fields Virology (eds Knipe, D. M. & Howley, P. M.) 2849–2883 (Lippincott Williams & Wilkins, Philadelphia, 2001).
Smith, G. L. & McFadden, G. Smallpox: anything to declare? Nature Rev. Immunol. 2, 521–527 (2002).
Roizman, B. & Pellet, P. E. in Fields Virology (eds Knipe, D. M. & Howley, P. M.) 2381–2397 (Lippincott Williams & Wilkins, Philadelphia, 2001).
Afonso, C. L. et al. The genome of fowlpox virus. J. Virol. 74, 3815–3831 (2000).
Parcells, M. S. et al. Marek's disease virus (MDV) encodes an interleukin-8 homolog (vIL-8): characterization of the vIL-8 protein and a vIL-8 deletion mutant MDV. J. Virol. 75, 5159–5173 (2001).
Lee, H. J., Essani, K. & Smith, G. L. The genome sequence of Yaba-like disease virus, a yatapoxvirus. Virology 281, 170–192 (2001).
Tulman, E. R. et al. Genome of lumpy skin disease virus. J. Virol. 75, 7122–7130 (2001).
Acknowledgements
I apologize to all colleagues whose work has not been cited in this review due to space restrictions. I thank T. Minson and P. Sissons for their continuous support. I am a Wellcome Senior Research Fellow.
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Glossary
- MOLECULAR MIMICRY
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The presence of viral proteins with a primary amino-acid sequence and structure that are related to those of host proteins, indicating that viruses might have 'captured' genes from the host during evolution.
- KAPOSI'S SARCOMA
-
A tumour of endothelial-cell origin that is found most frequently in immunosuppressed patients, particularly in HIV-infected individuals. Kaposi's sarcoma-associated herpesvirus has been implicated as a co-factor in the formation of Kaposi's sarcoma.
- VIRUS ATTENUATION
-
Reduction of the potential of a virus to cause disease.
- TANDEM AFFINITY PURIFICATION
-
A biochemical method to purify protein complexes interacting with a target protein. The method requires fusion of a tag, at either the amino- or carboxy-terminus, to the protein of interest to facilitate purification of the complex. This protocol is used in combination with mass spectrometry and the availability of complete genomic sequences to allow the identification of interacting partners.
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Alcami, A. Viral mimicry of cytokines, chemokines and their receptors. Nat Rev Immunol 3, 36–50 (2003). https://doi.org/10.1038/nri980
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DOI: https://doi.org/10.1038/nri980
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