1887

Journal of General Virology header logo

Volume 94, Issue 7

Activation of CCR2+ human proinflammatory monocytes by human herpesvirus-6B chemokine N-terminal peptide Free

Abstract

Human monocytes expressing CCR2 with CD14 and CD16 can mediate antigen presentation, and promote inflammation, brain infiltration and immunosenescence. Recently identified roles are in human immunodeficiency virus infection, tuberculosis and parasitic disease. Human herpesvirus 6B (HHV-6B) encodes a chemokine, U83B, which is monospecific for CCR2, and is distinct from the related HHV-6A U83A, which activates CCR1, CCR4, CCR5, CCR6 and CCR8 on immune effector cells and dendritic cells. These differences could alter leukocyte-subset recruitment for latent/lytic replication and associated neuroinflammatory pathology. Therefore, cellular interactions between U83A and U83B could help dictate potential tropism differences between these viruses. U83A specificity is maintained in the 38-residue N-terminal spliced-truncated form. Here, we sought to determine the basis for the chemokine receptor specificity differences and identify possible applications. To do this we first analysed variation in a natural host population in sub-Saharan Africa where both viruses are equally prevalent and compared these to global strains. Analyses of U83 N-terminal variation in 112 HHV-6A and HHV-6B infections identified 6/38 U83A or U83B-specific residues. We also identified a unique single U83A-specific substitution in one U83B sequence, ‘U83BA’. Next, the variation effects were tested by deriving N-terminal (NT) 17-mer peptides and assaying activation of ex vivo human leukocytes, the natural host and cellular target. Chemotaxis of CCR2+ leukocytes was potently induced by U83B-NT, but not U83BA-NT or U83A-NT. Analyses of the U83B-NT activated population identified migrated CCR2+, but not CCR5+, leukocytes. The U83BA-NT asparagine-lysine14 substitution disrupted activity, thus defining CCR2 specificity and acting as a main determinant for HHV-6A/B differences in cellular interactions. A flow-cytometry-based shape-change assay was designed, and used to provide further evidence that U83B-NT could activate CCR2+CD14+CD16+ monocytes. This defines a potential antiviral target for HHV-6A/B disease and novel peptide immunomodulator for proinflammatory monocytes.

  • Received:
  • Accepted:
  • Published Online:
© 2013 SGM
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.050153-0
2013-07-01
2024-04-20
Loading full text...

Full text loading...

/deliver/fulltext/jgv/94/7/1624.html?itemId=/content/journal/jgv/10.1099/vir.0.050153-0&mimeType=html&fmt=ahah

References

  1. Adams M. J., Carstens E. B. 2012; Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2012). Arch Virol 157:1411–1422 [View Article][PubMed]
     [Google Scholar]
  2. Ahlqvist J., Fotheringham J., Akhyani N., Yao K., Fogdell-Hahn A., Jacobson S. 2005; Differential tropism of human herpesvirus 6 (HHV-6) variants and induction of latency by HHV-6A in oligodendrocytes. J Neurovirol 11:384–394 [View Article][PubMed]
     [Google Scholar]
  3. Arai H., Monteclaro F. S., Tsou C. L., Franci C., Charo I. F. 1997; Dissociation of chemotaxis from agonist-induced receptor internalization in a lymphocyte cell line transfected with CCR2B. Evidence that directed migration does not require rapid modulation of signaling at the receptor level. J Biol Chem 272:25037–25042 [View Article][PubMed]
     [Google Scholar]
  4. Arbuckle J. H., Medveczky P. G. 2011; The molecular biology of human herpesvirus-6 latency and telomere integration. Microbes Infect 13:731–741 [View Article][PubMed]
     [Google Scholar]
  5. Arbuckle J. H., Medveczky M. M., Luka J., Hadley S. H., Luegmayr A., Ablashi D., Lund T. C., Tolar J., De Meirleir K. other authors 2010; The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro. Proc Natl Acad Sci U S A 107:5563–5568 [View Article][PubMed]
     [Google Scholar]
  6. Balboa L., Romero M. M., Basile J. I., Sabio y García C. A., Schierloh P., Yokobori N., Geffner L., Musella R. M., Castagnino J. other authors 2011; Paradoxical role of CD16+CCR2+CCR5+ monocytes in tuberculosis: efficient APC in pleural effusion but also mark disease severity in blood. J Leukoc Biol 90:69–75 [View Article][PubMed]
     [Google Scholar]
  7. Bates M., Monze M., Bima H., Kapambwe M., Clark D., Kasolo F. C., Gompels U. A. 2009; Predominant human herpesvirus 6 variant A infant infections in an HIV-1 endemic region of Sub-Saharan Africa. J Med Virol 81:779–789 [View Article][PubMed]
     [Google Scholar]
  8. Buckner C. M., Calderon T. M., Willams D. W., Belbin T. J., Berman J. W. 2011; Characterization of monocyte maturation/differentiation that facilitates their transmigration across the blood-brain barrier and infection by HIV: implications for NeuroAIDS. Cell Immunol 267:109–123 [View Article][PubMed]
     [Google Scholar]
  9. Catusse J., Parry C. M., Dewin D. R., Gompels U. A. 2007; Inhibition of HIV-1 infection by viral chemokine U83A via high-affinity CCR5 interactions that block human chemokine-induced leukocyte chemotaxis and receptor internalization. Blood 109:3633–3639 [View Article][PubMed]
     [Google Scholar]
  10. Catusse J., Clark D. J., Gompels U. A. 2009; CCR5 signalling, but not DARC or D6 regulatory, chemokine receptors are targeted by herpesvirus U83A chemokine which delays receptor internalisation via diversion to a caveolin-linked pathway. J Inflamm (Lond) 6:22 [View Article][PubMed]
     [Google Scholar]
  11. Chenna R., Sugawara H., Koike T., Lopez R., Gibson T. J., Higgins D. G., Thompson J. D. 2003; Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Res 31:3497–3500 [View Article][PubMed]
     [Google Scholar]
  12. Chimma P., Roussilhon C., Sratongno P., Ruangveerayuth R., Pattanapanyasat K., Pérignon J. L., Roberts D. J., Druilhe P. 2009; A distinct peripheral blood monocyte phenotype is associated with parasite inhibitory activity in acute uncomplicated Plasmodium falciparum malaria. PLoS Pathog 5:e1000631 [View Article][PubMed]
     [Google Scholar]
  13. CIGNIS (Chilenje Infant Growth, Nutrition and Infection) Study Team 2010; Micronutrient fortification to improve growth and health of maternally HIV-unexposed and exposed Zambian infants: a randomised controlled trial. PLoS ONE 5:e11165 [View Article][PubMed]
     [Google Scholar]
  14. Cros J., Cagnard N., Woollard K., Patey N., Zhang S. Y., Senechal B., Puel A., Biswas S. K., Moshous D. other authors 2010; Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33:375–386 [View Article][PubMed]
     [Google Scholar]
  15. Dewin D. R., Catusse J., Gompels U. A. 2006; Identification and characterization of U83A viral chemokine, a broad and potent beta-chemokine agonist for human CCRs with unique selectivity and inhibition by spliced isoform. J Immunol 176:544–556[PubMed] [CrossRef]
     [Google Scholar]
  16. Donati D., Martinelli E., Cassiani-Ingoni R., Ahlqvist J., Hou J., Major E. O., Jacobson S. 2005; Variant-specific tropism of human herpesvirus 6 in human astrocytes. J Virol 79:9439–9448 [View Article][PubMed]
     [Google Scholar]
  17. Epstein L. G., Shinnar S., Hesdorffer D. C., Nordli D. R., Hamidullah A., Benn E. K. T., Pellock J. M., Frank L. M., Lewis D. V. other authors 2012; Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia 53:1481–1488 [View Article][PubMed]
     [Google Scholar]
  18. French C., Menegazzi P., Nicholson L., Macaulay H., DiLuca D., Gompels U. A. 1999; Novel, nonconsensus cellular splicing regulates expression of a gene encoding a chemokine-like protein that shows high variation and is specific for human herpesvirus 6. Virology 262:139–151 [View Article][PubMed]
     [Google Scholar]
  19. Hall C. B., Long C. E., Schnabel K. C., Caserta M. T., McIntyre K. M., Costanzo M. A., Knott A., Dewhurst S., Insel R. A., Epstein L. G. 1994; Human herpesvirus-6 infection in children. A prospective study of complications and reactivation. N Engl J Med 331:432–438 [View Article][PubMed]
     [Google Scholar]
  20. Hall C. B., Caserta M. T., Schnabel K. C., McDermott M. P., Lofthus G. K., Carnahan J. A., Gilbert L. M., Dewhurst S. 2006; Characteristics and acquisition of human herpesvirus (HHV) 7 infections in relation to infection with HHV-6. J Infect Dis 193:1063–1069 [View Article][PubMed]
     [Google Scholar]
  21. Hall C. B., Caserta M. T., Schnabel K. C., Shelley L. M., Carnahan J. A., Marino A. S., Yoo C., Lofthus G. K. 2010; Transplacental congenital human herpesvirus 6 infection caused by maternal chromosomally integrated virus. J Infect Dis 201:505–507 [View Article][PubMed]
     [Google Scholar]
  22. Kasolo F. C., Mpabalwani E., Gompels U. A. 1997; Infection with AIDS-related herpesviruses in human immunodeficiency virus-negative infants and endemic childhood Kaposi’s sarcoma in Africa. J Gen Virol 78:847–855[PubMed]
     [Google Scholar]
  23. Kühl U., Pauschinger M., Noutsias M., Seeberg B., Bock T., Lassner D., Poller W., Kandolf R., Schultheiss H. P. 2005a; High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idiopathic” left ventricular dysfunction. Circulation 111:887–893 [View Article][PubMed]
     [Google Scholar]
  24. Kühl U., Pauschinger M., Seeberg B., Lassner D., Noutsias M., Poller W., Schultheiss H. P. 2005b; Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 112:1965–1970 [View Article][PubMed]
     [Google Scholar]
  25. Lentz M. R., Kim W. K., Kim H., Soulas C., Lee V., Venna N., Halpern E. F., Rosenberg E. S., Williams K., González R. G. 2011; Alterations in brain metabolism during the first year of HIV infection. J Neurovirol 17:220–229 [View Article][PubMed]
     [Google Scholar]
  26. Luppi M., Barozzi P., Morris C., Maiorana A., Garber R., Bonacorsi G., Donelli A., Marasca R., Tabilio A., Torelli G. 1999; Human herpesvirus 6 latently infects early bone marrow progenitors in vivo. J Virol 73:754–759[PubMed]
     [Google Scholar]
  27. Lusso P., Markham P. D., Tschachler E., di Marzo Veronese F., Salahuddin S. Z., Ablashi D. V., Pahwa S., Krohn K., Gallo R. C. 1988; In vitro cellular tropism of human B-lymphotropic virus (human herpesvirus-6). J Exp Med 167:1659–1670 [View Article][PubMed]
     [Google Scholar]
  28. Lusso P., De Maria A., Malnati M., Lori F., DeRocco S. E., Baseler M., Gallo R. C. 1991; Induction of CD4 and susceptibility to HIV-1 infection in human CD8+ T lymphocytes by human herpesvirus 6. Nature 349:533–535 [View Article][PubMed]
     [Google Scholar]
  29. Lusso P., Garzino-Demo A., Crowley R. W., Malnati M. S. 1995; Infection of gamma/delta T lymphocytes by human herpesvirus 6: transcriptional induction of CD4 and susceptibility to HIV infection. J Exp Med 181:1303–1310 [View Article][PubMed]
     [Google Scholar]
  30. Lüttichau H. R., Clark-Lewis I., Jensen P. O., Moser C., Gerstoft J., Schwartz T. W. 2003; A highly selective CCR2 chemokine agonist encoded by human herpesvirus 6. J Biol Chem 278:10928–10933 [View Article][PubMed]
     [Google Scholar]
  31. Merino A., Buendia P., Martin-Malo A., Aljama P., Ramirez R., Carracedo J. 2011; Senescent CD14+CD16+ monocytes exhibit proinflammatory and proatherosclerotic activity. J Immunol 186:1809–1815 [View Article][PubMed]
     [Google Scholar]
  32. Morissette G., Flamand L. 2010; Herpesviruses and chromosomal integration. J Virol 84:12100–12109 [View Article][PubMed]
     [Google Scholar]
  33. Noutsias M., Rohde M., Göldner K., Block A., Blunert K., Hemaidan L., Hummel M., Blohm J. H., Lassner D. other authors 2011; Expression of functional T-cell markers and T-cell receptor Vbeta repertoire in endomyocardial biopsies from patients presenting with acute myocarditis and dilated cardiomyopathy. Eur J Heart Fail 13:611–618 [View Article][PubMed]
     [Google Scholar]
  34. Rogacev K. S., Seiler S., Zawada A. M., Reichart B., Herath E., Roth D., Ulrich C., Fliser D., Heine G. H. 2011; CD14++CD16+ monocytes and cardiovascular outcome in patients with chronic kidney disease. Eur Heart J 32:84–92 [View Article][PubMed]
     [Google Scholar]
  35. Sabroe I., Hartnell A., Jopling L. A., Bel S., Ponath P. D., Pease J. E., Collins P. D., Williams T. J. 1999; Differential regulation of eosinophil chemokine signaling via CCR3 and non-CCR3 pathways. J Immunol 162:2946–2955[PubMed]
     [Google Scholar]
  36. Schmidt-Hieber M., Schwender J., Heinz W. J., Zabelina T., Kühl J. S., Mousset S., Schüttrumpf S., Junghanss C., Silling G. other authors 2011; Viral encephalitis after allogeneic stem cell transplantation: a rare complication with distinct characteristics of different causative agents. Haematologica 96:142–149 [View Article][PubMed]
     [Google Scholar]
  37. Seeley W. W., Marty F. M., Holmes T. M., Upchurch K., Soiffer R. J., Antin J. H., Baden L. R., Bromfield E. B. 2007; Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurology 69:156–165 [View Article][PubMed]
     [Google Scholar]
  38. Shantsila E., Wrigley B., Tapp L., Apostolakis S., Montoro-Garcia S., Drayson M. T., Lip G. Y. 2011; Immunophenotypic characterization of human monocyte subsets: possible implications for cardiovascular disease pathophysiology. J Thromb Haemost 9:1056–1066 [View Article][PubMed]
     [Google Scholar]
  39. Shin H., Iwasaki A. 2012; A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 491:463–467 [View Article][PubMed]
     [Google Scholar]
  40. Signoret N., Hewlett L., Wavre S., Pelchen-Matthews A., Oppermann M., Marsh M. 2005; Agonist-induced endocytosis of CC chemokine receptor 5 is clathrin dependent. Mol Biol Cell 16:902–917 [View Article][PubMed]
     [Google Scholar]
  41. Sjahril R., Isegawa Y., Tanaka T., Nakano K., Yoshikawa T., Asano Y., Ohshima A., Yamanishi K., Sugimoto N. 2009; Relationship between U83 gene variation in human herpesvirus 6 and secretion of the U83 gene product. Arch Virol 154:273–283 [View Article][PubMed]
     [Google Scholar]
  42. van Gassen K. L., de Wit M., Koerkamp M. J., Rensen M. G., van Rijen P. C., Holstege F. C., Lindhout D., de Graan P. N. 2008; Possible role of the innate immunity in temporal lobe epilepsy. Epilepsia 49:1055–1065 [View Article][PubMed]
     [Google Scholar]
  43. Waterhouse A. M., Procter J. B., Martin D. M. A., Clamp M., Barton G. J. 2009; Jalview Version 2–a multiple sequence alignment editor and analysis workbench. Bioinformatics 25:1189–1191 [View Article][PubMed]
     [Google Scholar]
  44. Williams D. W., Eugenin E. A., Calderon T. M., Berman J. W. 2012; Monocyte maturation, HIV susceptibility, and transmigration across the blood brain barrier are critical in HIV neuropathogenesis. J Leukoc Biol 91:401–415 [View Article][PubMed]
     [Google Scholar]
  45. Wong K. L., Tai J. J., Wong W. C., Han H., Sem X., Yeap W. H., Kourilsky P., Wong S. C. 2011; Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood 118:e16–e31 [View Article][PubMed]
     [Google Scholar]
  46. Zawada A. M., Rogacev K. S., Rotter B., Winter P., Marell R. R., Fliser D., Heine G. H. 2011; SuperSAGE evidence for CD14++CD16+ monocytes as a third monocyte subset. Blood 118:e50–e61 [View Article][PubMed]
     [Google Scholar]
  47. Zerr D. M., Meier A. S., Selke S. S., Frenkel L. M., Huang M. L., Wald A., Rhoads M. P., Nguy L., Bornemann R. other authors 2005; A population-based study of primary human herpesvirus 6 infection. N Engl J Med 352:768–776 [View Article][PubMed]
     [Google Scholar]
  48. Zerr D. M., Fann J. R., Breiger D., Boeckh M., Adler A. L., Xie H., Delaney C., Huang M. L., Corey L., Leisenring W. M. 2011; HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients. Blood 117:5243–5249 [View Article][PubMed]
     [Google Scholar]
  49. Ziegler-Heitbrock L., Ancuta P., Crowe S., Dalod M., Grau V., Hart D. N., Leenen P. J., Liu Y. J., MacPherson G. other authors 2010; Nomenclature of monocytes and dendritic cells in blood. Blood 116:e74–e80 [View Article][PubMed]
     [Google Scholar]
  50. Zou P., Isegawa Y., Nakano K., Haque M., Horiguchi Y., Yamanishi K. 1999; Human herpesvirus 6 open reading frame U83 encodes a functional chemokine. J Virol 73:5926–5933[PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.050153-0
Loading
Activation of CCR2+ human proinflammatory monocytes by human herpesvirus-6B chemokine N-terminal peptide
J. Gen. Virol. 94, 1624 (2013); https://doi.org/10.1099/vir.0.050153-0
/content/journal/jgv/10.1099/vir.0.050153-0
/content/journal/jgv/10.1099/vir.0.050153-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error