1887

Abstract

Human cytomegalovirus (HCMV) is an opportunistic human pathogen that establishes a lifelong latent infection, which can reactivate periodically. If unchecked by a robust immune response, this reactivation can result in severe disease in immunocompromised patients. Reactivation of latent virus in myeloid progenitor cells is concomitant with cellular differentiation through regulation of the major immediate-early promoter (MIEP) by chromatin remodelling. In this study, we analysed the expression of the latent gene transcript UL81–82as (LUNA). LUNA is expressed in latently infected CD34 cells and its expression decreases as CD34 cells differentiate to immature dendritic cells. Upon maturation (and HCMV reactivation), a second wave of transcription occurs, consistent with expression during lytic infection. Furthermore, we show that the LUNA promoter is associated with acetylated histones during HCMV latency in experimentally and naturally infected CD34 cells, thus suggesting that latent gene promoters are, like the MIEP, regulated by post-translational modifications of their associated histone proteins.

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2010-03-01
2019-11-12
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References

  1. Bain, M., Mendelson, M. & Sinclair, J. ( 2003; ). ETS-2 repressor factor (ERF) mediates repression of the human cytomegalovirus major immediate-early promoter in undifferentiated non-permissive cells. J Gen Virol 84, 41–49.[CrossRef]
    [Google Scholar]
  2. Bego, M. G. & St Jeor, S. ( 2006; ). Human cytomegalovirus infection of cells of hematopoietic origin: HCMV-induced immunosuppression, immune evasion, and latency. Exp Hematol 34, 555–570.[CrossRef]
    [Google Scholar]
  3. Bego, M., Maciejewski, J., Khaiboullina, S., Pari, G. & St Jeor, S. ( 2005; ). Characterization of an antisense transcript spanning the UL81–82 locus of human cytomegalovirus. J Virol 79, 11022–11034.[CrossRef]
    [Google Scholar]
  4. Boyes, J., Byfield, P., Nakatani, Y. & Ogryzko, V. ( 1998; ). Regulation of activity of the transcription factor GATA-1 by acetylation. Nature 396, 594–598.[CrossRef]
    [Google Scholar]
  5. Cheung, A. K., Abendroth, A., Cunningham, A. L. & Slobedman, B. ( 2006; ). Viral gene expression during the establishment of human cytomegalovirus latent infection in myeloid progenitor cells. Blood 108, 3691–3699.[CrossRef]
    [Google Scholar]
  6. Crough, T. & Khanna, R. ( 2009; ). Immunobiology of human cytomegalovirus: from bench to bedside. Clin Microbiol Rev 22, 76–98.[CrossRef]
    [Google Scholar]
  7. Cuevas-Bennett, C. & Shenk, T. ( 2008; ). Dynamic histone H3 acetylation and methylation at human cytomegalovirus promoters during replication in fibroblasts. J Virol 82, 9525–9536.[CrossRef]
    [Google Scholar]
  8. Ferreira, R., Ohneda, K., Yamamoto, M. & Philipsen, S. ( 2005; ). GATA1 function, a paradigm for transcription factors in hematopoiesis. Mol Cell Biol 25, 1215–1227.[CrossRef]
    [Google Scholar]
  9. Fox, A. H., Liew, C., Holmes, M., Kowalski, K., Mackay, J. & Crossley, M. ( 1999; ). Transcriptional cofactors of the FOG family interact with GATA proteins by means of multiple zinc fingers. EMBO J 18, 2812–2822.[CrossRef]
    [Google Scholar]
  10. Goodrum, F. D., Jordan, C. T., High, K. & Shenk, T. ( 2002; ). Human cytomegalovirus gene expression during infection of primary hematopoietic progenitor cells: a model for latency. Proc Natl Acad Sci U S A 99, 16255–16260.[CrossRef]
    [Google Scholar]
  11. Goodrum, F., Reeves, M., Sinclair, J., High, K. & Shenk, T. ( 2007; ). Human cytomegalovirus sequences expressed in latently infected individuals promote a latent infection in vitro. Blood 110, 937–945.[CrossRef]
    [Google Scholar]
  12. Groves, I. J., Reeves, M. B. & Sinclair, J. H. ( 2009; ). Lytic infection of permissive cells with human cytomegalovirus is regulated by an intrinsic ‘pre-immediate-early’ repression of viral gene expression mediated by histone post-translational modification. J Gen Virol 90, 2364–2374.[CrossRef]
    [Google Scholar]
  13. Hahn, G., Jores, R. & Mocarski, E. S. ( 1998; ). Cytomegalovirus remains latent in a common precursor of dendritic and myeloid cells. Proc Natl Acad Sci U S A 95, 3937–3942.[CrossRef]
    [Google Scholar]
  14. Hertel, L., Lacaille, V. G., Strobl, H., Mellins, E. D. & Mocarski, E. S. ( 2003; ). Susceptibility of immature and mature Langerhans cell-type dendritic cells to infection and immunomodulation by human cytomegalovirus. J Virol 77, 7563–7574.[CrossRef]
    [Google Scholar]
  15. Hummel, M. & Abecassis, M. M. ( 2002; ). A model for reactivation of cmv from latency. J Clin Virol 25, (Suppl. 2), S123–S136.[CrossRef]
    [Google Scholar]
  16. Hung, H. L., Lau, J., Kim, A. Y., Weiss, M. J. & Blobel, G. A. ( 1999; ). CREB-binding protein acetylates hematopoietic transcription factor GATA-1 at functionally important sites. Mol Cell Biol 19, 3496–3505.
    [Google Scholar]
  17. Jenkins, C., Abendroth, A. & Slobedman, B. ( 2004; ). A novel viral transcript with homology to human interleukin-10 is expressed during latent human cytomegalovirus infection. J Virol 78, 1440–1447.[CrossRef]
    [Google Scholar]
  18. Khoshnevis, M. & Tyring, S. K. ( 2002; ). Cytomegalovirus infections. Dermatol Clin 20, 291–299.[CrossRef]
    [Google Scholar]
  19. Kondo, K., Xu, J. & Mocarski, E. S. ( 1996; ). Human cytomegalovirus latent gene expression in granulocyte–macrophage progenitors in culture and in seropositive individuals. Proc Natl Acad Sci U S A 93, 11137–11142.[CrossRef]
    [Google Scholar]
  20. Kotenko, S. V., Saccani, S., Izotova, L. S., Mirochnitchenko, O. V. & Pestka, S. ( 2000; ). Human cytomegalovirus harbors its own unique IL-10 homolog (CMVIL-10). Proc Natl Acad Sci U S A 97, 1695–1700.[CrossRef]
    [Google Scholar]
  21. Lathey, J. L. & Spector, S. A. ( 1991; ). Unrestricted replication of human cytomegalovirus in hydrocortisone-treated macrophages. J Virol 65, 6371–6375.
    [Google Scholar]
  22. Liu, B. & Stinski, M. F. ( 1992; ). Human cytomegalovirus contains a tegument protein that enhances transcription from promoters with upstream ATF and AP-1 cis-acting elements. J Virol 66, 4434–4444.
    [Google Scholar]
  23. Liu, R., Baillie, J., Sissons, J. G. & Sinclair, J. H. ( 1994; ). The transcription factor YY1 binds to negative regulatory elements in the human cytomegalovirus major immediate early enhancer/promoter and mediates repression in non-permissive cells. Nucleic Acids Res 22, 2453–2459.[CrossRef]
    [Google Scholar]
  24. Lunetta, J. M. & Wiedeman, J. A. ( 2000; ). Latency-associated sense transcripts are expressed during in vitro human cytomegalovirus productive infection. Virology 278, 467–476.[CrossRef]
    [Google Scholar]
  25. Mendelson, M., Monard, S., Sissons, P. & Sinclair, J. ( 1996; ). Detection of endogenous human cytomegalovirus in CD34+ bone marrow progenitors. J Gen Virol 77, 3099–3102.[CrossRef]
    [Google Scholar]
  26. Minton, E. J., Tysoe, C., Sinclair, J. H. & Sissons, J. G. ( 1994; ). Human cytomegalovirus infection of the monocyte/macrophage lineage in bone marrow. J Virol 68, 4017–4021.
    [Google Scholar]
  27. Mocarski, E. S., Hahn, G., White, K. L., Xu, J., Slobedman, B., Hertel, L., Aguirre, S. A. & Noda, S. ( 2006; ). Myeloid cell recruitment and function in pathogenesis and latency. In Cytomegaloviruses: Molecular Biology and Immunology, pp. 465–481. Edited by M. J. Reddehase. Wymondham, UK: Caister Academic Press.
  28. Murphy, J. C., Fischle, W., Verdin, E. & Sinclair, J. H. ( 2002; ). Control of cytomegalovirus lytic gene expression by histone acetylation. EMBO J 21, 1112–1120.[CrossRef]
    [Google Scholar]
  29. Nitzsche, A., Paulus, C. & Nevels, M. ( 2008; ). Temporal dynamics of cytomegalovirus chromatin assembly in productively infected human cells. J Virol 82, 11167–11180.[CrossRef]
    [Google Scholar]
  30. Petrucelli, A., Rak, M., Grainger, L. & Goodrum, F. ( 2009; ). Characterization of a novel Golgi apparatus-localized latency determinant encoded by human cytomegalovirus. J Virol 83, 5615–5629.[CrossRef]
    [Google Scholar]
  31. Prosch, S., Docke, W. D., Reinke, P., Volk, H. D. & Kruger, D. H. ( 1999; ). Human cytomegalovirus reactivation in bone-marrow-derived granulocyte/monocyte progenitor cells and mature monocytes. Intervirology 42, 308–313.[CrossRef]
    [Google Scholar]
  32. Reeves, M. B., Lehner, P. J., Sissons, J. G. & Sinclair, J. H. ( 2005a; ). An in vitro model for the regulation of human cytomegalovirus latency and reactivation in dendritic cells by chromatin remodelling. J Gen Virol 86, 2949–2954.[CrossRef]
    [Google Scholar]
  33. Reeves, M. B., Macary, P. A., Lehner, P. J., Sissons, J. G. & Sinclair, J. H. ( 2005b; ). Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc Natl Acad Sci U S A 102, 4140–4145.[CrossRef]
    [Google Scholar]
  34. Reeves, M., Murphy, J., Greaves, R., Fairley, J., Brehm, A. & Sinclair, J. ( 2006; ). Autorepression of the human cytomegalovirus major immediate-early promoter/enhancer at late times of infection is mediated by the recruitment of chromatin remodeling enzymes by IE86. J Virol 80, 9998–10009.[CrossRef]
    [Google Scholar]
  35. Riegler, S., Hebart, H., Einsele, H., Brossart, P., Jahn, G. & Sinzger, C. ( 2000; ). Monocyte-derived dendritic cells are permissive to the complete replicative cycle of human cytomegalovirus. J Gen Virol 81, 393–399.
    [Google Scholar]
  36. Sindre, H., Tjoonnfjord, G. E., Rollag, H., Ranneberg-Nilsen, T., Veiby, O. P., Beck, S., Degre, M. & Hestdal, K. ( 1996; ). Human cytomegalovirus suppression of and latency in early hematopoietic progenitor cells. Blood 88, 4526–4533.
    [Google Scholar]
  37. Slobedman, B. & Mocarski, E. S. ( 1999; ). Quantitative analysis of latent human cytomegalovirus. J Virol 73, 4806–4812.
    [Google Scholar]
  38. Soderberg-Naucler, C., Fish, K. N. & Nelson, J. A. ( 1997; ). Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell 91, 119–126.[CrossRef]
    [Google Scholar]
  39. Spaete, R. R. & Mocarski, E. S. ( 1985; ). Regulation of cytomegalovirus gene expression: α and β promoters are trans activated by viral functions in permissive human fibroblasts. J Virol 56, 135–143.
    [Google Scholar]
  40. Strobl, H., Bello-Fernandez, C., Riedl, E., Pickl, W. F., Majdic, O., Lyman, S. D. & Knapp, W. ( 1997; ). FLT3 ligand in cooperation with transforming growth factor-β1 potentiates in vitro development of Langerhans-type dendritic cells and allows single-cell dendritic cell cluster formation under serum-free conditions. Blood 90, 1425–1434.
    [Google Scholar]
  41. Taylor-Wiedeman, J., Sissons, J. G., Borysiewicz, L. K. & Sinclair, J. H. ( 1991; ). Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol 72, 2059–2064.[CrossRef]
    [Google Scholar]
  42. Taylor-Wiedeman, J., Sissons, P. & Sinclair, J. ( 1994; ). Induction of endogenous human cytomegalovirus gene expression after differentiation of monocytes from healthy carriers. J Virol 68, 1597–1604.
    [Google Scholar]
  43. Tevosian, S. G., Deconinck, A. E., Cantor, A. B., Rieff, H. I., Fujiwara, Y., Corfas, G. & Orkin, S. H. ( 1999; ). FOG-2: a novel GATA-family cofactor related to multitype zinc-finger proteins friend of GATA-1 and U-shaped. Proc Natl Acad Sci U S A 96, 950–955.[CrossRef]
    [Google Scholar]
  44. Thompson, R. L. & Sawtell, N. M. ( 2006; ). Evidence that the herpes simplex virus type 1 ICP0 protein does not initiate reactivation from latency in vivo. J Virol 80, 10919–10930.[CrossRef]
    [Google Scholar]
  45. Thompson, R. L., Preston, C. M. & Sawtell, N. M. ( 2009; ). De novo synthesis of VP16 coordinates the exit from HSV latency in vivo. PLoS Pathog 5, E1000352 [CrossRef]
    [Google Scholar]
  46. Tsai, F. Y. & Orkin, S. H. ( 1997; ). Transcription factor GATA-2 is required for proliferation/survival of early hematopoietic cells and mast cell formation, but not for erythroid and myeloid terminal differentiation. Blood 89, 3636–3643.
    [Google Scholar]
  47. Weiss, M. J. & Orkin, S. H. ( 1995; ). GATA transcription factors: key regulators of hematopoiesis. Exp Hematol 23, 99–107.
    [Google Scholar]
  48. White, K. L., Slobedman, B. & Mocarski, E. S. ( 2000; ). Human cytomegalovirus latency-associated protein PORF94 is dispensable for productive and latent infection. J Virol 74, 9333–9337.[CrossRef]
    [Google Scholar]
  49. Whitman, A. G., Bryan, B. A., Dyson, O. F., Patel, D. K., Ramasamy, D., Anantharaman, S., Reber, A. J. & Akula, S. M. ( 2005; ). AIDS related viruses, their association with leukemia, and RAF signaling. Curr HIV Res 3, 319–327.[CrossRef]
    [Google Scholar]
  50. Wright, E., Bain, M., Teague, L., Murphy, J. & Sinclair, J. ( 2005; ). ETS-2 repressor factor recruits histone deacetylase to silence human cytomegalovirus immediate-early gene expression in non-permissive cells. J Gen Virol 86, 535–544.[CrossRef]
    [Google Scholar]
  51. Yee, L. F., Lin, P. L. & Stinski, M. F. ( 2007; ). Ectopic expression of HCMV IE72 and IE86 proteins is sufficient to induce early gene expression but not production of infectious virus in undifferentiated promonocytic THP-1 cells. Virology 363, 174–188.[CrossRef]
    [Google Scholar]
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