1887

Abstract

Cellular signalling pathways are critical in regulating the balance between latency and lytic replication of herpesviruses. Here, we investigated the effect of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway on replication of two gamma-2 herpesviruses, murine gammaherpesvirus-68 (MHV-68) and human herpesvirus-8/Kaposi's sarcoma-associated herpesvirus (HHV-8/KSHV). We found that infection of MHV-68 induced PI3K-dependent Akt activation and the lytic replication of MHV-68 was enhanced by inhibiting the PI3K-Akt pathway with both chemical inhibitors and RNA interference technology. Inhibiting the activity of Akt using Akt inhibitor VIII also facilitated the reactivation of KSHV from latency. Both lytic replication and latency depend on the activity of viral transactivator RTA and we further show that the activity of RTA is increased by reducing Akt1 expression. The data suggest that the PI3K-Akt pathway suppresses the activity of RTA and thereby contributes to the maintenance of viral latency and promotes tumorigenesis.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.015073-0
2010-02-01
2019-11-13
Loading full text...

Full text loading...

/deliver/fulltext/jgv/91/2/463.html?itemId=/content/journal/jgv/10.1099/vir.0.015073-0&mimeType=html&fmt=ahah

References

  1. Brown, H. J., McBride, W. H., Zack, J. A. & Sun, R. ( 2005; ). Prostratin and bortezomib are novel inducers of latent Kaposi's sarcoma-associated herpesvirus. Antivir Ther 10, 745–751.
    [Google Scholar]
  2. Cooray, S. ( 2004; ). The pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survival. J Gen Virol 85, 1065–1076.[CrossRef]
    [Google Scholar]
  3. Darr, C. D., Mauser, A. & Kenney, S. ( 2001; ). Epstein–Barr virus immediate-early protein BRLF1 induces the lytic form of viral replication through a mechanism involving phosphatidylinositol-3 kinase activation. J Virol 75, 6135–6142.[CrossRef]
    [Google Scholar]
  4. Dawson, C. W., Tramountanis, G., Eliopoulos, A. G. & Young, L. S. ( 2003; ). Epstein–Barr virus latent membrane protein 1 (LMP1) activates the phosphatidylinositol 3-Kinase/Akt pathway to promote cell survival and induce actin filament remodeling. J Biol Chem 278, 3694–3704.[CrossRef]
    [Google Scholar]
  5. Hay, N. ( 2005; ). The Akt-mTOR tango and its relevance to cancer. Cancer Cell 8, 179–183.[CrossRef]
    [Google Scholar]
  6. Hwang, S., Wu, T.-T., Tong, L. M., Kim, K. S., Martinez-Guzman, D., Colantonio, A. D., Uittenbogaart, C. H. & Sun, R. ( 2008; ). Persistent gammaherpesvirus replication and dynamic interaction with the host in vivo. J Virol 82, 12498–12509.[CrossRef]
    [Google Scholar]
  7. Izumiya, Y., Lin, S.-F., Ellison, T., Chen, L.-Y., Izumiya, C., Luciw, P. & Kung, H.-J. ( 2003; ). Kaposi's sarcoma-associated herpesvirus K-bZIP is a coregulator of K-Rta: physical association and promoter-dependent transcriptional repression. J Virol 77, 1441–1451.[CrossRef]
    [Google Scholar]
  8. Lin, S.-F., Robinson, D. R., Miller, G. & Kung, H.-J. ( 1999; ). Kaposi's sarcoma-associated herpesvirus encodes a bZIP protein with homology to BZLF1 of Epstein–Barr virus. J Virol 73, 1909–1917.
    [Google Scholar]
  9. Lindsley, C. W., Zhao, Z., Leister, W. H., Robinson, R. G., Barnett, S. F., Defeo-Jones, D., Jones, R. E., Hartman, G. D., Huff, J. R. & other authors ( 2005; ). Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg Med Chem Lett 15, 761–764.[CrossRef]
    [Google Scholar]
  10. Liu, X., Shi, Y., Birnbaum, M. J., Ye, K., De Jong, R., Oltersdorf, T., Giranda, V. L. & Luo, Y. ( 2006; ). Quantitative analysis of anti-apoptotic function of Akt in Akt1 and Akt2 double knock-out mouse embryonic fibroblast cells under normal and stressed conditions. J Biol Chem 281, 31380–31388.[CrossRef]
    [Google Scholar]
  11. Lukac, D. M., Renne, R., Kirshner, J. R. & Ganem, D. ( 1998; ). Reactivation of Kaposi's sarcoma-associated herpesvirus infection from latency by expression of the ORF 50 transactivator, a homolog of the EBV R protein. Virology 252, 304–312.[CrossRef]
    [Google Scholar]
  12. Lukac, D. M., Kirshner, J. R. & Ganem, D. ( 1999; ). Transcriptional activation by the product of open reading frame 50 of Kaposi's sarcoma-associated herpesvirus is required for lytic viral reactivation in B cells. J Virol 73, 9348–9361.
    [Google Scholar]
  13. Montaner, S., Sodhi, A., Pece, S., Mesri, E. A. & Gutkind, J. S. ( 2001; ). The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor promotes endothelial cell survival through the activation of Akt/Protein kinase B. Cancer Res 61, 2641–2648.
    [Google Scholar]
  14. Morrison, J. A., Gulley, M. L., Pathmanathan, R. & Raab-Traub, N. ( 2004; ). Differential signaling pathways are activated in the Epstein–Barr virus-associated malignancies nasopharyngeal carcinoma and Hodgkin lymphoma. Cancer Res 64, 5251–5260.[CrossRef]
    [Google Scholar]
  15. Pavlova, I., Lin, C. Y. & Speck, S. H. ( 2005; ). Murine gammaherpesvirus 68 Rta-dependent activation of the gene 57 promoter. Virology 333, 169–179.[CrossRef]
    [Google Scholar]
  16. Philp, A. J., Campbell, I. G., Leet, C., Vincan, E., Rockman, S. P., Whitehead, R. H., Thomas, R. J. & Phillips, W. A. ( 2001; ). The phosphatidylinositol 3′-kinase p85α gene is an oncogene in human ovarian and colon tumors. Cancer Res 61, 7426–7429.
    [Google Scholar]
  17. Renne, R., Zhong, W., Herndier, B., McGrath, M., Abbey, N., Kedes, D. & Ganem, D. ( 1996; ). Lytic growth of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in culture. Nat Med 2, 342–346.[CrossRef]
    [Google Scholar]
  18. Rickabaugh, T. M., Brown, H. J., Wu, T. T., Song, M. J., Hwang, S., Deng, H., Mitsouras, K. & Sun, R. ( 2005; ). Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 RTA reactivates murine gammaherpesvirus 68 from latency. J Virol 79, 3217–3222.[CrossRef]
    [Google Scholar]
  19. Ringel, M. D., Hayre, N., Saito, J., Saunier, B., Schuppert, F., Burch, H., Bernet, V., Burman, K. D., Kohn, L. D. & Saji, M. ( 2001; ). Overexpression and overactivation of Akt in thyroid carcinoma. Cancer Res 61, 6105–6111.
    [Google Scholar]
  20. Sadagopan, S., Sharma-Walia, N., Veettil, M. V., Raghu, H., Sivakumar, R., Bottero, V. & Chandran, B. ( 2007; ). Kaposi's sarcoma-associated herpesvirus induces sustained NF-κB activation during de novo infection of primary human dermal microvascular endothelial cells that is essential for viral gene expression. J Virol 81, 3949–3968.[CrossRef]
    [Google Scholar]
  21. Shayesteh, L., Lu, Y., Kuo, W. L., Baldocchi, R., Godfrey, T., Collins, C., Pinkel, D., Powell, B., Mills, G. B. & Gray, J. W. ( 1999; ). PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21, 99–102.[CrossRef]
    [Google Scholar]
  22. Sin, S.-H., Roy, D., Wang, L., Staudt, M. R., Fakhari, F. D., Patel, D. D., Henry, D., Harrington, W. J., Jr, Damania, B. A. & Dittmer, D. P. ( 2007; ). Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling. Blood 109, 2165–2173.[CrossRef]
    [Google Scholar]
  23. Sodhi, A., Montaner, S., Patel, V., Gomez-Roman, J. J., Li, Y., Sausville, E. A., Sawai, E. T. & Gutkind, J. S. ( 2004; ). Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor. Proc Natl Acad Sci U S A 101, 4821–4826.[CrossRef]
    [Google Scholar]
  24. Song, M. J., Brown, H. J., Wu, T. T. & Sun, R. ( 2001; ). Transcription activation of polyadenylated nuclear RNA by Rta in human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus. J Virol 75, 3129–3140.[CrossRef]
    [Google Scholar]
  25. Stallone, G., Schena, A., Infante, B., Di Paolo, S., Loverre, A., Maggio, G., Ranieri, E., Gesualdo, L., Schena, F. P. & Grandaliano, G. ( 2005; ). Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med 352, 1317–1323.[CrossRef]
    [Google Scholar]
  26. Sun, R., Lin, S. F., Gradoville, L., Yuan, Y., Zhu, F. & Miller, G. ( 1998; ). A viral gene that activates lytic cycle expression of Kaposi's sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A 95, 10866–10871.[CrossRef]
    [Google Scholar]
  27. Sun, M., Paciga, J. E., Feldman, R. I., Yuan, Z., Coppola, D., Lu, Y. Y., Shelley, S. A., Nicosia, S. V. & Cheng, J. Q. ( 2001a; ). Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERα) via interaction between ERα and PI3K. Cancer Res 61, 5985–5991.
    [Google Scholar]
  28. Sun, M., Wang, G., Paciga, J. E., Feldman, R. I., Yuan, Z. Q., Ma, X. L., Shelley, S. A., Jove, R., Tsichlis, P. N. & other authors ( 2001b; ). AKT1/PKBα kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am J Pathol 159, 431–437.[CrossRef]
    [Google Scholar]
  29. Swart, R., Ruf, I. K., Sample, J. & Longnecker, R. ( 2000; ). Latent membrane protein 2A-mediated effects on the phosphatidylinositol 3-Kinase/Akt pathway. J Virol 74, 10838–10845.[CrossRef]
    [Google Scholar]
  30. Tiwari, V., Shukla, S. Y., Yue, B. Y. J. T. & Shukla, D. ( 2007; ). Herpes simplex virus type 2 entry into cultured human corneal fibroblasts is mediated by herpesvirus entry mediator. J Gen Virol 88, 2106–2110.[CrossRef]
    [Google Scholar]
  31. Tomlinson, C. C. & Damania, B. ( 2004; ). The K1 protein of Kaposi's sarcoma-associated herpesvirus activates the Akt signaling pathway. J Virol 78, 1918–1927.[CrossRef]
    [Google Scholar]
  32. Uddin, S., Hussain, A. R., Al-Hussein, K. A., Manogaran, P. S., Wickrema, A., Gutierrez, M. I. & Bhatia, K. G. ( 2005; ). Inhibition of phosphatidylinositol 3′-kinase/AKT signaling promotes apoptosis of primary effusion lymphoma cells. Clin Cancer Res 11, 3102–3108.[CrossRef]
    [Google Scholar]
  33. Vanhaesebroeck, B., Leevers, S. J., Ahmadi, K., Timms, J., Katso, R., Driscoll, P. C., Woscholski, R., Parker, P. J. & Waterfield, M. D. ( 2001; ). Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 70, 535–602.[CrossRef]
    [Google Scholar]
  34. Virgin, H. W., IV, Latreille, P., Wamsley, P., Hallsworth, K., Weck, K. E., Dal Canto, A. J. & Speck, S. H. ( 1997; ). Complete sequence and genomic analysis of murine gammaherpesvirus 68. J Virol 71, 5894–5904.
    [Google Scholar]
  35. Vivanco, I. & Sawyers, C. L. ( 2002; ). The phosphatidylinositol 3-Kinase-AKT pathway in human cancer. Nat Rev Cancer 2, 489–501.[CrossRef]
    [Google Scholar]
  36. Wu, T. T., Tong, L., Rickabaugh, T., Speck, S. & Sun, R. ( 2001; ). Function of Rta is essential for lytic replication of murine gammaherpesvirus 68. J Virol 75, 9262–9273.[CrossRef]
    [Google Scholar]
  37. Xu, Y., AuCoin, D. P., Huete, A. R., Cei, S. A., Hanson, L. J. & Pari, G. S. ( 2005; ). A Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 ORF50 deletion mutant is defective for reactivation of latent virus and DNA replication. J Virol 79, 3479–3487.[CrossRef]
    [Google Scholar]
  38. Yu, F., Harada, J. N., Brown, H. J., Deng, H., Song, M. J., Wu, T.-T., Kato-Stankiewicz, J., Nelson, C. G., Vieira, J. & other authors ( 2007; ). Systematic identification of cellular signals reactivating Kaposi sarcoma-associated herpesvirus. PLoS Pathog 3, e44 [CrossRef]
    [Google Scholar]
  39. zur Hausen, H., Bornkamm, G. W., Schmidt, R. & Hecker, E. ( 1979; ). Tumor initiators and promoters in the induction of Epstein–Barr virus. Proc Natl Acad Sci U S A 76, 782–785.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.015073-0
Loading
/content/journal/jgv/10.1099/vir.0.015073-0
Loading

Data & Media loading...

Most Cited This Month

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