Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Jun 25;93(13):6641–6646. doi: 10.1073/pnas.93.13.6641

Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma.

W Zhong 1, H Wang 1, B Herndier 1, D Ganem 1
PMCID: PMC39079  PMID: 8692871

Abstract

Kaposi sarcoma (KS) is the leading neoplasm of HIV-infected patients and is also found in several HIV-negative populations. Recently, DNA sequences from a novel herpesvirus, termed KS-associated herpesvirus (KSHV), or human herpesvirus 8 (HHV-8) have been identified within KS tissue from both HIV-positive and HIV-negative cases; infection with this agent has been proposed as a possible factor in the etiology or pathogenesis of the tumor. Here we have examined the pattern of KSHV/HHV-8 gene expression in KS and find it to be highly restricted. We identify and characterize two small transcripts that represent the bulk of the virus-specific RNA transcribed from over 120 kb of the KSHV genome in infected cells. One transcript is predicted to encode a small membrane protein; the other is an unusual polyadenylylated RNA that accumulates in the nucleus to high copy number. This pattern of viral gene expression suggests that most infected cells in KS are latently infected, with lytic viral replication likely restricted to a much smaller subpopulation of cells. These findings have implications for the therapeutic utility of currently available antiviral drugs targeted against the lytic replication cycle.

Full text

PDF
6644

Images in this article

6642Fig. 1
on p.6642
6643Fig. 2
on p.6643
6644Fig. 3
on p.6644
6645Fig. 5
on p.6645

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ambroziak J. A., Blackbourn D. J., Herndier B. G., Glogau R. G., Gullett J. H., McDonald A. R., Lennette E. T., Levy J. A. Herpes-like sequences in HIV-infected and uninfected Kaposi's sarcoma patients. Science. 1995 Apr 28;268(5210):582–583. doi: 10.1126/science.7725108. [DOI] [PubMed] [Google Scholar]
  2. Beral V. Epidemiology of Kaposi's sarcoma. Cancer Surv. 1991;10:5–22. [PubMed] [Google Scholar]
  3. Beral V., Peterman T. A., Berkelman R. L., Jaffe H. W. Kaposi's sarcoma among persons with AIDS: a sexually transmitted infection? Lancet. 1990 Jan 20;335(8682):123–128. doi: 10.1016/0140-6736(90)90001-l. [DOI] [PubMed] [Google Scholar]
  4. Boshoff C., Schulz T. F., Kennedy M. M., Graham A. K., Fisher C., Thomas A., McGee J. O., Weiss R. A., O'Leary J. J. Kaposi's sarcoma-associated herpesvirus infects endothelial and spindle cells. Nat Med. 1995 Dec;1(12):1274–1278. doi: 10.1038/nm1295-1274. [DOI] [PubMed] [Google Scholar]
  5. Boshoff C., Whitby D., Hatziioannou T., Fisher C., van der Walt J., Hatzakis A., Weiss R., Schulz T. Kaposi's-sarcoma-associated herpesvirus in HIV-negative Kaposi's sarcoma. Lancet. 1995 Apr 22;345(8956):1043–1044. doi: 10.1016/s0140-6736(95)90780-7. [DOI] [PubMed] [Google Scholar]
  6. Brockdorff N., Ashworth A., Kay G. F., McCabe V. M., Norris D. P., Cooper P. J., Swift S., Rastan S. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell. 1992 Oct 30;71(3):515–526. doi: 10.1016/0092-8674(92)90519-i. [DOI] [PubMed] [Google Scholar]
  7. Brown C. J., Hendrich B. D., Rupert J. L., Lafrenière R. G., Xing Y., Lawrence J., Willard H. F. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell. 1992 Oct 30;71(3):527–542. doi: 10.1016/0092-8674(92)90520-m. [DOI] [PubMed] [Google Scholar]
  8. Cesarman E., Chang Y., Moore P. S., Said J. W., Knowles D. M. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med. 1995 May 4;332(18):1186–1191. doi: 10.1056/NEJM199505043321802. [DOI] [PubMed] [Google Scholar]
  9. Chang Y., Cesarman E., Pessin M. S., Lee F., Culpepper J., Knowles D. M., Moore P. S. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994 Dec 16;266(5192):1865–1869. doi: 10.1126/science.7997879. [DOI] [PubMed] [Google Scholar]
  10. Chuck S., Grant R. M., Katongole-Mbidde E., Conant M., Ganem D. Frequent presence of a novel herpesvirus genome in lesions of human immunodeficiency virus-negative Kaposi's sarcoma. J Infect Dis. 1996 Jan;173(1):248–251. doi: 10.1093/infdis/173.1.248. [DOI] [PubMed] [Google Scholar]
  11. Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. DiMaio D. Transforming activity of bovine and human papillomaviruses in cultured cells. Adv Cancer Res. 1991;56:133–159. doi: 10.1016/s0065-230x(08)60480-7. [DOI] [PubMed] [Google Scholar]
  13. Elion G. B., Furman P. A., Fyfe J. A., de Miranda P., Beauchamp L., Schaeffer H. J. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5716–5720. doi: 10.1073/pnas.74.12.5716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hansen L. J., Tennant B. C., Seeger C., Ganem D. Differential activation of myc gene family members in hepatic carcinogenesis by closely related hepatitis B viruses. Mol Cell Biol. 1993 Jan;13(1):659–667. doi: 10.1128/mcb.13.1.659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hirsch R., Colgrove R., Ganem D. Replication of duck hepatitis B virus in two differentiated human hepatoma cell lines after transfection with cloned viral DNA. Virology. 1988 Nov;167(1):136–142. doi: 10.1016/0042-6822(88)90062-1. [DOI] [PubMed] [Google Scholar]
  16. Howe J. G., Shu M. D. Upstream basal promoter element important for exclusive RNA polymerase III transcription of the EBER 2 gene. Mol Cell Biol. 1993 May;13(5):2655–2665. doi: 10.1128/mcb.13.5.2655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kozak M. The scanning model for translation: an update. J Cell Biol. 1989 Feb;108(2):229–241. doi: 10.1083/jcb.108.2.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lee S. I., Murthy S. C., Trimble J. J., Desrosiers R. C., Steitz J. A. Four novel U RNAs are encoded by a herpesvirus. Cell. 1988 Aug 26;54(5):599–607. doi: 10.1016/s0092-8674(88)80004-7. [DOI] [PubMed] [Google Scholar]
  19. Lerner M. R., Andrews N. C., Miller G., Steitz J. A. Two small RNAs encoded by Epstein-Barr virus and complexed with protein are precipitated by antibodies from patients with systemic lupus erythematosus. Proc Natl Acad Sci U S A. 1981 Feb;78(2):805–809. doi: 10.1073/pnas.78.2.805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Miwa T., Kedes L. Duplicated CArG box domains have positive and mutually dependent regulatory roles in expression of the human alpha-cardiac actin gene. Mol Cell Biol. 1987 Aug;7(8):2803–2813. doi: 10.1128/mcb.7.8.2803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Miwa T., Manabe Y., Kurokawa K., Kamada S., Kanda N., Bruns G., Ueyama H., Kakunaga T. Structure, chromosome location, and expression of the human smooth muscle (enteric type) gamma-actin gene: evolution of six human actin genes. Mol Cell Biol. 1991 Jun;11(6):3296–3306. doi: 10.1128/mcb.11.6.3296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mohun T. J., Taylor M. V., Garrett N., Gurdon J. B. The CArG promoter sequence is necessary for muscle-specific transcription of the cardiac actin gene in Xenopus embryos. EMBO J. 1989 Apr;8(4):1153–1161. doi: 10.1002/j.1460-2075.1989.tb03486.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Moore P. S., Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med. 1995 May 4;332(18):1181–1185. doi: 10.1056/NEJM199505043321801. [DOI] [PubMed] [Google Scholar]
  24. Petti L., Nilson L. A., DiMaio D. Activation of the platelet-derived growth factor receptor by the bovine papillomavirus E5 transforming protein. EMBO J. 1991 Apr;10(4):845–855. doi: 10.1002/j.1460-2075.1991.tb08017.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Renne R., Zhong W., Herndier B., McGrath M., Abbey N., Kedes D., Ganem D. Lytic growth of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in culture. Nat Med. 1996 Mar;2(3):342–346. doi: 10.1038/nm0396-342. [DOI] [PubMed] [Google Scholar]
  26. Schalling M., Ekman M., Kaaya E. E., Linde A., Biberfeld P. A role for a new herpes virus (KSHV) in different forms of Kaposi's sarcoma. Nat Med. 1995 Jul;1(7):707–708. doi: 10.1038/nm0795-707. [DOI] [PubMed] [Google Scholar]
  27. Su I. J., Hsu Y. S., Chang Y. C., Wang I. W. Herpesvirus-like DNA sequence in Kaposi's sarcoma from AIDS and non-AIDS patients in Taiwan. Lancet. 1995 Mar 18;345(8951):722–723. [PubMed] [Google Scholar]
  28. Wang D., Liebowitz D., Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985 Dec;43(3 Pt 2):831–840. doi: 10.1016/0092-8674(85)90256-9. [DOI] [PubMed] [Google Scholar]
  29. Whitby D., Howard M. R., Tenant-Flowers M., Brink N. S., Copas A., Boshoff C., Hatzioannou T., Suggett F. E., Aldam D. M., Denton A. S. Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma. Lancet. 1995 Sep 23;346(8978):799–802. doi: 10.1016/s0140-6736(95)91619-9. [DOI] [PubMed] [Google Scholar]
  30. zur Hausen H., O'Neill F. J., Freese U. K., Hecker E. Persisting oncogenic herpesvirus induced by the tumour promotor TPA. Nature. 1978 Mar 23;272(5651):373–375. doi: 10.1038/272373a0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES