Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Nov 15;100(10):2606–2610. doi: 10.1172/JCI119804

Identification of the gene encoding the major latency-associated nuclear antigen of the Kaposi's sarcoma-associated herpesvirus.

D H Kedes 1, M Lagunoff 1, R Renne 1, D Ganem 1
PMCID: PMC508462  PMID: 9366576

Abstract

Over 85% of patients with Kaposi's sarcoma (KS) are seropositive for antibodies to the latency-associated nuclear antigen (LANA) expressed in B cell lines infected with Kaposi's sarcoma-associated herpesvirus (KSHV). The presence of antibodies to LANA strongly correlates with the risk of developing the disease. However, the identity of the protein(s) comprising LANA and the corresponding gene(s) has remained unclear. To identify potential latent gene candidates for LANA, we probed total RNA extracted from BCBL-1 cells (a B cell line latently infected with KSHV) using lambda clones that span the KSHV genome. One region encoding latent transcripts spanned KSHV open reading frames (orfs) 71 (K13), 72 (v-cyclin), and 73. Among these, however, only orf 73, when expressed in heterologous mammalian cell systems, reacted with KSHV antibody-positive human sera, resulting in a punctate nuclear staining pattern reminiscent of LANA in BCBL-1 cells. Furthermore, extracts from cells expressing the orf 73 protein product specifically blocked the binding of KS patient antibodies to LANA. Finally, seroreactivity with recombinant orf 73 protein exactly paralleled reactivity with classical LANA as expressed in BCBL-1 cells, both in KS patients and in other groups. Together, these data support the identification of KSHV orf 73 as the gene encoding the dominant immunogenic component of LANA.

Full Text

The Full Text of this article is available as a PDF (255.5 KB).

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. 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]
  6. Chang Y., Ziegler J., Wabinga H., Katangole-Mbidde E., Boshoff C., Schulz T., Whitby D., Maddalena D., Jaffe H. W., Weiss R. A. Kaposi's sarcoma-associated herpesvirus and Kaposi's sarcoma in Africa. Uganda Kaposi's Sarcoma Study Group. Arch Intern Med. 1996 Jan 22;156(2):202–204. [PubMed] [Google Scholar]
  7. 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]
  8. Gao S. J., Kingsley L., Hoover D. R., Spira T. J., Rinaldo C. R., Saah A., Phair J., Detels R., Parry P., Chang Y. Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. N Engl J Med. 1996 Jul 25;335(4):233–241. doi: 10.1056/NEJM199607253350403. [DOI] [PubMed] [Google Scholar]
  9. Gao S. J., Kingsley L., Li M., Zheng W., Parravicini C., Ziegler J., Newton R., Rinaldo C. R., Saah A., Phair J. KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma. Nat Med. 1996 Aug;2(8):925–928. doi: 10.1038/nm0896-925. [DOI] [PubMed] [Google Scholar]
  10. Goedert J. J., Kedes D. H., Ganem D. Antibodies to human herpesvirus 8 in women and infants born in Haiti and the USA. Lancet. 1997 May 10;349(9062):1368–1368. doi: 10.1016/S0140-6736(05)63204-7. [DOI] [PubMed] [Google Scholar]
  11. Jones J. L., Hanson D. L., Chu S. Y., Ward J. W., Jaffe H. W. AIDS-associated Kaposi's sarcoma. Science. 1995 Feb 24;267(5201):1078–1079. doi: 10.1126/science.7855583. [DOI] [PubMed] [Google Scholar]
  12. Kedes D. H., Ganem D., Ameli N., Bacchetti P., Greenblatt R. The prevalence of serum antibody to human herpesvirus 8 (Kaposi sarcoma-associated herpesvirus) among HIV-seropositive and high-risk HIV-seronegative women. JAMA. 1997 Feb 12;277(6):478–481. [PubMed] [Google Scholar]
  13. Kedes D. H., Operskalski E., Busch M., Kohn R., Flood J., Ganem D. The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission. Nat Med. 1996 Aug;2(8):918–924. doi: 10.1038/nm0896-918. [DOI] [PubMed] [Google Scholar]
  14. Lagunoff M., Ganem D. The structure and coding organization of the genomic termini of Kaposi's sarcoma-associated herpesvirus. Virology. 1997 Sep 15;236(1):147–154. doi: 10.1006/viro.1997.8713. [DOI] [PubMed] [Google Scholar]
  15. Lennette E. T., Blackbourn D. J., Levy J. A. Antibodies to human herpesvirus type 8 in the general population and in Kaposi's sarcoma patients. Lancet. 1996 Sep 28;348(9031):858–861. doi: 10.1016/S0140-6736(96)03240-0. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Moore P. S., Kingsley L. A., Holmberg S. D., Spira T., Gupta P., Hoover D. R., Parry J. P., Conley L. J., Jaffe H. W., Chang Y. Kaposi's sarcoma-associated herpesvirus infection prior to onset of Kaposi's sarcoma. AIDS. 1996 Feb;10(2):175–180. doi: 10.1097/00002030-199602000-00007. [DOI] [PubMed] [Google Scholar]
  18. O'Neill E., Douglas J. L., Chien M. L., Garcia J. V. Open reading frame 26 of human herpesvirus 8 encodes a tetradecanoyl phorbol acetate- and butyrate-inducible 32-kilodalton protein expressed in a body cavity-based lymphoma cell line. J Virol. 1997 Jun;71(6):4791–4797. doi: 10.1128/jvi.71.6.4791-4797.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Rainbow L., Platt G. M., Simpson G. R., Sarid R., Gao S. J., Stoiber H., Herrington C. S., Moore P. S., Schulz T. F. The 222- to 234-kilodalton latent nuclear protein (LNA) of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) is encoded by orf73 and is a component of the latency-associated nuclear antigen. J Virol. 1997 Aug;71(8):5915–5921. doi: 10.1128/jvi.71.8.5915-5921.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Russo J. J., Bohenzky R. A., Chien M. C., Chen J., Yan M., Maddalena D., Parry J. P., Peruzzi D., Edelman I. S., Chang Y. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14862–14867. doi: 10.1073/pnas.93.25.14862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Simpson G. R., Schulz T. F., Whitby D., Cook P. M., Boshoff C., Rainbow L., Howard M. R., Gao S. J., Bohenzky R. A., Simmonds P. Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen. Lancet. 1996 Oct 26;348(9035):1133–1138. doi: 10.1016/S0140-6736(96)07560-5. [DOI] [PubMed] [Google Scholar]
  24. Soulier J., Grollet L., Oksenhendler E., Cacoub P., Cazals-Hatem D., Babinet P., d'Agay M. F., Clauvel J. P., Raphael M., Degos L. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood. 1995 Aug 15;86(4):1276–1280. [PubMed] [Google Scholar]
  25. Struhl K. Yeast transcriptional regulatory mechanisms. Annu Rev Genet. 1995;29:651–674. doi: 10.1146/annurev.ge.29.120195.003251. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Zhong W., Wang H., Herndier B., Ganem D. Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6641–6646. doi: 10.1073/pnas.93.13.6641. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES