[Frontiers in Bioscience 7, d726-730, March 1, 2002]

THE KSHV LATENCY-ASSOCIATED NUCLEAR ANTIGEN: A MULTIFUNCTIONAL PROTEIN

Takashi Komatsu, Mary E. Ballestas, Andrew J. Barbera, Kenneth M. Kaye

Department of Medicine, Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Ave.,Boston, MA

TABLE OF CONTENTS

1. Abstract
2. LANA1 and Epidemiology
3. Transcription and Sequence
4. LANA1 Expression in KS, PEL, and Multicastleman's Disease
5. LANA1 shares Homology with ORF 73's of other Gamma-2 Herpesviruses
6. LANA1 Subcellular Localization
7. LANA1 mediates KSHV episome persistence by acting on Terminal Repeat (TR) DNA
8. LANA1 potential for gene therapy
9. LANA1 Transcriptional Regulation
10. LANA1 interacts with cellular proteins
11. Conclusion
12. References

1. ABSTRACT

Kaposi's sarcoma(KS)-associated herpes virus (KSHV) or human herpesvirus 8 (HHV-8) is highly associated with KS, primary effusion lymphoma (PEL), and multicentric Castleman's disease, an aggressive lymphoproliferative disorder (1-3). Most tumor cells are latently infected with KSHV in which a small subset of viral genes are expressed (4-6). Of these latently expressed genes, the latency-associated nuclear antigen (LANA1, LNA, or LNA1) is the only protein consistently shown to be highly expressed by in situ hybridization and immunohistochemistry (7-10). In the past few years multiple functions have been demonstrated for LANA1. Here we review LANA1's roles in KSHV infection. Topics discussed include LANA1's roles in episome persistence, regulation of transcription and interaction with cellular proteins.

2. LANA1 AND EPIDEMIOLOGY

LANA1 was initially detected as punctate nuclear staining by indirect immunofluorescence microscopy performed on KSHV infected PEL cell lines using serum from KSHV infected individuals (8, 11). Subsequently, base-line anti-LANA1 reactivity was used as a marker for KSHV infection (8, 12). Work with the anti-LANA1 assay in a clinic-based population found an HHV-8 seroprevalence of 27 percent in homosexual or bisexual men (8). Similar estimates have been obtained with other serologic assays that measure antibodies to lytic-phase viral antigens (11, 13). After the KSHV genome was sequenced, LANA1 was mapped to KSHV ORF73 (9, 10, 14).

3. TRANSCRIPTION AND SEQUENCE

LANA1 is expressed from a polycistronic message which also contains ORF 71 (v-FLIP) and ORF72 (v-cyclin), both of which are downstream of ORF73 (10, 15, 16). The LANA1 message is spliced once upstream of ORF73, although an unspliced message has also been described (15). Potential transcription factor binding sites for SP-1, IRF 1, IRF 2 and c-myc are upstream of the transcription initiation site (15, 16). Reporter assays in 293 and BJAB cells showed robust activation using the ORF 73 promoter (15, 16). ORF 73 promoter sequence was furthermore subject to cell cycle regulation, although whether this phenomenon is a result of the presence of v-cyclin on the same transcript remains to be determined (16).

KSHV ORF 73 encodes a protein of variable size in different viral isolates. LANA1 encodes an N-terminal proline rich domain, an internal glutamine rich and acidic repeat domain followed by a leucine zipper motif (Figure 1) (17, 18). The number of repeat elements can vary between KSHV isolates, and accounts for the different LANA1 sizes (19). However, within any one isolate, the number of repeats remains stable, during both lytic and latent infection.

4. LANA1 EXPRESSION IN KS, PEL, AND MULTICASTLEMAN'S DISEASE

LANA1 is expressed in KS, multicentric Castleman's disease, and primary effusion lymphoma (PEL) In KS, LANA1 is expressed in the spindle cells in early patch and plaque stages as well as the advanced nodular stage (7, 10, 20, 21). These results suggest a role for KSHV in the early pathogenesis of KS development. In multicentric Castleman's disease, LANA1 is expressed in the mantle zone of lymph node follicles in large immunoblastic B cells (7). LANA1 is also expressed in primary PEL cells as well as PEL cell lines (7, 22).

5. LANA1 SHARES HOMOLOGY WITH ORF 73'S OF OTHER GAMMA-2 HERPESVIRUSES

LANA1 is homologous to ORF 73s of other gamma-2 herpesviruses (17, 18, 23) but ORF 73's of other gamma-2 herpesviruses vary in the regions of homology that they share with KSHV LANA1. For instance, rhesus rhadinovirus (RRV) ORF 73 (447 aa), (24, 25) and murine herpesvirus 68 (MHV 68) ORF 73 (314 aa) (23) both have an N-terminal proline rich domain similar to LANA1, but this domain is absent in herpesvirus saimiri (HVS) ORF 73 (407 aa) (26). HVS ORF73, unlike RRV or MHV 68 ORF 73, has a repeat region rich in glutamic acid. However all the viral ORF73s share homology at their C-termini which suggests conserved function(s) for this domain.

6. LANA1 SUBCELLULAR LOCALIZATION

Detailed analyses of the subcellular distribution of LANA1 have been performed by confocal microscopy. Three-dimensional computer controlled wide field epifluorescence microscopy demonstrated that LANA1 resides in irregularly shaped bodies which preferentially associate with the border of heterochromatin in BCBL-1 PEL cell nuclei (27). LANA1 does not colocalize with ND10 PML bodies (27). Both the N- and C- terminal LANA1 domains are capable of localizing to the nucleus (28). Recent work shows that a region encompassing amino acids 5 to 22 is sufficient to mediate a specific interaction of LANA1 with chromosomes during mitosis (29) and that LANA1 nuclear localization also maps to a signal comprising amino acids 24 to 30 (29).

Confocal microscopy demonstrated that LANA1 and KSHV genomes colocalize in PEL cells in interphase nuclei and along chromosomes (30, 31). These findings were consistent with the independent findings that LANA1 (32) and KSHV DNA (1) associate with chromosomes in PEL cells. These results also suggested a role for LANA1 in KSHV episome persistence.

7. LANA1 MEDIATES KSHV EPISOME PERSISTENCE BY ACTING ON TERMINAL REPEAT (TR) DNA

LANA1 is necessary and sufficient for the persistence of KSHV episomes containing a specific cis-acting KSHV sequence (30). We have recently localized the cis-acting sequence to the 0.8 kb KSHV TR unit (33). In KSHV-uninfected cells, a plasmid containing KSHV TR elements persists as an episome in the presence of LANA1 (30). Of note, LANA1 bound in vitro to the KSHV Z6 cosmid, which includes the KSHV TR elements (31). More recently, LANA1 was shown to bind to nt 603 to 622 of the KSHV TR (33, 34). High copy number, tandemly repeated TRs likely mediate focal concentration of LANA1 to dots in KSHV infected cells.

Since LANA1 colocalizes with KSHV genomes on chromosomes and mediates episome persistence of KSHV DNA, these data are consistent with the model that LANA1 functions to tether KSHV TR DNA to chromosomes during mitosis in order to mediate efficient segregation to progeny nuclei (30, 31). This model of tethering to mediate efficient persistence has been previously proposed for EBV EBNA1 and the bovine papillomavirus E2 proteins (35-40). EBNA1 mediates EBV episome persistence by acting on a 1.8 kb EBV (oriP) element (36) which contains multiple EBNA1 binding sites (35). The functional homology between LANA1 and EBNA1 exists in the absence of any real sequence homology (30). Further, LANA1 does not colocalize with the Epstein-Barr (EBV) EBNA1 protein in the context of PEL cells coinfected with KSHV and EBV (32).

8. LANA1 POTENTIAL FOR GENE THERAPY

Adenoviruses, retroviruses, and adeno-associated viruses (AAV) are currently used to deliver genes to tumor cells or to supply a functional gene product in cells lacking one. However, these approaches have potential drawbacks. Retroviral vectors integrate into host chromosomes and therefore are subject to position effect variegation in which gene expression is affected by the integration site (41). Infectious viral vectors may elicit an immune response, creating difficulties in immune competent individuals. Therefore, the potential of plasmid-based expression vectors has led to increasing interest. A plasmid expressing specific genes of interest which contains the cis-acting TR unit and a promoter driving the expression of LANA1 should be maintained extrachromosomally, replicate during the cell cycle, and be efficiently partitioned to daughter cells during mitosis.

9. LANA1 TRANSCRIPTIONAL REGULATION

Multiple LANA1 effects on transcription have been demonstrated. LANA1 repressed the EBV virus-latency promoters Cp and Qp in Hela or Rael cells (42). However, in a different report, LANA1 activated both the EBV LMP1 and C promoters in BJAB cells and 293 cells (43). These different observations may be due to different cell types used in the experiments. LANA1 also modulates NF-kappa B-dependent transcription (43, 44). The internal repeats and the C-terminal domain of LANA1 both bind to the C/H3 region of (CREB)-binding protein (CBP) (45). Many proteins, including NF-kappa B, use CBP either as a co-activator or target it as an integrator of transcriptional regulation (46).

LANA1 domains were fused to the Gal4 DNA-binding domain to investigate LANA1 transcriptional regulation (28). Both the LANA1 N- and C-terminal regions repressed transcription with similar efficiency to the wildtype LANA1 in 293T cells (28). However, in HeLa cells, only the N-terminal regions of LANA1 repressed transcription (42).

A recent report demonstrated that LANA1 transactivates the telomerase reverse transcriptase promoter in 293T, 293, and BJAB cells (47). Telomerase reverse transcriptase is the subunit responsible for the enzymatic activity of telomerase. In addition, five Sp1 sites lay adjacent to the promoter, and experiments show that LANA1 affects the Sp1-DNA complex in the context of BJAB nuclear extracts.

10. LANA1 INTERACTS WITH CELLULAR PROTEINS

Yeast two-hybrid analysis using the LANA1 C-terminus as bait identified RING3 as a LANA1 interacting protein (48). RING3 belongs to the Drosophila female sterile homeotic (fsh) family of proteins (48). Since work has shown that RING3 is a potential mitogen-activated nuclear serine/threonine kinase, its ability to affect LANA1 phosphorylation has been investigated (48). RING3 induces LANA1 phosphorylation on serine and threonine residues in in vitro kinase assays and phosphorylation occurs between LANA1 amino acids 951 to 1107. However, RING3 does not directly phosphorylate LANA1 since a mutation in the RING3 catalytic residues which ablates kinase activity does not reduce LANA1 phosphorylation. Instead, RING3 appears to recruit a kinase which phosphorylates LANA1 (48).

LANA1 also interacts with the tumor suppressor gene product p53 (49). LANA1 bound to p53 in vitro and in co-immunoprecipitation assays from cells. LANA1 also inhibited p53 transactivation in reporter assays. Co-expression of LANA1 reduced p53 mediated apoptosis in SAOS-2 cells and NIH/3T3 cells. LANA1's did not cause p53 degradation or alter p53's ability to bind DNA. The p53- binding domain, and transcriptional repression activity defined in these studies appears to map outside of the first 440 LANA1 amino acids. Therefore, LANA1 may contribute to oncogenesis by promoting cell survival through alteration of p53 function (49).

LANA1 residues 803-990 interact with the "pocket" region of the retinoblastoma protein (pRb) (50). LANA1 transactivated an artificial promoter carrying the cell cycle transcription factor E2F DNA-binding sequences and also upregulated the cyclin E (CCNEI) promoter, but not the B-myb (MYBL2) promoter (50). LANA1 overcame the RB induced flat cell phenotype in SAOS cells and transformed primary rat embryo fibroblasts together with the cellular oncogene Harvey rat sarcoma viral oncogene homolog (Hras), (50). These findings indicate that LANA1 may contribute to oncogenesis by targeting the retinoblastoma protein-E2F transcriptional regulatory pathway.

11. CONCLUSION

LANA1 has a central role in KSHV biology. LANA1 mediates KSHV episome persistence and has transcriptional regulatory properties. LANA1 also interacts with multiple cell proteins. Future work should further define LANA1's role in tumorigenesis and the molecular mechanisms by which LANA1 functions.

12. REFERENCES

1. Cesarman, E., P.S. Moore, P.H. Rao, P.H., G. Inghirami, D.M. Knowles & Y. Chang: In vitro establishment and characterization of two acquired immunodeficiency syndrome-related lymphoma cell lines (BC-1 and BC-2) containing Kaposi's sarcoma-associated herpesvirus-like (KSHV) DNA sequences. Blood 86, 2708-2714 (1995)

2. Chang, Y., E. Cesarman, M.S. Pessin, F. Lee, J. Culpepper, D.M. Knowles & P.S. Moore: Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266, 1865-1869 (1994)

3. Dupin, N., T.L. Diss, P. Kellam, M. Tulliez, M.Q. Du, D. Sicard, R.A. Weiss, P.G. Isaacson & C. Boshoff: HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood 95, 1406-1412 (2000)

4. Boshoff, C., T.F. Schulz, M.M. Kennedy, A.K. Graham, C. Fisher, A. Thomas, J.O. McGee, R.A. Weiss & O.L. JJ: Kaposi's sarcoma-associated herpesvirus infects endothelial and spindle cells. Nat Med 1, 1274-1278 (1995)

5. Staskus, K.A., W. Zhong, K. Gebhard, B. Herndier, H. Wang, R. Renne, J. Beneke, J. Pudney, D.J. Anderson, D. Ganem & A.T. Haase: Kaposi's sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. J Virol 71, 715-719 (1997)

6. Zhong, W., H. Wang, B. Herndier & D. Ganem: Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma. Proc Natl Acad Sci U S A 93, 6641-6646 (1996)

7. Dupin, N., C. Fisher, P. Kellam, S. Ariad, M. Tulliez, N. Franck, E. van Marck, D. Salmon, I. Gorin, J.P. Escande, R.A. Weiss, K. Alitalo & C. Boshoff: Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. Proc Natl Acad Sci U S A 96, 4546-4551 (1999)

8. Kedes, D.H., E. Operskalski, M. Busch, R. Kohn, J. Flood & D. Ganem: 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 2, 918-924 (1996)

9. Kellam, P., C. Boshoff, D. Whitby, S. Matthews, R.A. Weiss & S.J. Talbot: Identification of a major latent nuclear antigen, LNA-1, in the human herpesvirus 8 genome. J Hum Virol 1, 19-29 (1997)

10. Rainbow, L., G.M. Platt, G.R. Simpson, R. Sarid, S.J. Gao, H. Stoiber, C.S. Herrington, P.S. Moore & T.F. Schulz: 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 71, 5915-5921 (1997)

11. Gao, S.J., L. Kingsley, D.R. Hoover, T.J. Spira, C.R. Rinaldo, A. Saah, J. Phair, R. Detels, P. Parry, Y. Chang & P.S. Moore: Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. N Engl J Med 335, 233-241 (1996)

12. Martin, J.N., D.E. Ganem, D.H. Osmond, K.A. Page-Shafer, D. Macrae & D.H. Kedes: Sexual transmission and the natural history of human herpesvirus 8 infection. N Engl J Med 338, 948-954 (1998)

13. Gao, S.J., L. Kingsley, M. Li, W. Zheng, C. Parravicini, J. Ziegler, R. Newton, C.R. Rinaldo, A. Saah, J. Phair, R. Detels, Y. Chang & P.S. Moore: KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma. Nat Med 2, 925-928 (1996)

14. Kedes, D.H., M. Lagunoff, R. Renne & D. Ganem: Identification of the gene encoding the major latency-associated nuclear antigen of the Kaposi's sarcoma-associated herpesvirus. J Clin Invest 100, 2606-2610 (1997)

15. Dittmer, D., M. Lagunoff, R. Renne, K. Staskus, A. Haase & D. Ganem: A cluster of latently expressed genes in Kaposi's sarcoma-associated herpesvirus. J Virol 72, 8309-8315 (1998)

16. Sarid, R., J.S. Wiezorek, P.S. Moore & Y. Chang: Characterization and cell cycle regulation of the major Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) latent genes and their promoter. J Virol 73, 1438-1446 (1999)

17. Russo, J.J., R.A. Bohenzky, M.C. Chien, J. Chen, M. Yan, D. Maddalena, J.P. Parry, D. Peruzzi, I.S. Edelman, Y. Chang & P.S. Moore: Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8) Proc Natl Acad Sci U S A 93, 14862-14867 (1996)

18. Neipel, F., J.C. Albrecht & B. Fleckenstein: Cell-homologous genes in the Kaposi's sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity? J Virol 71, 4187-4192 (1997)

19. Gao, S.J., Y.J. Zhang, J.H. Deng, C.S. Rabkin, O. Flore & H.B. Jenson: Molecular polymorphism of Kaposi's sarcoma-associated herpesvirus (Human herpesvirus 8) latent nuclear antigen: evidence for a large repertoire of viral genotypes and dual infection with different viral genotypes. J Infect Dis 180, 1466-1476 (1999)

20. Katano, H., Y. Sato, T. Kurata, S. Mori & T. Sata: High expression of HHV-8-encoded ORF73 protein in spindle-shaped cells of Kaposi's sarcoma. Am J Pathol 155, 47-52 (1999)

21. Sturzl, M., C. Hohenadl, C. Zietz, E. Castanos-Velez, A. Wunderlich, G. Ascherl, P. Biberfeld, P. Monini, P.J. Browning & B. Ensoli: Expression of K13/v-FLIP gene of human herpesvirus 8 and apoptosis in Kaposi's sarcoma spindle cells. J Natl Cancer Inst 91, 1725-1733 (1999)

22. Jones, D., M.E. Ballestas, K.M. Kaye, J.M. Gulizia, G.L. Winters, J. Fletcher, D.T. Scadden & J.C. Aster: Primary-effusion lymphoma and Kaposi's sarcoma in a cardiac-transplant recipient. N Engl J Med 339, 444-449 (1998)

23. Virgin, H.W.t., P. Latreille, P. Wamsley, K. Hallsworth, K.E. Weck, A.J. Dal Canto & S.H. Speck: Complete sequence and genomic analysis of murine gammaherpesvirus 68. J Virol 71, 5894-5904 (1997)

24. Alexander, L., L. Denekamp, A. Knapp, M.R. Auerbach, B. Damania & R.C. Desrosiers: The primary sequence of rhesus monkey rhadinovirus isolate 26-95: sequence similarities to Kaposi's sarcoma-associated herpesvirus and rhesus monkey rhadinovirus isolate 17577. J. Virol. 74, 3388-3398 (2000)

25. Searles, R.P., E.P. Bergquam, M.K. Axthelm & S.W. Wong: Sequence and genomic analysis of a Rhesus macaque rhadinovirus with similarity to Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. J Virol 73, 3040-3053 (1999)

26. Albrecht, J., J. Nicholas, D. Biller, K.K. Cameron, C. Newman, B. Biesinger, S. Wittmann, M.A. Craxton, H. Coleman & B. Fleckenstein: Primary structure of the herpesvirus saimiri genome. J. Virology 66, 5047-5058 (1992)

27. Szekely, L., C. Kiss, K. Mattsson, E. Kashuba, K. Pokrovskaja, A. Juhasz, P. Holmvall & G. Klein: Human herpesvirus-8-encoded LNA-1 accumulates in heterochromatin- associated nuclear bodies. J Gen Virol 80, 2889-2900 (1999)

28. Schwam, D.R., R.L. Luciano, S.S. Mahajan, L. Wong & A.C. Wilson: Carboxy terminus of human herpesvirus 8 latency-associated nuclear antigen mediates dimerization, transcriptional repression, and targeting to nuclear bodies. J. Virology 74, 8532-8540 (2000)

29. Piolot, T., M. Tramier, M. Coppey, J.C. Nicolas & V. Marechal: Close but distinct regions of human herpesvirus 8 latency-associated nuclear antigen 1 are responsible for nuclear targeting and binding to human mitotic chromosomes. J. Virology 75, 3948-3959 (2001)

30. Ballestas, M.E., P.A. Chatis & K.M. Kaye: Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 284, 641-644 (1999)

31. Cotter, M.A.n. & E.S. Robertson: The latency-associated nuclear antigen tethers the Kaposi's sarcoma-associated herpesvirus genome to host chromosomes in body cavity-based lymphoma cells. Virology 264, 254-264 (1999)

32. Szekely, L., F. Chen, N. Teramoto, B. Ehlin-Henriksson, K. Pokrovskaja, A. Szeles, A. Manneborg-Sandlund, M. Lowbeer, E.T. Lennette & G. Klein: Restricted expression of Epstein-Barr virus (EBV)-encoded, growth transformation-associated antigens in an EBV- and human herpesvirus type 8-carrying body cavity lymphoma line. J Gen Virol 79, 1445-1452 (1998)

33. Ballestas, M.E. & K.M. Kaye: Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 mediates episome persistence through cis-acting terminal repeat (TR) sequence and specifically binds TR DNA. J. Virology 75, 3250-3258 (2001)

34. Garber, A.C., M.A. Shu, J. Hu & R. Renne: DNA binding and modulation of gene expression by the latency-associated nuclear antigen of kaposi's sarcoma-associated herpesvirus. J. Virology 75, 7882-7892 (2001)

35. Rawlins, D., G. Milman, S.D. Hayward, & G.S. Hayward: (1985) Sequence-specific DNA binding of the Epstein-Barr virus nuclear antigen (EBNA-1) to clustered sites in the plasmid maintenance region. Cell 42, 859-868.

36. Yates, J., N. Warren, D. Reisman & B. Sugden: A cis-acting element from the Epstein-Barr viral genome that permits stable replication of recombinant plasmids in latently infected cells. Proc. Natl. Acad. Sci USA 81, 3806-3810 (1984)

37. Yates, J., N. Warren & B. Sugden: Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. Nature 313, 812-815 (1985)

38. Lehman, C. & M.R. Botchan: Segregation of viral plasmids depends on tethering to chromosomes and is regulated by phosphorylation. Proc. Natl. Acad. Sci. USA 95, 4338-4343 (1998)

39. Skiadopoulos, M. & A.A. McBride: Bovine papillomavirus type 1 genomes and the E2 transactivator protein are closely associated with mitotic chromatin. J. Virology 72, 2079-2088 (1998)

40. Harris, A., B.D. Young & B.E. Griffin: Random association of Epstein-Barr virus genomes with host cell metaphase chromosomes in Burkitt's lymphoma-derived cell lines. J. Virology 56, 328-332 (1985)

41. Laible, G., A. Wolf, R. Dorn, G. Reuter, C. Nislow, A. Lebersorger, D. Popkin, L. Pillus & T. Jenuwein: Mammalian homologues of the Polycomb-group gene Enhancer of zeste mediate gene silencing in Drosophila heterochromatin and at S. cerevisiae telomeres. EMBO J. 16, 3219-3232 (1997)

42. Krithivas, A., D.B. Young, G. Liao, D. Greene & S.D. Hayward: Human herpesvirus 8 LANA interacts with proteins of the mSin3 corepressor complex and negatively regulates Epstein-Barr virus gene expression in dually infected PEL cells. J. Virology 74, 9637-9645 (2000)

43. Groves, A., M.A. Cotter, C. Subramanian & E.S. Robertson: The Latency-Associated Nuclear Antigen Encoded by Kaposi's Sarcoma-Associated Herpesvirus Activates Two Major Essential Epstein-Barr Virus Latent Promoters. J. Virol. 75, 9446-9457 (2001)

44. Renne, R., C. Barry, D. Dittmer, N. Compitello, P.O. Brown & D. Ganem: Modulation of cellular and viral gene expression by the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J. Virology 75, 458-468 (2001)

45. Lim, C., Y. Gwack, S. Hwang, S. Kim & J. Choe: The transcriptional activity of CREB-binding protein is modulated by the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpes virus. J Biol Chem 276, 31016-31022 (2001)

46. Gerritsen, M., A.J. Williams, A.S. Neish, S. Moore, Y. Shi, Y. & T. Cillins: CREB-binding protein/p300 are transcriptional coactivators of p65. Proc. Natl. Acad. Sci. 94, 2927-2932 (1997)

47. Knight, J., M.A. Cotter & E.S. Robertson: The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus transactivates the telomerase reverse transcriptase promoter. J Biol Chem 276, 22971-22978 (2001)

48. Platt, G.M., G.R. Simpson, S. Mittnacht & T.F. Schulz: Latent nuclear antigen of Kaposi's sarcoma-associated herpesvirus interacts with RING3, a homolog of the Drosophila female sterile homeotic (fsh) gene. J Virol 73, 9789-9795 (1999)

49. Friborg, J., Jr., W. Kong, M.O. Hottiger & G.J. Nabel: p53 inhibition by the Lana protein of Kshv protects against cell death. Nature 402, 889-894 (1999)

50. Radkov, S.A., P. Kellam & C. Boshoff: The latent nuclear antigen of Kaposi sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene Hras transforms primary rat cells. Nature 6, 1121-1127 (2000)

Abbreviations: KSHV (Kaposi's sarcoma-associated herpes virus); HHV8 (human herpesvirus 8); PEL (primary effusion lymphoma); (PEL), latency-associated nuclear antigen (LANA1, LNA, or LNA1)

Key Words: KSHV (Kaposi's sarcoma-associated herpes virus); HHV8 (human herpesvirus 8); PEL (primary effusion lymphoma); (PEL), latency-associated nuclear antigen (LANA1, LNA, or LNA1), Review

Send correspondence to: Dr Kenneth M. Kaye, Department of Medicine, Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Ave., Boston, MA 02115, Tel: 617-525-4256, Fax: 617-525-4251, E-mail: kkaye@rics.bwh.harvard.edu