A viral gene that activates lytic cycle expression of Kaposi's sarcoma-associated herpesvirus.

Herpesviruses exist in two states, latency and a lytic productive cycle. Here we identify an immediate-early gene encoded by Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus eight (HHV8) that activates lytic cycle gene expression from the latent viral genome. The gene is a homologue of Rta, a transcriptional activator encoded by Epstein-Barr virus (EBV). KSHV/Rta activated KSHV early lytic genes, including virus-encoded interleukin 6 and polyadenylated nuclear RNA, and a late gene, small viral capsid antigen. In cells dually infected with Epstein-Barr virus and KSHV, each Rta activated only autologous lytic cycle genes. Expression of viral cytokines under control of the KSHV/Rta gene is likely to contribute to the pathogenesis of KSHV-associated diseases.

[1]  E. Thiry,et al.  Bovine herpesvirus 4: genomic organization and relationship with two other gammaherpesviruses, Epstein-Barr virus and herpesvirus saimiri. , 1996, Veterinary microbiology.

[2]  G. Hayward,et al.  Kaposi's sarcoma-associated human herpesvirus-8 encodes homologues of macrophage inflammatory protein-1 and interleukin-6 , 1997, Nature Medicine.

[3]  A. Haase,et al.  Kaposi's sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells , 1997, Journal of virology.

[4]  S. Kenney,et al.  Epstein-Barr viral latency is disrupted by the immediate-early BRLF1 protein through a cell-specific mechanism. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[5]  J M Hardwick,et al.  The Epstein-Barr virus R transactivator (Rta) contains a complex, potent activation domain with properties different from those of VP16 , 1992, Journal of virology.

[6]  G. Miller The switch between latency and replication of Epstein-Barr virus. , 1990, The Journal of infectious diseases.

[7]  J. Steitz,et al.  14 The Diverse World of Small Ribonucleoproteins , 1993 .

[8]  K. Takada,et al.  Identification of an enhancer-type sequence that is responsive to Z and R trans-activators of Epstein-Barr virus. , 1989, Virology.

[9]  B. Ganem RNA world , 1987, Nature.

[10]  R. Sun,et al.  Selective switch between latency and lytic replication of Kaposi's sarcoma herpesvirus and Epstein-Barr virus in dually infected body cavity lymphoma cells , 1997, Journal of virology.

[11]  T. Kouzarides,et al.  Epstein‐Barr virus BZLF1 trans‐activator specifically binds to a consensus AP‐1 site and is related to c‐fos. , 1989, The EMBO journal.

[12]  E. Cesarman,et al.  Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. , 1994, Science.

[13]  S. Altman,et al.  Identification and characterization of an RNA molecule that copurifies with RNase P activity from HeLa cells. , 1989, Genes & development.

[14]  M. Marschall,et al.  Identification of proteins encoded by Epstein-Barr virus trans-activator genes , 1989, Journal of virology.

[15]  E. Cesarman,et al.  Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. , 1995, The New England journal of medicine.

[16]  R. Buckland,et al.  Characterization of an R-binding site mediating the R-induced activation of the Epstein-Barr virus BMLF1 promoter , 1992, Journal of virology.

[17]  E. Kieff Epstein-Barr virus and its replication , 1996 .

[18]  S. Rose-John,et al.  Development of an interleukin (IL) 6 receptor antagonist that inhibits IL-6-dependent growth of human myeloma cells , 1994, The Journal of experimental medicine.

[19]  P. Sperryn,et al.  Blood. , 1989, British journal of sports medicine.

[20]  J. Said,et al.  Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients. , 1997, Science.

[21]  S. Akira,et al.  The evidence for interleukin-6 as an autocrine growth factor in malignancy. , 1992, Seminars in cancer biology.

[22]  R. Sun,et al.  Polyadenylylated nuclear RNA encoded by Kaposi sarcoma-associated herpesvirus. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  W. Zhong,et al.  Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[24]  M. McGrath,et al.  Lytic growth of Kaposi's sarcoma–associated herpesvirus (human herpesvirus 8) in culture , 1996, Nature Medicine.

[25]  A. Nienhuis,et al.  Dysregulated interleukin 6 expression produces a syndrome resembling Castleman's disease in mice. , 1990, The Journal of clinical investigation.

[26]  Albrecht,et al.  Primary structure of the herpesvirus saimiri genome , 1992, Journal of virology.

[27]  V. Georgiev Virology , 1955, Nature.

[28]  J. Countryman,et al.  Activation of expression of latent Epstein-Barr herpesvirus after gene transfer with a small cloned subfragment of heterogeneous viral DNA. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[29]  J. Russo,et al.  Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[30]  S. Miles Kaposi sarcoma: a cytokine-responsive neoplasia? , 1992, Cancer treatment and research.

[31]  J. Giot,et al.  Epstein‐Barr virus bicistronic mRNAs generated by facultative splicing code for two transcriptional trans‐activators. , 1989, The EMBO journal.

[32]  R. Gallo,et al.  Cytokines and Growth Factors in the Pathogenesis of AIDS‐Associated Kaposi's Sarcoma , 1992, Immunological reviews.

[33]  R. Sun,et al.  Identification, expression, and immunogenicity of Kaposi's sarcoma-associated herpesvirus-encoded small viral capsid antigen , 1997, Journal of virology.

[34]  P. Lieberman,et al.  A new Epstein-Barr virus transactivator, R, induces expression of a cytoplasmic early antigen , 1988, Journal of virology.

[35]  D. Norman,et al.  Production of cytokines by bone marrow cells obtained from patients with multiple myeloma , 1989 .

[36]  C. Boshoff,et al.  Molecular Mimicry of Human Cytokine and Cytokine Response Pathway Genes by KSHV , 1996, Science.

[37]  J. Hardwick,et al.  An enhancer within the divergent promoter of Epstein-Barr virus responds synergistically to the R and Z transactivators , 1990, Journal of virology.

[38]  E. Cesarman,et al.  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. , 1995, Blood.

[39]  Phillip A. Sharp,et al.  Split genes and RNA splicing , 1994, Cell.

[40]  E. Cesarman,et al.  Primary characterization of a herpesvirus agent associated with Kaposi's sarcomae , 1996, Journal of virology.

[41]  J. Sample,et al.  The zta transactivator involved in induction of lytic cycle gene expression in Epstein-Barr virus-infected lymphocytes binds to both AP-1 and ZRE sites in target promoter and enhancer regions , 1990, Journal of virology.