Abstract

Herpesvirus saimiri (H.
s aimi ri) is a lymphotropic or gamma herpesvirus and causes malignant lymphomas of monkeys. Epstein-Barr virus (EBV) is also a lymphotropic herpesvirus and is a well recognized cause of malignant lymphomas of humans; EBV is related to H.
s aimi ri in the arrangement of its genes. The principal hypothesis of this research plan is that gene products of H.
s aimi ri activate lymphokines and activation of lymphokines contribute to oncogenic transformation. The experimental approach of the planned studies is based on three novel findings; (i) A strain of H.
s aimi ri is highly oncogenic in rabbits; evaluation of H.
s aimi ri mutants now can be done without the use of primate species. (ii) Rabbit lymphocytes transformed by the highly oncogenic strain contain a 1.2 KB polyadenylated RNA and four small U-like RNAs transcribed from a 4 KB region of the genome involved in oncogenic transformation. (iii) H.
s aimi ri transformed lymphocytes secrete IL-4 and express large numbers of IL-2 receptors.
AIM 1. Characterize the 1.2 KB RNA and small Unlike RNAS. The RNAs will be mapped, and the nucleotide sequence will be determined.
AIM 2. Identify the putative protein encode by the 1.2 KB RN.A Sequences-of the 1.2 KB RNA will be expressed in E. coli and fusion proteins will be used to immunize rabbits. Subcellular localization of the putative protein in transformed lymphocytes will be tested by immunofluorescence, the size of the protein will be determined.
AIM 3. Identify the gene(s) contribute to the oncogenicity of a highly oncogenic strain. Recombinant viruses will be constructed; cloned DNA fragments of a highly oncogenic strain will be introduced into the genome of another strain which is nononcogenic in New Zealand white rabbits. oncogenic potential of recombinant viruses will be tested in rabbits.
AIM 4. Test recombinant viruses for activation of lymphokines, We will test whether secretion of IL-4 and expression of IL-2 receptors is stimulated by infection/superinfection with a panel of recombinant viruses.
AIM 5. Test which viral gene(s) can activate lymphokines. The first approach will be to express cloned viral genes in lymphocytes and test whether these viral genes stimulate secretion of IL-4 and expression of IL-2 receptor. The second approach will test whether cloned viral genes can trans-activate cis-acting regulatory elements of lymphokine genes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043264-08
Application #
2091149
Study Section
Experimental Immunology Study Section (EI)
Project Start
1986-05-01
Project End
1994-12-31
Budget Start
1993-05-01
Budget End
1994-12-31
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
University of South Florida
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612

  Publications

Lund, T C; Medveczky, M M; Medveczky, P G (1999) Interferon-alpha induction of STATs1, -3 DNA binding and growth arrest is independent of Lck and active mitogen-activated kinase in T cells. Cell Immunol 192:133-9
Lund, T C; Coleman, C; Horvath, E et al. (1999) The Src-family kinase Lck can induce STAT3 phosphorylation and DNA binding activity. Cell Signal 11:789-96
Lund, T C; Prator, P C; Medveczky, M M et al. (1999) The Lck binding domain of herpesvirus saimiri tip-484 constitutively activates Lck and STAT3 in T cells. J Virol 73:1689-94
Lund, T C; Garcia, R; Medveczky, M M et al. (1997) Activation of STAT transcription factors by herpesvirus Saimiri Tip-484 requires p56lck. J Virol 71:6677-82
Medveczky, M M; Horvath, E; Lund, T et al. (1997) In vitro antiviral drug sensitivity of the Kaposi's sarcoma-associated herpesvirus. AIDS 11:1327-32
Lund, T; Medveczky, M M; Neame, P J et al. (1996) A herpesvirus saimiri membrane protein required for interleukin-2 independence forms a stable complex with p56lck. J Virol 70:600-6
Kung, S H; Medveczky, P G (1996) Identification of a herpesvirus Saimiri cis-acting DNA fragment that permits stable replication of episomes in transformed T cells. J Virol 70:1738-44
Lund, T; Medveczky, M M; Geck, P et al. (1995) A herpesvirus saimiri protein required for interleukin-2 independence is associated with membranes of transformed T cells. J Virol 69:4495-9
Chou, C S; Medveczky, M M; Geck, P et al. (1995) Expression of IL-2 and IL-4 in T lymphocytes transformed by herpesvirus saimiri. Virology 208:418-26
Chou, C S; Geck, P; Medveczky, M M et al. (1995) Induction of a herpesvirus saimiri small RNA AU binding factor (AUBF70) activity and lymphokine mRNAs by T cell mitogens. Arch Virol 140:415-35

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