THE ROLE OF THE EPSTEIN-BARR AND HUMAN
IMMUNODEFICIENCY VIRUSES IN AIDS LYMPHOMA

SUSAN M. ASTRIN, Ph.D., Senior Member

Immunosuppressed individuals are at increased risk for the development of non-Hodgkin's lymphoma. The risk of lymphoma for individuals undergoing organ transplants has been estimated at 2%. In addition, greater than 20% of individuals infected with the human immunodeficiency virus (HIV)-1 will eventually develop a Bcell lymphoma. Our recent studies indicate that a subset of these lymphomas have a viral etiology involving Epstein-Barr virus (EBV) alone or HIV and EBV.

We have demonstrated that it is possible to malignantly transform primary human B cells by the addition of HIV, as long as some cells in the population contain EBV. By infecting B cells from an EBV-seropositive individual with HIV, we have developed a cell line, BHIV, which contains both EBV and HIV genomes. This cell line overexpresses cmyc, grows in 1% serum, clones in soft agar and forms malignant tumors when injected into SCID mice (Laurence and Astrin, Proc. Natl. Acad. Sci. USA 88:7635, 1991). The B-HIV cell line is polyclonal with respect to HIV integration (1). Thus, it is unlikely that transformation is due to insertional mutagenesis. B cells from the same donor, when infected with exogenous EBV, became immortalized, but did not overexpress cmyc, grow in 1% serum, clone in soft agar, or form malignant tumors in SCID mice. We attribute these additional properties to the presence of the HIV genome in BHIV.

We have determined that about 20% of AIDS lymphomas contain both EBV and HIV genomes. These findings, along with the data on transformation in vitro, indicate that both viruses may be involved in the etiology of this subset of tumors. The EBV genes involved in immortalization are most likely involved in the transformation process. In addition, we envision two potential roles for HIV. First, HIV is able to activate expression of EBV and may play a role in the spread of EBV to other B cells. Second, we have recently shown that the HIV tat gene product can act to deregulate c-myc expression. This deregulation is likely to be a key event in tumorigenesis.

The proto-oncogene, c-myc, activates gene expression only when dimerized with the transcription factor, Max. Major efforts have been made to identify the targets of cmyc/Max activation. One of the most interesting targets is ornithine decarboxylase (ODC), an enzyme that catalyzes the rate-limiting step in the synthesis of polyamines. The polyamines, spermine and spermidine, are necessary components of cells and are thought to regulate important processes. It has been demonstrated that cells depleted of polyamines cannot progress through the S phase of the cell cycle. Also, the highest concentration of polyamines in the cell occurs just prior to S phase; cells in G-0 have relatively low amounts of polyamines. Thus, polyamines may be necessary for the replication of chromatin. In addition, it has been shown that deregulated expression of ODC, and consequently of polyamines, results in malignant transformation of a number of cell types. These findings indicate that the deregulation of ODC resulting from c-myc overexpression may be an important factor in the induction and maintenance of the malignant phenotype in virally transformed B cells. We plan to investigate the role of ODC in the process of malignant transformation initiated by EBV alone and by EBV plus HIV in future experiments.

1.   RODRIGUEZ-ALFAGEME, C., CHEN, Z., SONODA, G., TESTA, J.R., DAMIANI, R.D., ASTRIN, S. B cells malignantly transformed by Human Immunodeficiency Virus are polyclonal. Virology 252:34-38, 1998.

^a   R.D. Damiani: Present address-SAP, America, Lester, PA 19113

^b   J. Laurence: Cornell University Medical College, New York, NY 10021

Illustrations or unpublished data in these reports should not be used without permission of the author.

Fox Chase Cancer Center

Scientific Report 1998