Patients with HIV-1 infection develop a broad spectrum of AIDS-associated malignancies including EBV+ and EBV- lymphomas, Kaposi's sarcoma, and other cancers such as basal cell carcinomas of skin and anogenital carcinomas. Fast evolving epidemiological and molecular analysis strongly suggest that EBV B cell lymphomas represent a significant proportion of more frequently occurring AIDS-associated malignancies. Although it can be argued that the pathogenesis of B cell neoplasms correlates solely to the immunodeficiency state, a mechanism can be proposed whereby an HIV protein acting with other cellular or viral co-factors, trans-activates an otherwise silent B cell growth factor gene(s). Excessive and aberrant production of such a B cell growth factor may lead to uncontrolled cell growth in the absence of EBV associated functions and c-myc translocations. This research is directed toward investigations of the interactions between viral and cellular genes in malignancies of B cell origin in HIV infected population. Emphasis will be placed on a T cell derived 12-kD human B cell growth factor, BCGF-12kD, and HIV trans-acting regulatory proteins including tat, nef, and vpr. The cDNA for BCGF-12kD has recently been identified in this laboratory (Sharma et al, Science 235:1481-1491, 1987). Our recent results strongly suggest that the BCGF-12kD gene is selectively expressed in EBV-B cell malignancies as compared to EBV transformed B cells and normal B cells. Furthermore, a mouse monoclonal antibody to BCGF-12kD synthetic peptide and BCGF-12kD anti-sense oligonucleotide inhibit the growth of EBV- malignant B cell lines as characterized by thymidine incorporation and the cellular growth. As a possible mechanism for the differential expression of the BCGF-12kD gene in EBV- B cell malignancies, we propose that interactions between the BCGF-12kD upstream regulatory regions and the transcription modulatory factors play an important role in development of malignancy. To that end, our recent results are of importance in that a specific binding to the BCGF-12kD upstream region is observed only with nuclear extract from EBV- malignant B cell lines. Therefore, a panel of EBV+ and EBV- B cell lines derived from non-AIDS lymphomas will be first used to establish the immunoregulatory role of BCGF-12kD by employing both immunological and molecular probes available to this laboratory. These studies will be expanded to include primary B cells or established B cell lines from AIDS patients. To investigate whether the tat protein trans-activates the BCGF-12kD promoter, the CAT assays will be done after transfecting a BCGF upstream regulatory region--CAT construct into constitutively Tat producing Hela or Jurkat cells. To test for the transforming activity, both the tat expression construct and the BCGF-12kD expression construct will be co-transfected into human B cells. It is anticipated that results generated in these studies should prove to be of vital importance to initiate the pathogenetic evaluation of B cell neoplasms in AIDS patients.
