One of the frequent consequences of chronic HIV infection is the development of AIDS associated lymphomas. These are uniformly high grade malignancies of B lymphocytes, and they fall into three histological categories: (i) small, noncleaved cell; (ii) large immunoblastic/plasmacytoid cell; and (3), large cell lymphoma. Involvement of Epstein-Barr virus (EBV) is frequently seen in the immunoblastic tumors, while the other tumor categories show frequent c- myc rearrangements and mutations of the p53 tumor suppressor gene. While EBV+ immunoblastic lymphomas have been observed in HIV infection of hu- PBL-SCID mice, the other AIDS-associated lymphomas have not been seen. We propose to study the link between HIV infection and chronic B cell activation, using PBL derived from HIV-infected individuals as well as normal PBL infected in the context of the hu-PBL-SCID model.
The specific aims of the project are to determine the response of resting, peripheral blood B cells or tonsillar, germinal center B cells to T cells or T cell clones infected with HIV or expressing HIV gp120 or gp41. CD4 T cell clones will be chosen on the basis of cytokine production to represent either the Th0, Th1, or Th2 subset. Selected combinations of T cell clones and B cells will be introduced into SCID mice to assess the extent of in vivo B cell proliferation, differentiation, and incidence of tumor formation. Peripheral blood B cells, tonsilar B cells, and follicular dendritic cells will be derived from normal donors and PBL from normal and HIV-seropositive donors. EBV seropositive donors who do not give rise to spontaneous tumors will be used. We will also examine expression of B cell genes that might block apoptosis and represent the first step towards malignant transformation under the differing conditions of T cell stimulation outlined in Aim 1. Expression of bcl-2 and the Epstein-Barr virus genes LMP (which transactivates bcl-2 expression), EBNA-2, and ZEBRA will be analyzed by a sensitive RNase protection assay. PBL and germinal center B cells from EBV-positive and EBV-negative donors will be compared. Finally, we will determine the relationship between different HIV-1 strains and specific activation of B cells expressing the VH3 immunoglobulin variable region. Preliminary evidence shows a correlation between the HIV strain used to infect hu- PBL-SCID mice, the rate of CD4 T cell depletion, and the extent of VH3 B cell stimulation. These data suggest that different gp120 molecules may interact differently with the Ig receptor on VH3-expressing B cells, and/or that the extent of CD4 T cell activation following HIV infection differs markedly among different virus strains.
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