Infection with HIV-1 is associated with the development of certain malignancies, including Kaposi's sarcoma, cervical carcinoma, NonHodgkin's and possibly Hodgkin's lymphoma. Non-Hodgkin's lymphomas, similar to those that develop with AIDS, are also found in congenitally immunodeficient or transplant recipients who have been chronically immunosuppressed to prevent rejection of bone marrow, cardiac or renal allografts. In this proposal we will test the hypothesis that the development of B cell lymphomas in HIV-1-infected patients is due to a failure of immunosurveillance by EBV-specific cytotoxic T lymphocytes associated with progressive immunodeficiency. We will also examine the hypothesis that most lymphomas which arise in HIV-1-infected individuals are derived from EBV-infected B cells. We will take advantage of the fact that B cell lymphomas develop spontaneously in SCID mice that have been reconstituted with the peripheral blood of donors with a history of prior EBV infection. We will reconstitute SCID mice with the peripheral blood of HIV-1-infected individuals in various stages of disease, who are either seropositive or seronegative for antibodies to the EBV nuclear antigens. Lymphomas that develop in these mice will be characterized for their clonality by the study of mouse sera for secreted immunoglobulin (Ig) subclass and of tumor DNA by Southern blot for Ig gene rearrangements. The lymphomas will also be screened for the presence of HIV and EBV genomic DNA by similar methods. A small number of viral insertion sites will also indicate oligoclonality. In AIDS patients who develop lymphoma, we will compare the lymphomas that develop in SCID mice with the patient's lymphoma as to immunoglobulin secretion, immunoglobulin gene rearrangement, chromosomal translocation and presence and insertion of viral DNA. To study the role of cytotoxic T lymphocytes in the containment of these lymphomas, we will develop HIV-specific and HIV-specific autologous T cell lines and use them to determine their ability to contain developing B cell lymphomas both in vitro and in vivo.
