Expression of the human immunodeficiency virus-Tat gene in lymphoid tissues of transgenic mice is associated with B-cell lymphoma

The human immunodeficiency virus type 1 (HIV-1) Tat gene, a potent transact ivator of viral and cellular genes, has been proposed as a key agent in the pathogenesis of acquired immune deficiency syndrome related disorders, inc luding nonHodgkin's lymphoma. In cultured cells, the HIV-1 Tat protein can induce the expression of the cytokines interleukin-6 (IL-6) and IL-10, whic h are known to induce proliferation and differentiation of lymphoid cells. Such alterations in cytokine expression, together with a secondary genetic event, are thought to ultimately lead to oncogenic transformation. To addre ss the influence of Tat on lymphoid development in the context of the whole organism, we produced several transgenic mouse lines that express the Tat gene under the control of an actin promoter. We show here that this promote r directs expression to a variety of sites, including spleen, bone marrow, and lymph nodes. Approximately 25% to 30% of the Tat-transgenic population developed enlarged spleens within 1 year after birth. On histological exami nation, a significant number of spleens from Tat-transgenic mice exhibited malignant lymphoma of B-cell origin. IgG heavy chain rearrangement confirme d the clonal B-cell nature of these lymphoproliferations. In contrast, T-ce ll receptor genes exhibited a germline (unrearranged) structure. Reverse tr anscription polymerase chain reaction analysis of transgenic spleens reveal ed that mRNA encoding cytokines IL-6 and IL-10 was upregulated, suggesting a possible mechanism for the B-cell expansion in vivo. (C) 1999 by The Amer ican Society of Hematology.