Expression of the Human Immunodeficiency Virus-Tat Gene in Lymphoid Tissues of Transgenic Mice Is Associated With B-Cell Lymphoma

Abstract

The human immunodeficiency virus type 1 (HIV-1) Tat gene, a potent transactivator of viral and cellular genes, has been proposed as a key agent in the pathogenesis of acquired immune deficiency syndrome related disorders, including 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, which 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 address 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 promoter 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 examination, a significant number of spleens from Tat-transgenic mice exhibited malignant lymphoma of B-cell origin. IgG heavy chain rearrangement confirmed the clonal B-cell nature of these lymphoproliferations. In contrast, T-cell receptor genes exhibited a germline (unrearranged) structure. Reverse transcription polymerase chain reaction analysis of transgenic spleens revealed that mRNA encoding cytokines IL-6 and IL-10 was upregulated, suggesting a possible mechanism for the B-cell expansion in vivo.