Human Kaposi's Sarcoma Cell-Mediated Tumorigenesis in Human Immunodeficiency Type 1 Tat-Expressing Transgenic Mice

Abstract

Background: The human immunodeficiency virus type 1 (HIV-1) transactivator (Tat) protein has been linked to the development and course of Kaposi's sarcoma (KS) associated with acquired immunodeficiency disease syndrome (AIDS–KS). Tat is an 86–101 amino-acid protein encoded by two exons. To evaluate the growth-promoting effects of Tat in AIDS–KS in vivo, we developed transgenic mice expressing the one-exon-encoded 72 amino-acid protein (Tat₇₂) and the two-exon-encoded 86 amino-acid protein (Tat₈₆). Methods: Human KS SLK cells were injected subcutaneously into CD4⁺ T-cell-depleted male mice, and the tumors that formed after 3–4 weeks were recovered and analyzed for the expression of Tat protein(s), different cytokine messenger RNAs (mRNAs), and matrix metalloproteinases (MMPs). All statistical tests were two-sided. Results: The average tumor weight was maximum in Tat₈₆ mice (∼600 mg) compared with Tat₇₂ (∼200 mg) and nontransgenic (∼100 mg) mice (P<.005). Histologic examination of tumors showed spindle-shaped SLK cells with prominent infiltrates of inflammatory cells. All of the tumors from Tat mice expressed abundant Tat mRNA, suggesting that the infiltrating mouse cells actively expressed Tat. A comparison of the growth-promoting cytokines in the tumors from Tat₈₆-transgenic and nontransgenic mice showed that the expression of the following cytokines was substantially increased in the tumors of the Tat₈₆ mice: tumor necrosis factor-α, interleukin 6, interleukin 8, granulocyte–macrophage colony-stimulating factor, and basic fibroblast growth factor. Furthermore, these tumors showed abundant expression of a 105-kd MMP activity associated with infiltrates of host leukocytes in the lesions. Conclusion: Our in vivo data clearly suggest that extracellular Tat can contribute to the growth and tumorigenesis of human KS cells.