Transforming growth factor beta increases the expression of HIV-1 gene in transfected human mesangial cells

Abstract

Human immunodeficiency virus type 1 (HIV) infection is often complicated by focal glomerulosclerosis (FGS) and other renal lesions collectively termed HIV associated nephropathy (HIVAN). FGS is characterized by glomerular mesangial expansion and increased synthesis of matrix components. The molecular pathogenic mechanisms associated with the development of HIV associated nephropathy are unknown. Experimental animal models suggest a role for cytokines and growth factors, particularly transforming growth factor β (TGF-β), in the pathogenesis of glomerulosclerosis. Patients with AIDS have elevated plasma and tissue levels of TGF-β. We carried out experiments to determine whether primary human mesangial cells (HMC) in culture can be transfected with HIV-1 genes. HMC were transfected with a chloramphenicol acetyl transferase (CAT) reporter construct containing HIV-1 LTR sequences. Our results show successful transfection of HMC with HIV-1 LTR gene. HMC transfected with LTR gene are responsive to the HIV-1 regulatory gene product Tat. To study whether TGF-β can modulate the expression of HIV-1 LTR gene in HMC, HMC transfected with an HIV-1 LTR CAT plasmid were treated with TGF-β and other growth factors two hours before harvest. TGF-β specifically increased the expression of the HIV-1 gene in HMC in a dose dependent manner. We further studied whether up-regulation of HIV-1 LTR expression in HMC was mediated by the effect of TGF-β on the interaction of transcription factors to their binding sites. Our results suggest that TGF-β treatment of HMC does not effect the binding of NF-κB, NF-1, or US-F transcription factors to their respective binding sites. Since patients with AIDS have elevated plasma and tissue levels of TGF-κ, our results may indicate that HIV-1 gene expression in renal tissue, in the presence of increased levels of TGF-κ, may contribute to the pathogenesis of HIV associated nephropathy. The mechanisms underlying the effect of TGF-κ on HIV-1 gene expression in HMC and their relationship to the pathogenesis of renal disease are currently unknown and require further study.