Transgenic mice provide a unique model system to investigate molecular and cellular mechanisms of HIV-1 pathogenesis. Studies in HIV-transgenic mice from several laboratories, including our own, have helped to clarify the role of HIV-1 gene products in inducing disease independent of opportunistic infection. Our laboratory has developed several mice transgenic for HIV-1 genes. Recent studies have extended the characterization of one of these transgenic lines, pNL4-3:d1443, which contains the viral ltrs, the env gene and the six accessory genes. Our work with this mouse model over the past year has focused on three disease processes. First, severe post-natal growth retardation and early mortality characterize the homozygous d1443 mouse, which makes this a model for HIV-associated pediatric growth retardation. Homozygous mice have marked hypoglycemia and reduced liver IGF-1 mRNA expression. Second, both the homozygotes and heterozygotes develop progressive renal disease, characterized by glomerulosclerosis and tubulointerstitial disease, which closely resembles HIV-associated nephropathy. This syndrome affects the majority of d1443 mice, and ultimately 40% of transgenic mice die of uremia. Two growth factors, TGFbeta and bFGF, are present in increased amounts in the interstitium of transgenic mice. We propose that TGFbeta increases accumulation of extracellular matrix protein and that bFGF stimulates cell proliferation. Third, d1443 mice develop focal epidermal papillomas, both spontaneously and with trauma. Using the appearance of UVB-induced papillomas as a test system, we have shown that oral administration of glutathione suppresses papilloma induction by 80%. Thus the d1443 mouse provides a convenient small animal model with which to investigate HIV-1 pathogenesis, as well as to test novel therapeutic approaches.
