Transgenic mice provide a unique model system to investigate the molecular and cellular mechanisms of HIV pathogenesis. Studies on 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. In the previous work carried out in the LOM a genetically engineered HIV-1 proviral genome lacking gag and pol, but containing the env, tat, rev, nef, vpr, vip and vpu genes under the control of the HIV-1 long terminal repeat (LTR) was introduced into the mouse genome by pronuclear microinjection. The resulting transgenic mice expressed viral mRNA and envelope glycoprotein in various tissues. The heterozygous mice developed renal disease, hyperproliferative skin disorders and cataract. The homozygous mice developed a diffuse epidermal hyperplasia, a syndrome characterized by growth failure, cachexia and lymphoproliferation and usually died before 30 days of age. These results argued for a role for one or more of the HIV-1 gene products in the pathogenesis of the disease. In the past year we have investigated the role of HIV-1 protein in skin transplant rejection, and have shown that transgenic skin expressing viral proteins is rejected by a congenic non-transgenic recipient animal but not by transgenic recipients. The data suggest that the transgenic mice become tolerant to viral proteins expressed in the skin. We have characterized the eye disease seen in transgenic mice, and found gp 120 expression in the lens fiber cells, suggesting that expression in these cells results in a disordered lens matrix and ultimately in nuclear cataracts. We have observed that mice homozygous for the HIV transgene maintain normal intrauterine growth throughout pregnancy and are born weighing the same as the heterozygous and normal nontransgenic mice. Preliminary studies showed that some pregnancy related hormones can regulate viral gene expression in these transgenic mice. Estrogen and progesterone can enhance and human chorionic gonadotropin can inhibit the level of viral gene expression in a tissue specific manner. We have examined the effect of beta human chorionic gonadotropin on the wasting syndrome seen in the homozygous HIV- 1 transgenic mouse, and found that this agent reduced transgene expression in muscle and improved survival in a dramatic fashion. In further characterizing the nephropathy, we have extended our studies of kidney disease to mice transgenic for an identical construct but lacking the nef gene, and have localized HIV-1 gene and protein expression to the glomerular epithelium. These cells are notable for being a major site of pathology in both the transgenic mice and human patients with HIV associated nephropathy, suggesting that they may be key target cells for HIV-1 mediated pathology.
