Cataractogenesis in Transgenic Mice Containing the HIV-1 Protease Linked to the Lens A-Crystallin Promoter

Several lines of transgenic mice were generated with either active or inactive forms of the human immunodeficiency virus type 1 (HIV-1) protease gene under the control of the mouse lens αA-crystallin promoter. Mice bearing the inactive protease coding sequence displayed no gross abnormalities in the lens, while mice with the active protease developed time-dependent bilateral cataracts. One line, TG , developed cataracts in utero while the second line, TG , developed cataracts postnatally. TG mice, homozygous for the transgene, developed severe microphthalmia and were significantly smaller than the control mice at postnatal day 30. two-dimensional-polyacrylamide gel electrophoresis analysis of the protein profiles of TG and TG lenses revealed extensive modifications in the lens crystallins. Proteolysis in the homozygous TG mouse lenses began at postnatal day 20 with the disappearance or partial loss of βB1-, βB3-, and βA3-crystallins and the appearance of crystallin fragments. Protein leakage and the gradual breakdown of cytoskeletal elements also occurred. In contrast, the opacification of the homozygous TG lenses appeared to have been influenced by differentiation and developmental processes. It apppears that HIV-1 protease expression activates other proteases, and these enzymes, in concert with the HIV-1 protease, are responsible for the protein modifications that eventually result in the opacification of the lens.