CATARACTOGENESIS IN TRANSGENIC MICE CONTAINING THE HIV-1 PROTEASE LINKED TO THE LENS ALPHA-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) prot ease gene under the control of the mouse lens alpha A-crystallin promo ter, Mice bearing the inactive protease coding sequence displayed no g ross abnormalities in the lens, while mice with the active protease de veloped time-dependent bilateral cataracts, One line, TG(61), develope d cataracts in utero while the second line, TG(72), developed cataract s postnatally. TG(61) mice, homozygous for the transgene, developed se vere microphthalmia and were significantly smaller than the control mi ce at postnatal day 30. two-dimensional-polyacrylamide gel electrophor esis analysis of the protein profiles of TG(72) and TG(61) lenses reve aled extensive modifications in the lens crystallins. Proteolysis in t he homozygous TG(72) mouse lenses began at postnatal day 20 with the d isappearance or partial loss of beta B1-, beta B3-, and beta A3-crysta llins and the appearance of crystallin fragments, Protein leakage and the gradual breakdown of cytoskeletal elements also occurred, In contr ast, the opacification of the homozygous TG(61) lenses appeared to hav e been influenced by differentiation and developmental processes. It a pppears 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.