HIV Type 1 Nef Perturbs Eye Lens Development in Transgenic Mice

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Abstract
HIV transgenic mice often display lens cataracts as a consequence of viral-specific expression of HIV gene products in the developing lens. Cataractous mouse lines encoding either HIV-1 proviral DNA, HIVΔGag/Pol] proviral DNA, or the HIV-1 nef gene alone were examined to ascertain the effect of Nef on murine lens development. Ocular disease was characterized by a progressive architectural disorganization within the lens fiber cell compartment developing in 100% of HIV-positive mice in five reported transgenic lines. Late embryonic stage transgenic lenses featured a mild microphthalmia, pyknotic nuclei within the lens fiber department, ballooning lens fiber cells, and elongated lens epithelial cells. Increased DNA fragmentation was evident in transgenic embryonic lenses, suggesting that cell death occurred by apoptosis. As studied in HIVΔGag/Pol] transgenic mice, HIV transcription was developmentally linked to αA- and αB-crystallin gene expression, preceded disease development (in E14.5–E16.5 embryos), and persisted for weeks after birth. HIV-1 Nef was the predominant HIV gene product detected in the lens fiber cells of this line and was expressed almost to the exclusion of other HIV gene products. Nef was implicated as a major determinant of disease because (1) cataracts developed in mice transgenic for Nef alone and (2) the expression of other HIV gene products in wild-type HIV provirus transgenic mice occurred without a concomitant change in lens pathology.