Neuropathology of NFHgp160 transgenic mice expressing HIV-1 env protein inneurons

The physiopathology of HIV-1 dementia remains largely hypothetical. Althoug h several sets of evidence point towards an indirect multicellular inflamma tory pathway, gp 120, one of the HIV-1 env products. was shown to be very c ytotoxic for neurons in vitro. To explore a direct pathway in the physiopat hology of dementia in AIDS. we developed transgenic mouse models carrying t he HIV-1 env proteins gp 120 and gp 41 (gp 160) under the control of the hu man light neurofilament and murine heavy neurofilament promoters. To date, this is the first mouse model in which the HIV-I env protein can be detecte d in neurons by immunohistochemistry. The expression is found in several br ainstem and spinal cord gray structures and in the cerebellum in one of the mouse lines bearing the NFHgp160 transgene. The morphological findings at 3 months are subtle and are dominated by a watery, dendritic degeneration a nd a reactive gliosis. At 12 months, the evidence of neuronal degeneration and loss is present along with various degenerative phenomena involving syn apses, dendrites and axons, including axonal swellings. Cytoskeletal abnorm alities were found by immunohistochemistry. Chronic inflammation was also o bserved in the leptomeninges of the spinal cord and brainstem and in the ce rebellar white matter. These models thus offer an exciting sequence of morp hological findings initiated by the neuronal expression of the HIV-I env pr oteins anti offer a different tool to explore the neuronal dysfunction in A IDS.