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(American Journal of Pathology. 1999;155:39-46.)
© 1999 American Society for Investigative Pathology

Short Communication

Evidence that Par-4 Participates in the Pathogenesis of HIV Encephalitis

Inna I. Kruman^*, Avindra Nath, William F. Maragos, Sic L. Chan^*, Melina Jones^§, Vivek M. Rangnekar^¶, Rebekah J. Jakel and Mark P. Mattson^*

From the Sanders-Brown Research Center on Aging,^*
the Department of Neurology,
the Department of Anatomy and Neurobiology,
the Department of Microbiology and Immunology,^§
and the Departments of Surgery and Microbiology and Immunology and Markey Cancer Center,^¶
University of Kentucky, Lexington, Kentucky

Progressive neuronal degeneration in brain regions involved in learning and memory processes is a common occurrence in patients infected with human immunodeficiency virus type 1 (HIV-1). We now report that levels of Par-4, a protein recently linked to neuronal apoptosis in Alzheimer's disease, are increased in neurons in hippocampus of human patients with HIV encephalitis and in monkeys infected with a chimeric strain of HIV-1 and simian immunodeficiency virus. Par-4 levels increased rapidly in cultured hippocampal neurons following exposure to the neurotoxic HIV-1 protein Tat, and treatment of the cultures with a Par-4 antisense oligonucleotide protected the neurons against Tat-induced apoptosis. Additional findings show that Par-4 participates at an early stage of Tat-induced neuronal apoptosis before caspase activation, oxidative stress, and mitochondrial dysfunction. Our data suggest that Par-4 may be a mediator of neuronal apoptosis in HIV encephalitis and that therapeutic approaches targeting the Par-4 apoptotic cascade may prove beneficial in preventing neuronal degeneration and associated dementia in patients infected with HIV-1.

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