HIV-1 Tat inhibits neprilysin and elevates amyloid beta

OBJECTIVE: Aging is a risk factor for amyloid beta (Abeta) accumulation and dementia. Since highly active antiretroviral therapies have effectively lengthened the life expectancy of individuals infected with HIV-1, we investigated the affect of HIV-1 Tat, a viral transactivating transcription factor, on Abeta degradation in the brain by neprilysin (NEP), a neuronal endopeptidase. DESIGN AND METHODS: Using neural cell membrane fractions from human brain aggregates, Tat inhibition of NEP activity was assessed in a fluorescence assay. Following treatment with Tat, conditioned medium of human brain aggregate cultures was assayed for Abeta1-40 by ELISA. We evaluated the potential consequence of Tat inhibition of NEP by immunostaining cortex sections from postmortem human brain for Abeta. RESULTS: In an in vitro assay, Tat inhibited NEP activity by 80%. The cysteine-rich domain of Tat was essential for NEP inhibition. Recombinant Tat added directly to brain cultures, resulted in a 125% increase in soluble Abeta. Postmortem human brain sections from patients with HIV-1 infection (n = 14; 31-58 years old) had a significant increase in Abeta, compared to controls (n = 5; 30-52 years old). Correlative analysis identified a statistically significant relationship between Abeta load and duration of HIV-1 seropositive status. CONCLUSION: We have shown that Tat, which is found in the brains of patients with HIV-1 infection, inhibits the Abeta-degrading enzyme, NEP. Abeta staining was significantly increased in human brain sections from individuals with HIV-1 infection compared to controls. These results have important implications for individuals living and aging with HIV-1 infection.