Increased Peroxynitrite Activity in AIDS Dementia Complex: Implications for the Neuropathogenesis of HIV-1 Infection

Abstract

Oxidative stress is suggested to be involved in several neurodegenerative diseases. One mechanism of oxidative damage is mediated by peroxynitrite, a neurotoxic reaction product of superoxide anion and nitric oxide. Expression of two cytokines and two key enzymes that are indicative of the presence of reactive oxygen intermediates and peroxynitrite was investigated in brain tissue of AIDS patients with and without AIDS dementia complex and HIV-seronegative controls. RNA expression of IL-1β, IL-10, inducible nitric oxide synthase, and superoxide dismutase (SOD) was found to be significantly higher in demented compared with nondemented patients. Immunohistochemical analysis showed that SOD was expressed in CD68-positive microglial cells while inducible nitric oxide synthase was detected in glial fibrillary acidic protein (GFAP)-positive astrocytes and in equal amounts in microglial cells. Approximately 70% of the HIV p24-Ag-positive macrophages did express SOD, suggesting a direct HIV-induced intracellular event. HIV-1 infection of macrophages resulted in both increased superoxide anion production and elevated SOD mRNA levels, compared with uninfected macrophages. Finally, we show that nitrotyrosine, the footprint of peroxynitrite, was found more intense and frequent in brain sections of demented patients compared with nondemented patients. These results indicate that, as a result of simultaneous production of superoxide anion and nitric oxide, peroxynitrite may contribute to the neuropathogenesis of HIV-1 infection.

Thioredoxin and Protein Nitrotyrosine in Bone Marrow Supernatant from Patients with Human Immunodeficiency Virus Infection

“…17 Staining for tissue nitrotyrosine is more commonly found and, when found, is more intense in brain sections from demented patients with HIV than in brain sections from HIV patients without dementia. 19 Peroxynitrite is also implicated in zidovudine cardiac toxicity. 18 Associations between Trx and apoptosis have been reported in HIV-infected monocytes.…”

“…11 ROS appear to play significant roles in a number of the pathologic manifestations of HIV infection. [12][13][14][15][16][17][18][19][20][21] In biologic systems, the ROS superoxide reacts with nitric oxide (NO) to form peroxynitrite. 22 Peroxynitrite can then exert a variety of effects on cellular function.…”

“…11 ROS appear to play significant roles in a number of the pathologic manifestations of HIV infection. 12–21…”

“…22 Peroxynitrite can then exert a variety of effects on cellular function. 19,23–25 Peroxynitrite causes irreversible nitration of protein tyrosine (pNT) residues, 22 which then serve as a persisting marker of its presence. Unlike other markers of NO production, such as nitrate-nitrite concentrations in tissue or biologic fluids, pNT content is not altered by recent diet.…”

Converging roles for sphingolipids and cell stress in the progression of neuro-AIDS

“…In brain tissues from HIV-1 infected patients, inducible nitric oxide synthase (produces the NO radical), and superoxide dismutase (catalyzes the dismutation of superoxide into oxygen and hydrogen peroxide) mRNA were found to be elevated and nitrotyrosine staining of brain tissues (an indicator of peroxynitrite damage on protiens), was more intense and found in more brain regions of demented patients compared with non-demented patients infected with HIV-1. (Boven, Gomes et al 1999) In addition to evidence of oxidatively damaged proteins, there are also biochemical and immunohistochemical findings of increased lipid peroxidation in brain tissues and CSF from HIV-1 infected patients with dementia. ( An abundance of evidence suggests that disruptions in cellular ion balance and mitochondrial function are decisive events that contribute to the formation of free radicals and neuronal dysfunction in HAND.…”