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Nitrosative stress with HIV dementia causes decreased L-prostaglandin D synthase activity

From the Departments Neurology, Pharmacology and Neuroscience, Johns Hopkins University, Baltimore, MD.

Address correspondence and reprint requests to Dr. Avindra Nath, Department of Neurology, 509 Pathology, 600 N. Wolfe St., Baltimore, MD anath1{at}jhmi.edu

Background: The prevalence of HIV-associated neurocognitive disorders is increasing as HIV-infected individuals are living longer. The clinical manifestations of the syndrome also continue to evolve under the influence of antiretroviral drugs and comorbidities such as drugs of abuse. However, there are no surrogate markers for the disease, either to identify it de novo or to track its progression, and there is no proven treatment with the exception of antiretroviral drugs.

Methods: Levels of nitric oxide, nitrate, and 3-nitrotyrosine (3-NT)–modified proteins were measured in the CSF of 46 patients with HIV infection stratified according to their neurocognitive status and history of IV drug use (IVD). The 3-NT–modified proteins were isolated and identified by tandem mass spectrometry, and the functional consequence of 3-NT modification of l-prostaglandin D synthase (l-PGDS), the most abundant protein, was determined.

Results: 3-NT–modified proteins were significantly elevated in patients with HIV infection who had progressive neurocognitive decline over the next 6 months and in patients with a history of IVD. Thirteen different proteins with 3-NT modification were identified in the CSF of these patients. l-PGDS was the most abundant. 3-NT modification of this protein resulted in loss of its enzymatic activity.

Conclusions: There is increased nitrosative stress in CSF of HIV-infected patients with active dementia and in patients with a history of IV drug use, measurement of which may serve as a surrogate marker for these patients. Nitrosative stress may also have important functional consequences and may impact the pathogenesis of HIV-associated neurocognitive disorders.

Abbreviations: 3-NT = 3-nitrotyrosine; AcD = active dementia; BSA = bovine serum albumin; D = dementia; DTT = dithiothreitol; HIVD = HIV dementia; HNE = hydroxynonenol ester; HPLC = high-performance liquid chromatography; ID = inactive dementia; IgG = immunoglobulin G; iNOS = inducible nitric oxide synthase; IVD = IV drug use; LC-MS/MS = liquid chromatography–tandem mass spectrometry; l-PGDS = l-prostaglandin D synthase; MS = mass spectrometry; MSK = Memorial Sloan-Kettering; MS/MS = tandem mass spectrometry; ND = no dementia; nitro-BSA = peroxynitrite-treated bovine serum albumin; NOS = nitric oxide synthase; PGD₂ = prostaglandin D₂; PGH₂ = prostaglandin H₂; SDS-PAGE = sodium dodecyl sulfate polyacrylamide gel electrophoresis.

Supplemental data at www.neurology.org

e-Pub ahead of print on December 12, 2007, at www.neurology.org.

Supported by NIH grants R01NS039253, P30 MH075673, R01MH071150, and R01NS049465.

Disclosure: The authors report no conflicts of interest.

Received February 27, 2007. Accepted in final form June 7, 2007.