3-nitrotyrosine and Encephalitis--Viral

HIV can infiltrate the brain and lead to HIV-associated neurocognitive disorders (HAND). The pathophysiology of HAND is poorly understood, and there are no diagnostic biomarkers for it. Previously, an increase in inducible nitric oxide synthase levels and protein tyrosine nitration in the brain were found to correlate with the severity of HAND.1,2 In this study, we analyzed human brains from individuals who had HIV infection without encephalitis and with encephalitis/HAND and compared them to the brains of healthy individuals. We identified the nitrated proteins and determined the sites of modification using affinity enrichment followed by high-resolution and high-mass-accuracy nanoLC-MS/MS. We found that nitrated proteins were predominantly present in the HIV-infected individuals with encephalitis, and, interestingly, the modifications were predominantly located on immunoglobulin variable regions. Our molecular model indicated potential interactions with HIV envelope proteins and changes on the heavy and light chain interface upon the nitration and nitrohydroxylation of these residues. Therefore, our findings suggest a role for these modifications in the immune response, which may have implications in disease pathogenesis.

Topics: Amino Acid Sequence; Antibodies; Brain; Brain Chemistry; Encephalitis, Viral; HIV Infections; HIV-1; Humans; Immunity, Innate; Immunoglobulin Variable Region; Models, Molecular; Molecular Sequence Data; Nitrates; Tyrosine

A mouse model system for a lethal encephalitis due to influenza has been established by stereotaxic microinjection with the recombinant R404BP strain of influenza A virus into the olfactory bulb of C57BL/6 mice. The virus infection spread selectively to neurons in nuclei of the broad areas of the brain parenchyma that have anatomical connections to the olfactory bulb, leading to apoptotic neurodegeneration. The inflammatory reaction at the extended stage of viral infection involved the vascular structures affected by induction of inducible nitric oxide synthase and protein nitration; those were related to the etiology of fatal brain edema. The intraperitoneal administration of amantadine inhibited the viral growth in the brain and saved mice from the lethal encephalitis. The severity of neuronal loss paralleled the time lag between the virus challenge and the start of amantadine treatment. Thus, early pharmacological intervention is essential to minimize neurological deficits due to influenza virus-induced neurodegeneration.

Topics: Amantadine; Animals; Antiviral Agents; Encephalitis, Viral; Female; Influenza A virus; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Orthomyxoviridae Infections; Recombination, Genetic; Tyrosine

We have recently demonstrated that increased blood-CNS barrier permeability and CNS inflammation in a conventional mouse model of experimental allergic encephalomyelitis are dependent upon the production of peroxynitrite (ONOO(-)), a product of the free radicals NO* and superoxide (O2*(-)). To determine whether this is a reflection of the physiological contribution of ONOO(-) to an immune response against a neurotropic pathogen, we have assessed the effects on adult rats acutely infected with Borna disease virus (BDV) of administration of uric acid (UA), an inhibitor of select chemical reactions associated with ONOO(-). The pathogenesis of acute Borna disease in immunocompetent adult rats results from the immune response to the neurotropic BDV, rather than the direct effects of BDV infection of neurons. An important stage in the BDV-specific neuroimmune response is the invasion of inflammatory cells into the CNS. UA treatment inhibited the onset of clinical disease, and prevented the elevated blood-brain barrier permeability as well as CNS inflammation seen in control-treated BDV-infected rats. The replication and spread of BDV in the CNS were unchanged by the administration of UA, and only minimal effects on the immune response to BDV Ags were observed. These results indicate that the CNS inflammatory response to neurotropic virus infection is likely to be dependent upon the activity of ONOO(-) or its products on the blood-brain barrier.

Topics: Acute Disease; Animals; Antigens, Viral; Blood-Brain Barrier; Borna Disease; Borna disease virus; Brain; Brain Chemistry; Chemotaxis, Leukocyte; Encephalitis, Viral; Female; Free Radical Scavengers; Free Radicals; Gene Expression Profiling; Immunocompetence; Inflammation; Lymphocyte Count; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidation-Reduction; Peroxynitrous Acid; Polymerase Chain Reaction; Rats; Rats, Inbred Lew; T-Lymphocyte Subsets; Tyrosine; Uric Acid; Virus Replication