Absence of the inducible form of nitric oxide synthase in the brains of patients with the acquired immunodeficiency syndrome.
A majority of human immunodeficiency virus type I (HIV-1)-infected-individuals manifest a plethora of central nervous system (CNS) diseases unrelated to opportunistic infections, including acquired immune deficiency syndrome (AIDS)-dementia complex (ADC), encephalitis, and various other disorders of the CNS. A series of devastating clinical conditions in the CNS of certain HIV-1-infected-individuals may be caused by infection of cells in the brain parenchyma. ADC is characterized by cognitive dysfunction, motor difficulties, coordination abnormalities and other neurological signs and symptoms, which develop in many HIV-1-infected-individuals. The precise molecular mechanisms leading to AIDS dementia remain incompletely explained. Various mechanisms including cytokine dysregulation, toxic effects of viral proteins and release of certain toxic substances from macrophages, especially nitric oxide, have been implicated as pathogenic mediators in the development of ADC. We have examined post mortem CNS tissues collected from 22 patients, previously diagnosed with AIDS, to explore if nitric oxide is responsible for the observed pathology in ADC. As controls, we utilized tissues collected from the brains of patients who expired without AIDS or other CNS pathologies. In addition, we also utilized post-mortem brain tissues from eight patients who were diagnosed with multiple sclerosis (MS) and were found to express inducible nitric oxide synthase (iNOS) in our previous studies, as positive controls. Highly sensitive in situ reverse transcriptase-initiated polymerase chain reaction (RT-IS-PCR) studies demonstrated that iNOS mRNA was present in the CNS tissues from all the positive MS controls, but were absent in all 22 specimens from AIDS patients, as well as in the brain tissues from normal controls. We have also analyzed the tissues for the presence of the NO reaction product, nitrotyrosine, to evaluate the presence of a protein nitrosalation adduct. Nitrotyrosine was not demonstrable in any of the AIDS brains. These findings indicate that iNOS may not play a significant role in the neuropathogenesis of most cases of ADC.
Bagasra
O
O
Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Bobroski
L
L
Sarker
A
A
Bagasra
A
A
Saikumari
P
P
Pomerantz
R J
RJ
D015526:AIDS Dementia Complex / Q000201:enzymology / Q000503:physiopathology*; D000163:Acquired Immunodeficiency Syndrome / Q000201:enzymology*; D000328:Adult; D015415:Biomarkers; D002478:Cells, Cultured; D002675:Child, Preschool; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D009103:Multiple Sclerosis / Q000201:enzymology; D009419:Nerve Tissue Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D015415:Biomarkers; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D013481:Superoxides; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase