|NeuroAids Vol. 2, Issue 9 (October 1999)|
Role of Nitric Oxide in HIV Dementia
Valina L. Dawson1
Q: What is nitric oxide (NO) and how does it injure the central
How production of NO kills cells is an active area of investigation. The mechanisms of iNOS mediated neurotoxicity are not yet understood but may also involve peroxynitrite formation. Cultured neurons die 5-7 days after iNOS induction in contrast to nNOS mediated cell death that is complete by 18-24 hours. Possibly, NO produced from iNOS interferes with critical cellular functions thus activating apoptotic mechanisms.
Q: What evidence suggests a role for NO in HIV dementia?
A role for iNOS in HIV dementia comes from both human postmortem studies and experimental models. There is a correlation between gp41 levels, iNOS expression, and severity and rate of progression of HIV dementia (5)(6)(7). Expression of gp41 and iNOS is predominantly localized to macrophage/microglia of the frontal lobe and basal ganglia (8)(9). Nitrotyrosine, a footprint for peroxynitrite production and thus NO formation, is more intense and frequent in brain sections from HIV demented patients (10). Morphologically, cell death appears apoptotic in HIV dementia patients (11)(12)(13)(14). In SIV models there is apoptotic cell death (15) and dendritic injury (16) reminiscent of the synaptic pruning observed in human HIV dementia (17)(18). In culture, gp41 can induce iNOS in glia (7)(19). Investigation of gp41 peptide fragments identified a key "neurotoxic" domain in the N-terminal region (20). Endogenously this "neurotoxic" domain could interact with adjacent cells leading to the induction of iNOS and perhaps other inflammatory mediators. NO generated from iNOS can contribute to neuronal dysfunction and ultimately neuronal death, and it may also contribute to blood brain barrier dysfunction.
Q: What potential therapeutic strategies might be applied to limit
NO-induced neuronal injury in HIV dementia?
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(6) Adamson DC, McArthur JC, Dawson TM, Dawson VL (1999). Rate and severity of HIV-associated dementia (HAD): correlations with Gp41 and iNOS. Mol Med 5(2):98-109. Medline
(7) Adamson DC, Dawson TM, Zink MC, Clements JE, Dawson VL (1996). Neurovirulent simian immunodeficiency virus infection induces neuronal, endothelial, and glial apoptosis. Mol Med 2(4):417-28. Medline
(8) Rostasy K, Monti L, Yiannoutsos C, Kneissl M, Bell J, Kemper TL, Hedreen JC, Navia BA (1999). Human immunodeficiency virus infection, inducible nitric oxide synthase expression, and microglial activation: pathogenetic relationship to the acquired immunodeficiency syndrome dementia complex. Ann Neurol 46(2):207-16. Medline
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(11) Adle-Biassette H, Chretien F, Wingertsmann L, Hery C, Ereau T, Scaravilli F, Tardieu M, Gray F (1999). Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damage. Neuropathol Appl Neurobiol 25(2):123-33. Medline
(12) Adle-Biassette H, Levy Y, Colombel M, Poron F, Natchev S, Keohane C, Gray F (1995). Neuronal apoptosis in HIV infection in adults. Neuropathol Appl Neurobiol 21(3):218-27. Medline
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(14) Shi B, De Girolami U, He J, Wang S, Lorenzo A, Busciglio J, Gabuzda D (1996). Apoptosis induced by HIV-1 infection of the central nervous system. J Clin Invest 98(9):1979-90. Medline
(15) Adamson DC, Wildemann B, Sasaki M, Glass JD, McArthur JC, Christov VI, Dawson TM, Dawson VL (1996). Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV-1 gp41. Science 274(5294):1917-21. Medline
(16) Li Q, Eiden LE, Cavert W, Reinhart TA, Rausch DM, Murray EA, Weihe E, Haase AT (1999). Increased expression of nitric oxide synthase and dendritic injury in simian immunodeficiency virus encephalitis. J Hum Virol 2(3):139-45. Medline
(17) Everall IP, Heaton RK, Marcotte TD, Ellis RJ, McCutchan JA, Atkinson JH, Grant I, Mallory M, Masliah E (1999). Cortical synaptic density is reduced in mild to moderate human immunodeficiency virus neurocognitive disorder. HNRC Group. HIV Neurobehavioral Research Center. Brain Pathol 9(2):209-17. Medline
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(19) Koka P, He K, Zack JA, Kitchen S, Peacock W, Fried I, Tran T, Yashar SS, Merrill JE (1995). Human immunodeficiency virus 1 envelope proteins induce interleukin 1, tumor necrosis factor alpha, and nitric oxide in glial cultures derived from fetal, neonatal, and adult human brain. J Exp Med 1995 Oct 1;182(4):941-51. Medline
(20) Adamson DC, Kopnisky KL, Dawson TM, Dawson VL (1999). Mechanisms and structural determinants of HIV-1 coat protein, gp41-induced neurotoxicity. J Neurosci 19(1):64-71. Medline
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