NeuroAIDS Banner
 
NeuroAids Vol. 2, Issue 9 (October 1999)       

Role of Nitric Oxide in HIV Dementia

Valina L. Dawson1

1Johns Hopkins University School of Medicine; Department of Neurology
600 N. Wolfe Street, Carnegie 214 Baltimore, Maryland 21287; USA
E-mail: vdawson@jhmi.edu

Keywords: gp41, inducible nitric oxide synthase, nitric oxide, nitrotyrosine.


Q: What is nitric oxide (NO) and how does it injure the central nervous system?
Nitric oxide (NO) is one of the smallest and most versatile bioactive molecules in the body. NO is generated following activation of NO synthase (NOS) of which there are three isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS) (1). nNOS regulates neuronal signaling but overactivation of nNOS mediates glutamate excitotoxicity. In excitotoxic injury NO reacts with superoxide anion to form peroxynitrite that damages DNA, RNA, protein and lipids resulting in mitochondrial impairment, activation of poly (ADP-ribose) polymerase, loss of energy and cell death (2). iNOS is not expressed in healthy tissue, but can be induced following various pathologic insults including viral infection. Unlike eNOS and nNOS, intracellular calcium levels do not regulate iNOS activity. Once translated, iNOS is functionally active and produces NO for sustained periods of time. Neuronal death following iNOS activation occurs slowly over time with the morphologic features of apoptosis (3).

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?
Early studies investigating toxic activities of HIV proteins focused on gp120. In experimental systems, gp120 can act synergistically with glutamate (4) to elicit excitotoxicity mediated by NO (5). However, evidence from human postmortem studies to support this experimentally-derived hypothesis has not been forthcoming. Numerous investigators have failed to observe gp120 in the brains of HIV infected patients. However, since other HIV proteins are present in the CNS, it follows that gp120 must also have been present at some point in time, but whether it is sufficient to induce toxicity is unknown.

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?
NO generated from iNOS can play an important role in limiting viral replication. Directly inhibiting iNOS to treat HIV dementia may amplify viral replication in HIV infected patients and result in more severe CNS disease. A more reasonable approach might be to develop small molecule mimics for the gp41 neurotoxic domain that would interfere with gp41 interactions with the host glia and thus prevent the induction of iNOS and cytokines in the CNS. Alternatively, identification of the NO cellular targets that mediate dendritic pruning and apoptosis could also provide new therapeutic targets. Finally, HIV dementia is likely a result of several neurotoxic events and any single therapy is unlikely to provide significant therapeutic benefit. Ultimately, the most effective way to treat HIV dementia is to prevent HIV from entering the brain or to eliminate HIV from the CNS reservoir.


References


Use the Back button in your browser to continue reading the article.


(1) Dawson VL, Dawson TM (1998). Nitric oxide in neurodegeneration. Prog Brain Res 118:215-29. Medline

(2) Szabo C, Dawson VL (1998). Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci 19(7):287-98. Medline

(3) Dawson VL, Brahmbhatt HP, Mong JA, Dawson TM (1994). Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures. Neuropharmacology 33(11):1425-30. Medline

(4) Lipton SA, Sucher NJ, Kaiser PK, Dreyer EB (1991). Synergistic effects of HIV coat protein and NMDA receptor-mediated neurotoxicity. Neuron 7(1):111-8. Medline

(5) Dawson VL, Dawson TM, Uhl GR, Snyder SH (1993). Human immunodeficiency virus type 1 coat protein neurotoxicity mediated by nitric oxide in primary cortical cultures. Proc Natl Acad Sci U S A 90(8):3256-9. Medline

(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

(9) Vincent VA, De Groot CJ, Lucassen PJ, Portegies P, Troost D, Tilders FJ, Van Dam AM (1999). Nitric oxide synthase expression and apoptotic cell death in brains of AIDS and AIDS dementia patients. AIDS 13(3):317-26. Medline

(10) Boven LA, Gomes L, Hery C, Gray F, Verhoef J, Portegies P, Tardieu M, Nottet HS (1999). Increased peroxynitrite activity in AIDS dementia complex: implications for the neuropathogenesis of HIV-1 infection. J Immunol 162(7):4319-27. Medline

(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

(13) Gelbard HA, James HJ, Sharer LR, Perry SW, Saito Y, Kazee AM, Blumberg BM, Epstein LG (1995).Apoptotic neurons in brains from paediatric patients with HIV-1 encephalitis and progressive encephalopathy. Neuropathol Appl Neurobiol 21(3):208-17. Medline

(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

(18) Masliah E, Heaton RK, Marcotte TD, Ellis RJ, Wiley CA, Mallory M, Achim CL, McCutchan JA, Nelson JA, Atkinson JH, Grant I (1997). Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. HNRC Group. The HIV Neurobehavioral Research Center. Ann Neurol 42(6):963-72. Medline

(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

 
Top
NeuroAids is a project of Science OnLine
funded through a grant from the National Institute of Mental Health.
AAAS Logo Copyright ©1998 by AAAS Science Publications, Inc.