Role of Nitric Oxide in HIV Dementia

Valina L. Dawson<sup>1

1</sup>Johns Hopkins University School of Medicine; Department of Neurology
600 N. Wolfe Street, Carnegie 214 Baltimore, Maryland 21287; USA
E-mail: [email protected]

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.

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