Correspondence

Nitric Oxide and AIDS Dementia

N Engl J Med 1995; 333:521-522August 24, 1995

Article

To the Editor:

Lipton and Gendelman ascribe a key role to macrophages and reactive oxygen intermediates in the pathogenesis of dementia associated with human immunodeficiency virus (HIV) infection (April 6 issue).1 Since inhibi-tors of nitric oxide synthase were found to prevent gp120-induced neurotoxic effects in vitro, the authors speculate that nitric oxide triggers neurologic damage. However, it is questionable whether macrophages from humans, unlike those from other species, can produce relevant amounts of nitric oxide. Other cells in the brain, such as astrocytes, could be a source of nitric oxide, but there is no evidence of enhanced formation of nitric oxide in HIV infection; moreover, no increase in nitrite or nitrate was found in cerebrospinal fluid from patients who had HIV infection with or without dementia.2

Because of a relative deficiency of pyruvoyltetrahydropterin synthase, human macrophages do not synthesize appropriate amounts of 5,6,7,8-tetrahydrobiopterin, which has a rate-limiting effect on cytokine-inducible nitric oxide synthase; instead, large amounts of neopterin derivatives are produced.3 Thus, the participation of macrophage-derived nitric oxide in the induction of brain damage in humans appears very unlikely. In contrast, evidence is accumulating that neopterin derivatives themselves belong to the cytotoxic arsenal of the activated human macrophage.3 These derivatives enhance radical-mediated effector functions and programmed cell death induced by tumor necrosis factor α.4 These data provide evidence that activated macrophages could indeed be relevant to the pathogenesis of AIDS dementia, but it appears that neopterin derivatives, rather than nitric oxide, are the important mediators. Further studies will clarify the actual involvement of neopterin derivatives in the development of neuropsychiatric symptoms, but it is known that AIDS dementia is correlated with increased neopterin concentrations in cerebrospinal fluid.1,5

Dietmar Fuchs, Ph.D.
Gabriele Baier-Bitterlich, Ph.D
Helmut Wachter, Ph.D.
University of Innsbruck, 6020 Innsbruck, Austria

5 References

1
Lipton SA, Gendelman HE. Dementia associated with the acquired immunodeficiency syndrome. N Engl J Med 1995;332:934-940
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2
Milstien S, Sakai N, Brew BJ, et al. Cerebrospinal fluid nitrite/nitrate levels in neurologic diseases. J Neurochem 1994;63:1178-1180
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3
Fuchs D, Murr C, Reibnegger G, et al. Nitric oxide synthase and antimicrobial armature of human macrophages. J Infect Dis 1994;169:224-225
CrossRef | Web of Science | Medline

4
Baier-Bitterlich G, Fuchs D, Murr C, et al. Effect of neopterin and 7,8-dihydroneopterin on tumor necrosis factor-alpha induced programmed cell death. FEBS Lett 1995;364:234-238
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5
Fuchs D, Chiodi F, Albert J, et al. Neopterin concentrations in cerebrospinal fluid and serum of individuals infected with HIV-1. AIDS 1989;3:285-288
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Author/Editor Response

The authors reply:

To the Editor: Fuchs et al. raise questions about statements we did not make in our article. We did not ascribe neuronal injury in AIDS dementia to reactive oxygen intermediates or solely to nitric oxide emanating from HIV-infected macrophages. In fact, we made the opposite point — namely, that “this free radical is not the primary or the sole factor in neuronal injury”; instead, several macrophage secretory products acting in concert are likely to be related to the neuronal damage observed in brain tissue from HIV-infected patients. We also emphasized that the neurotoxic effects of macrophage factors can be blocked by antagonists of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors. This blockage would not occur if the macrophage toxins consisted only of nitric oxide or reactive oxygen species. Indeed, when these molecules are released from macrophages, they contribute to neuronal injury by a pathway that is separate from the NMDA receptor.

Another issue that merits comment is the production of nitric oxide from human macrophages. We and our colleagues have definitively shown that HIV-infected human macrophages produce nitric oxide, albeit in modest amounts.1 To demonstrate this effect conclusively, we used sensitive and specific chemical methods involving spin traps. This technique was not used in the study cited by Fuchs et al. in which nitric oxide was not detected. In addition, Fuchs et al. state that 5,6,7,8-tetrahydrobiopterin, which has a rate-limiting effect on the cytokine-inducible form of nitric oxide synthase, is relatively deficient in human macrophages. This statement appears to be disingenuous, however, given that in previous correspondence2 attempting to refute the work of others, Fuchs et al. argued that a “deficiency of BH4 [5,6,7,8-tetrahydrobiopterin] cannot explain the inability to detect nitric oxide (NO) production by human macrophages.”

It is true, as Fuchs et al. state, that neopterin and its chemically reduced form, 7,8-dihydroneopterin, can be made in excess as degradation products by cells unable to sustain 5,6,7,8-tetrahydrobiopterin synthesis. However, 5,6,7,8-tetrahydrobiopterin has recently been shown to generate superoxide anions, which react with nitric oxide to inactivate it through the formation of peroxynitrite.3 In contrast to the statements of Fuchs et al., therefore, a deficiency in 5,6,7,8-tetrahydrobiopterin could lead to a relative increase in the level of nitric oxide because of a diminished reaction with superoxide to form peroxynitrite. Since peroxynitrite, not nitric oxide, is neurotoxic, this effect might result in the relative sparing of neurons from injury.4

In response to the important question that Fuchs et al. raise about the possible role of neopterins in AIDS dementia: the influence of this family of substances, produced by human macrophages, is under investigation by several groups, including ours and is specifically mentioned in our review. However, the redox actions of neopterins are complex. For example, neopterin (or a congener) was recently shown to be neuroprotective5 rather than neurodestructive, yet only the latter possibility is noted by Fuchs et al. The exact mechanism (or mechanisms) and effects of neopterin and its redox congeners in neuronal injury or protection remain to be elucidated.

Numerous regulatory molecules are synthesized by HIV-infected and immune-activated macrophages in the brain, and possibly by other non-neuronal cells such as astrocytes. Many of these factors appear to participate in pathways leading to neuronal injury and may contribute to AIDS dementia. In contrast, other factors may represent attempts at neuroprotective and reparative processes, and these too need to be characterized. Clinical trials of the NMDA antagonist memantine are scheduled to begin later this year under the auspices of the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases, in conjunction with the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke. The results of such trials may shed light on the pathway (or pathways) to neuronal injury in patients with AIDS dementia.

Stuart A. Lipton, M.D., Ph.D.
Harvard Medical School, Boston, MA 02115

Howard E. Gendelman, M.D.
Univerity of Nebraska Medical Center, Omaha, NE 68198

5 References

1
Bukrinsky MI, Nottet HS, Schmidtmayerova H, et al. Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (HIV-1)-infected monocytes: implications for HIV-associated neurological disease. J Exp Med 1995;181:735-745
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2
Fuchs D, Murr C, Reibnegger G, et al. Nitric oxide synthase and antimicrobial armature of human macrophages. J Infect Dis 1994;169:224-225
CrossRef | Web of Science | Medline

3
Mayer B, Klatt P, Werner ER, Schmidt K. Kinetics and mechanism of tetrahydrobiopterin-induced oxidation of nitric oxide. J Biol Chem 1995;270:655-659
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4
Lipton SA, Choi Y-B, Pan Z-H, et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 1993;364:626-632
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5
Arai T, Watanabe K, Nakao S, et al. Effects of neopterin on ischemic neuronal damage in gerbils. Neurosci Lett 1994;173:107-110
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