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Pathways to neuronal injury and apoptosis in HIV-associated dementia

Abstract

Human immunodeficiency virus-1 (HIV-1) can induce dementia with alarming occurrence worldwide. The mechanism remains poorly understood, but discovery in brain of HIV-1-binding sites (chemokine receptors) provides new insights. HIV-1 infects macrophages and microglia, but not neurons, although neurons are injured and die by apoptosis. The predominant pathway to neuronal injury is indirect through release of macrophage, microglial and astrocyte toxins, although direct injury by viral proteins might also contribute. These toxins overstimulate neurons, resulting in the formation of free radicals and excitotoxicity, similar to other neurodegenerative diseases. Recent advances in understanding the signalling pathways mediating these events offer hope for therapeutic intervention.

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Figure 1: Current model of HIV-related neuronal damage involving cell–cell signalling.
Figure 2: Microglial/macrophage signalling in HAD.
Figure 3: Astrocyte signalling in HAD.
Figure 4: Neuronal signalling in HAD.

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Acknowledgements

We dedicate this work to the memory of T. Sandson for his compassionate treatment of patients with HIV-associated dementia. We sincerely apologize to our colleagues whose works we could not cite owing to space and reference limitations. We thank members of our laboratory for their hard work and helpful discussions. M.K. is supported by the American Foundation for AIDS Research. S.A.L. and G.A.G. are supported by the National Institutes of Health. S.A.L. is or has recently been a consultant to Allergan, Alcon and Neurobiologicial Technologies, Inc. in the field of neuroprotective agents.

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Kaul, M., Garden, G. & Lipton, S. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410, 988–994 (2001). https://doi.org/10.1038/35073667

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