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Review
. 2008 Jan 1:13:2484-94.
doi: 10.2741/2860.

HIV's double strike at the brain: neuronal toxicity and compromised neurogenesis

Marcus Kaul  1
Affiliations
Review

HIV's double strike at the brain: neuronal toxicity and compromised neurogenesis

Marcus Kaul. Front Biosci. .

Abstract

Infection with the human immunodeficiency virus-1 (HIV-1) and acquired immunodeficiency syndrome (AIDS) are often associated with severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction and frank dementia. HIV-1-infected peripheral immune cells, in particular macrophages, appear to infiltrate the CNS, release neurotoxins and provoke a neuropathological response involving all cell types in the brain. In the CNS, HIV-1 and its components initiate activation of chemokine receptors, inflammatory mediators and glutamate receptor-mediated excitotoxicity, all of which can activate numerous downstream signaling pathways and disturb neuronal and glial function. Recent experimental evidence suggests that disturbance by HIV-1 results not only in neuronal injury and death but also in impairment of neurogenesis. This article will review recently identified pathological mechanisms which potentially contribute to the development of neurocognitive impairment and dementia in association with HIV-1 infection.

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Figures

Figure 1
Figure 1
Current model of HIV-1 neuropathology and potential sites for therapeutic intervention (protective factors are shown in italic): Immune-activated and HIV-infected, brain-infiltrating macrophages (Mphi) and microglia release potentially neurotoxic substances. These substances include quinolinic acid and other excitatory amino acids such as glutamate and l-cysteine, arachidonic acid, NTox, free radicals, TNF-alpha, and probably others. These factors from macrophages/microglia and also possibly from reactive astrocytes contribute to neuronal injury, dendritic and synaptic damage, and apoptosis as well as to astrocytosis. Entry of HIV-1 into macrophages/microglia occurs via gp120 binding, and therefore it is not surprising that gp120 (or a fragment thereof) is capable of activating uninfected macrophages/microglia to release similar factors to those secreted in response to productive HIV infection. Macrophages/microglia express CCR5 and CXCR4 chemokine receptors on their surface in addition to CD4 and viral gp120 binds via these receptors. Neurons and astrocytes also possess CXCR4 and CCR5 receptors on their surface, raising the possibility of direct interaction with gp120. Macrophages/microglia and astrocytes have mutual feed-back loops (bidirectional arrow). Cytokines participate in this multi-cellular network in several ways. For example, HIV-infection or gp120-stimulation of macrophages/microglia enhances their production of TNF-alpha and IL-1beta (cytokines-arrow). The TNF-alpha and IL-1beta produced by macrophages/microglia stimulate astrocytosis. Arachidonate released from Mphi/microglia impairs astrocyte clearing of the neurotransmitter glutamate and thus contributes to excitotoxicity. In conjunction with cytokines, the alpha-chemokine SDF-1 stimulates reactive astrocytes to release glutamate in addition to the free radical nitric oxide (NO·), which in turn may react with superoxide (O2·-) to form the neurotoxic molecule peroxynitrite (ONOO-). Neuronal injury is primarily mediated by overactivation of NMDARs with resultant excessive influx of Ca2+. This, in turn, leads to overactivation of a variety of potentially harmful signaling systems, the formation of free radicals, and release of additional neurotransmitter glutamate. Glutamate subsequently overstimulates NMDARs on neighboring neurons, resulting in further injury. This final common pathway of neurotoxic action can be blocked by NMDAR antagonists. For certain neurons, depending on their exact repertoire of ionic channels, this form of damage can also be ameliorated to some degree by calcium channel antagonists or non-NMDAR antagonists. HAART suppresses HIV-1 infection primarily in the periphery but has limited effect in the CNS. If present, MIP-1beta and RANTES, agonists of β-chemokine receptors, which are expressed in the CNS on neurons, astrocytes and microglia, can confer partial protection against neuronal apoptosis induced by HIV/gp120 or NMDA. Modified from (117).
Figure 2
Figure 2
Current model of HIV-1 interference with the function of neural progenitor cells and potential sites for therapeutic intervention (protective factors are shown in italic): Exposure to chemokines, SDF-1 and Eotaxin, or HIV-1/gp120 of mouse or human neural progenitor cells (NPCs) reduces proliferation and promotes quiescence. ApoE3 inhibits these effects on NPCs. NPCs express nestin and show decreased proliferation as judged by decreased BrdU incorporation. However, NPCs do not undergo apoptosis, as evidenced by lack of TUNEL staining and nuclear condensation under the same conditions (16,20,116). HIV/gp120 impairs proliferation of progenitors through activation of a pathway consisting of p38MAPK, MAPK-activated protein kinase 2 and Cdc25B/C which results in cell-cycle arrest in the G1 phase. It is not clear yet in how far this effect is reversible. Modified from (117).
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References

    1. Petito CK, Cho ES, Lemann W, Navia BA, Price RW. Neuropathology of acquired immunodeficiency syndrome (AIDS): an autopsy review. J Neuropathol. Exp. Neurol. 1986;45:635–646. - PubMed
    1. Glass JD, Wesselingh SL, Selnes OA, McArthur JC. Clinical-neuropathologic correlation in HIV-associated dementia. Neurology. 1993;43:2230–2237. - PubMed
    1. Kaul M, Garden GA, Lipton SA. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature. 2001;410:988–994. - PubMed
    1. Power C, Gill MJ, Johnson RT. Progress in clinical neurosciences: the neuropathogenesis of HIV infection: host-virus interaction and the impact of therapy. Can. J Neurol Sci. 2002;29:19–32. - PubMed
    1. Gendelman HE, Grant I, Lipton SA, Everall I, Swindells S. The neurology of AIDS. 2nd ed. Oxford University Press; London: 2005.

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