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HIV-associated neurocognitive disorder: pathogenesis and therapeutic opportunities.

Lindl KA, Marks DR, Kolson DL, Jordan-Sciutto KL - J Neuroimmune Pharmacol (2010)

Bottom Line: Human immunodeficiency virus type 1 (HIV) infection presently affects more that 40 million people worldwide, and is associated with central nervous system (CNS) disruption in at least 30% of infected individuals.Identifying such molecular and pharmacological targets requires an understanding of the events preceding irreversible neuronal damage in the CNS, such as actions of neurotoxins (HIV proteins and cellular factors), disruption of ion channel properties, synaptic damage, and loss of adult neurogenesis.By considering the specific mechanisms and consequences of HIV neuropathogenesis, unified approaches for neuroprotection will likely emerge using a tailored, combined, and non-invasive approach.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Room 312 Levy Building, Philadelphia, PA 19104-6030, USA.

ABSTRACT
Human immunodeficiency virus type 1 (HIV) infection presently affects more that 40 million people worldwide, and is associated with central nervous system (CNS) disruption in at least 30% of infected individuals. The use of highly active antiretroviral therapy has lessened the incidence, but not the prevalence of mild impairment of higher cognitive and cortical functions (HIV-associated neurocognitive disorders) as well as substantially reduced a more severe form dementia (HIV-associated dementia). Furthermore, improving neurological outcomes will require novel, adjunctive therapies that are targeted towards mechanisms of HIV-induced neurodegeneration. Identifying such molecular and pharmacological targets requires an understanding of the events preceding irreversible neuronal damage in the CNS, such as actions of neurotoxins (HIV proteins and cellular factors), disruption of ion channel properties, synaptic damage, and loss of adult neurogenesis. By considering the specific mechanisms and consequences of HIV neuropathogenesis, unified approaches for neuroprotection will likely emerge using a tailored, combined, and non-invasive approach.

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Diagram detailing the numerous processes evoked by HIV infection in the brain that affect neuronal function and survival. Excess glutamate from the extracellular fluid and released from astrocytes causes excitotoxic mechanisms, such as dendritic beading, sustained NMDAR activation, increased calcium influx, and increased intracellular release of calcium. Ultimately, these processes lead to disruption of the postsynaptic density and loss of synapses. Viral proteins such, as gp120 and TAT, activate chemokine receptors, CXCR4 and CCR5, and can increase voltage-gated calcium (Cav) channels and potassium channels (Kv), leading to activation of cellular death pathways that result in mitochondrial depolarization, cytochrome p450 (Cp450) release, and ultimately DNA fragmentation associated with apoptosis. Viral proteins can also evoke increased Na+/H+ exchange, thereby increasing the pH inside astrocytes which promotes increased glutamate release and decreased glutamate uptake, thereby furthering excitotoxic damage
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Fig2: Diagram detailing the numerous processes evoked by HIV infection in the brain that affect neuronal function and survival. Excess glutamate from the extracellular fluid and released from astrocytes causes excitotoxic mechanisms, such as dendritic beading, sustained NMDAR activation, increased calcium influx, and increased intracellular release of calcium. Ultimately, these processes lead to disruption of the postsynaptic density and loss of synapses. Viral proteins such, as gp120 and TAT, activate chemokine receptors, CXCR4 and CCR5, and can increase voltage-gated calcium (Cav) channels and potassium channels (Kv), leading to activation of cellular death pathways that result in mitochondrial depolarization, cytochrome p450 (Cp450) release, and ultimately DNA fragmentation associated with apoptosis. Viral proteins can also evoke increased Na+/H+ exchange, thereby increasing the pH inside astrocytes which promotes increased glutamate release and decreased glutamate uptake, thereby furthering excitotoxic damage

Mentions: Synaptic disruption. In addition to neuronal death, HAND is associated with neuronal damage, particularly synaptic disruption. The etiologies described in this review, specifically inflammation and excitotoxicity, provide mechanisms by which this HIV-associated synaptic damage may occur. Activation of calcium-dependent proteases that disrupt the postsynaptic density (PSD) is a likely mechanism by which synapses may be altered in the HIV-infected CNS. The smooth ER, which extends into the dendritic spine, contains IP3 receptors that are tethered to mGluR and NMDARs by a complex of adaptor proteins, including Shank, GCAP, Homer, and PSD-95 (Tu et al. 1999; Sheng and Kim 2000, Sheng and Sala 2001; Sheng and Hoogenraad 2007). Secondary IP3-mediated calcium influxes are thought to play a role in LTP, however, prolonged synaptic depolarization and IP3-mediated signaling can also activate calpain proteases that can cleave PSD-95 which releases it from NMDAR (Lu et al. 2000). This could cause a large-scale decoupling of the postsynaptic complex from IP3 receptors. Interestingly, PSD-95 loss is also a hallmark sign of neurodegeneration (Gardoni 2008; Gardoni et al. 2009); hence, uncoupling or disruption of the PSD may be an important step in synaptic dysfunction and damage. Thus, inhibition of IP3-mediated calcium currents may prevent calpain or other protease activation, as well as block kinase enzymes from phosphorylating and modulating Kv channels. A summary of synaptic/cellular neurotoxic pathways and synaptic damage is presented in Figs. 1 and 2 to recapitulate the major findings discussed in this section and to illustrate the complexity of the pathological mechanisms evoked by CNS HIV infection.


HIV-associated neurocognitive disorder: pathogenesis and therapeutic opportunities.

Lindl KA, Marks DR, Kolson DL, Jordan-Sciutto KL - J Neuroimmune Pharmacol (2010)

Diagram detailing the numerous processes evoked by HIV infection in the brain that affect neuronal function and survival. Excess glutamate from the extracellular fluid and released from astrocytes causes excitotoxic mechanisms, such as dendritic beading, sustained NMDAR activation, increased calcium influx, and increased intracellular release of calcium. Ultimately, these processes lead to disruption of the postsynaptic density and loss of synapses. Viral proteins such, as gp120 and TAT, activate chemokine receptors, CXCR4 and CCR5, and can increase voltage-gated calcium (Cav) channels and potassium channels (Kv), leading to activation of cellular death pathways that result in mitochondrial depolarization, cytochrome p450 (Cp450) release, and ultimately DNA fragmentation associated with apoptosis. Viral proteins can also evoke increased Na+/H+ exchange, thereby increasing the pH inside astrocytes which promotes increased glutamate release and decreased glutamate uptake, thereby furthering excitotoxic damage
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2914283&req=5

Fig2: Diagram detailing the numerous processes evoked by HIV infection in the brain that affect neuronal function and survival. Excess glutamate from the extracellular fluid and released from astrocytes causes excitotoxic mechanisms, such as dendritic beading, sustained NMDAR activation, increased calcium influx, and increased intracellular release of calcium. Ultimately, these processes lead to disruption of the postsynaptic density and loss of synapses. Viral proteins such, as gp120 and TAT, activate chemokine receptors, CXCR4 and CCR5, and can increase voltage-gated calcium (Cav) channels and potassium channels (Kv), leading to activation of cellular death pathways that result in mitochondrial depolarization, cytochrome p450 (Cp450) release, and ultimately DNA fragmentation associated with apoptosis. Viral proteins can also evoke increased Na+/H+ exchange, thereby increasing the pH inside astrocytes which promotes increased glutamate release and decreased glutamate uptake, thereby furthering excitotoxic damage
Mentions: Synaptic disruption. In addition to neuronal death, HAND is associated with neuronal damage, particularly synaptic disruption. The etiologies described in this review, specifically inflammation and excitotoxicity, provide mechanisms by which this HIV-associated synaptic damage may occur. Activation of calcium-dependent proteases that disrupt the postsynaptic density (PSD) is a likely mechanism by which synapses may be altered in the HIV-infected CNS. The smooth ER, which extends into the dendritic spine, contains IP3 receptors that are tethered to mGluR and NMDARs by a complex of adaptor proteins, including Shank, GCAP, Homer, and PSD-95 (Tu et al. 1999; Sheng and Kim 2000, Sheng and Sala 2001; Sheng and Hoogenraad 2007). Secondary IP3-mediated calcium influxes are thought to play a role in LTP, however, prolonged synaptic depolarization and IP3-mediated signaling can also activate calpain proteases that can cleave PSD-95 which releases it from NMDAR (Lu et al. 2000). This could cause a large-scale decoupling of the postsynaptic complex from IP3 receptors. Interestingly, PSD-95 loss is also a hallmark sign of neurodegeneration (Gardoni 2008; Gardoni et al. 2009); hence, uncoupling or disruption of the PSD may be an important step in synaptic dysfunction and damage. Thus, inhibition of IP3-mediated calcium currents may prevent calpain or other protease activation, as well as block kinase enzymes from phosphorylating and modulating Kv channels. A summary of synaptic/cellular neurotoxic pathways and synaptic damage is presented in Figs. 1 and 2 to recapitulate the major findings discussed in this section and to illustrate the complexity of the pathological mechanisms evoked by CNS HIV infection.

Bottom Line: Human immunodeficiency virus type 1 (HIV) infection presently affects more that 40 million people worldwide, and is associated with central nervous system (CNS) disruption in at least 30% of infected individuals.Identifying such molecular and pharmacological targets requires an understanding of the events preceding irreversible neuronal damage in the CNS, such as actions of neurotoxins (HIV proteins and cellular factors), disruption of ion channel properties, synaptic damage, and loss of adult neurogenesis.By considering the specific mechanisms and consequences of HIV neuropathogenesis, unified approaches for neuroprotection will likely emerge using a tailored, combined, and non-invasive approach.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Room 312 Levy Building, Philadelphia, PA 19104-6030, USA.

ABSTRACT
Human immunodeficiency virus type 1 (HIV) infection presently affects more that 40 million people worldwide, and is associated with central nervous system (CNS) disruption in at least 30% of infected individuals. The use of highly active antiretroviral therapy has lessened the incidence, but not the prevalence of mild impairment of higher cognitive and cortical functions (HIV-associated neurocognitive disorders) as well as substantially reduced a more severe form dementia (HIV-associated dementia). Furthermore, improving neurological outcomes will require novel, adjunctive therapies that are targeted towards mechanisms of HIV-induced neurodegeneration. Identifying such molecular and pharmacological targets requires an understanding of the events preceding irreversible neuronal damage in the CNS, such as actions of neurotoxins (HIV proteins and cellular factors), disruption of ion channel properties, synaptic damage, and loss of adult neurogenesis. By considering the specific mechanisms and consequences of HIV neuropathogenesis, unified approaches for neuroprotection will likely emerge using a tailored, combined, and non-invasive approach.

Show MeSH
Related in: MedlinePlus