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Viral and cellular factors underlying neuropathogenesis in HIV associated neurocognitive disorders (HAND).

Rao VR, Ruiz AP, Prasad VR - AIDS Res Ther (2014)

Bottom Line: Over the past 10 years, there has been a significant progress in our understanding of the mechanisms and the risk factors involved in the development of HAND.These include: interaction with endothelial cells, resulting in the impairment of the blood brain barrier; interaction with the astrocytes, leading to metabolic and neurotransmitter imbalance; interactions with resident immune cells in the brain, leading to release of toxic cytokines and chemokines.In addition, we review host factors and viral genotypic differences that affect phenotypic pathological outcomes, as well as recent advances in treatment options to specifically address the neurotoxic mechanisms in play.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.

ABSTRACT
As the HIV-1 epidemic enters its fourth decade, HIV-1 associated neurological disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of anti-retroviral therapy. Advancing age and increased life expectancy of the HIV-1 infected population have been shown to increase the risk of cognitive dysfunction. Over the past 10 years, there has been a significant progress in our understanding of the mechanisms and the risk factors involved in the development of HAND. Key events that lead up to neuronal damage in HIV-1 infected individuals can be categorized based on the interaction of HIV-1 with the various cell types, including but not limited to macrophages, brain endothelial cells, microglia, astrocytes and the neurons. This review attempts to decipher these interactions, beginning with HIV-1 infection of macrophages and ultimately resulting in the release of neurotoxic viral and host products. These include: interaction with endothelial cells, resulting in the impairment of the blood brain barrier; interaction with the astrocytes, leading to metabolic and neurotransmitter imbalance; interactions with resident immune cells in the brain, leading to release of toxic cytokines and chemokines. We also review the mechanisms underlying neuronal damage caused by the factors mentioned above. We have attempted to bring together recent findings in these areas to help appreciate the viral and host factors that bring about neurological dysfunction. In addition, we review host factors and viral genotypic differences that affect phenotypic pathological outcomes, as well as recent advances in treatment options to specifically address the neurotoxic mechanisms in play.

No MeSH data available.


Related in: MedlinePlus

Mechanisms of Tat neurotoxicity. (1) Tat binds to the NMDA receptor and drives the phosphorylation of an intracellular NMDAR subunit, causing excess opening of cation channels and toxic accumulation of calcium [62]. (2) When applied to neurons, Tat is able to induce the activation of PLC and drive the IP3-mediated release of intracellular calcium from ER stores, further contributing to calcium toxicity and apoptosis [63]. (3) Tat can bind to LRP receptors, and be taken up as part of a macromolecular complex including NMDAR and neuronal nitric oxide synthase (nNOS) that induces cellular apoptosis [65]. Tat can also drive the internalization of the LRP receptor, reducing the uptake of LRP receptor ligands amyloid-β peptide and Apolipoprotein E, which may contribute to systemic neuronal dysfunction [64]. (4) Tat interferes with the activity of dopamine transporter, diminishing the reuptake of dopamine by pre-synaptic neurons and interfering with signal transmission [67].
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Figure 3: Mechanisms of Tat neurotoxicity. (1) Tat binds to the NMDA receptor and drives the phosphorylation of an intracellular NMDAR subunit, causing excess opening of cation channels and toxic accumulation of calcium [62]. (2) When applied to neurons, Tat is able to induce the activation of PLC and drive the IP3-mediated release of intracellular calcium from ER stores, further contributing to calcium toxicity and apoptosis [63]. (3) Tat can bind to LRP receptors, and be taken up as part of a macromolecular complex including NMDAR and neuronal nitric oxide synthase (nNOS) that induces cellular apoptosis [65]. Tat can also drive the internalization of the LRP receptor, reducing the uptake of LRP receptor ligands amyloid-β peptide and Apolipoprotein E, which may contribute to systemic neuronal dysfunction [64]. (4) Tat interferes with the activity of dopamine transporter, diminishing the reuptake of dopamine by pre-synaptic neurons and interfering with signal transmission [67].

Mentions: The viral protein Tat also causes neurotoxicity via multiple pathways. Similar to gp120, Tat can activate NMDA receptors and drive the toxic influx of Ca2+ ions [62] (Figure 3). In addition to calcium dysregulation through the NMDAR, Tat can induce the phospholipase C-driven activation of inositol 1,4,5-triphosphate, which increases the intracellular levels of [Ca2+] by mobilizing stores in the endoplasmic reticulum and contributes to calcium toxicity and cell death [63]. Tat also binds LRP in neurons, causing LRP internalization and a decrease in uptake of natural LRP ligands such as amyloid-β peptide and Apolipoprotein E [64] (Figure 3). The interaction of Tat with LRP can lead to the formation of an apoptosis-promoting complex including postsynaptic density protein-95 (PSD-95), NMDA receptors and neuronal nitric oxide synthase (nNOS) [65]. Tat has been found to interfere with the expression of miRNAs in neurons, increasing the levels of CREB-targeting miR-34a and leading to neuronal dysfunction [66]. Tat can also interfere with the ability of dopamine transporter to reuptake dopamine [67]. This likely contributes to the particularly severe damage rendered to dopaminergic-rich regions in the brains of patients with severe HAND [51].


Viral and cellular factors underlying neuropathogenesis in HIV associated neurocognitive disorders (HAND).

Rao VR, Ruiz AP, Prasad VR - AIDS Res Ther (2014)

Mechanisms of Tat neurotoxicity. (1) Tat binds to the NMDA receptor and drives the phosphorylation of an intracellular NMDAR subunit, causing excess opening of cation channels and toxic accumulation of calcium [62]. (2) When applied to neurons, Tat is able to induce the activation of PLC and drive the IP3-mediated release of intracellular calcium from ER stores, further contributing to calcium toxicity and apoptosis [63]. (3) Tat can bind to LRP receptors, and be taken up as part of a macromolecular complex including NMDAR and neuronal nitric oxide synthase (nNOS) that induces cellular apoptosis [65]. Tat can also drive the internalization of the LRP receptor, reducing the uptake of LRP receptor ligands amyloid-β peptide and Apolipoprotein E, which may contribute to systemic neuronal dysfunction [64]. (4) Tat interferes with the activity of dopamine transporter, diminishing the reuptake of dopamine by pre-synaptic neurons and interfering with signal transmission [67].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4043700&req=5

Figure 3: Mechanisms of Tat neurotoxicity. (1) Tat binds to the NMDA receptor and drives the phosphorylation of an intracellular NMDAR subunit, causing excess opening of cation channels and toxic accumulation of calcium [62]. (2) When applied to neurons, Tat is able to induce the activation of PLC and drive the IP3-mediated release of intracellular calcium from ER stores, further contributing to calcium toxicity and apoptosis [63]. (3) Tat can bind to LRP receptors, and be taken up as part of a macromolecular complex including NMDAR and neuronal nitric oxide synthase (nNOS) that induces cellular apoptosis [65]. Tat can also drive the internalization of the LRP receptor, reducing the uptake of LRP receptor ligands amyloid-β peptide and Apolipoprotein E, which may contribute to systemic neuronal dysfunction [64]. (4) Tat interferes with the activity of dopamine transporter, diminishing the reuptake of dopamine by pre-synaptic neurons and interfering with signal transmission [67].
Mentions: The viral protein Tat also causes neurotoxicity via multiple pathways. Similar to gp120, Tat can activate NMDA receptors and drive the toxic influx of Ca2+ ions [62] (Figure 3). In addition to calcium dysregulation through the NMDAR, Tat can induce the phospholipase C-driven activation of inositol 1,4,5-triphosphate, which increases the intracellular levels of [Ca2+] by mobilizing stores in the endoplasmic reticulum and contributes to calcium toxicity and cell death [63]. Tat also binds LRP in neurons, causing LRP internalization and a decrease in uptake of natural LRP ligands such as amyloid-β peptide and Apolipoprotein E [64] (Figure 3). The interaction of Tat with LRP can lead to the formation of an apoptosis-promoting complex including postsynaptic density protein-95 (PSD-95), NMDA receptors and neuronal nitric oxide synthase (nNOS) [65]. Tat has been found to interfere with the expression of miRNAs in neurons, increasing the levels of CREB-targeting miR-34a and leading to neuronal dysfunction [66]. Tat can also interfere with the ability of dopamine transporter to reuptake dopamine [67]. This likely contributes to the particularly severe damage rendered to dopaminergic-rich regions in the brains of patients with severe HAND [51].

Bottom Line: Over the past 10 years, there has been a significant progress in our understanding of the mechanisms and the risk factors involved in the development of HAND.These include: interaction with endothelial cells, resulting in the impairment of the blood brain barrier; interaction with the astrocytes, leading to metabolic and neurotransmitter imbalance; interactions with resident immune cells in the brain, leading to release of toxic cytokines and chemokines.In addition, we review host factors and viral genotypic differences that affect phenotypic pathological outcomes, as well as recent advances in treatment options to specifically address the neurotoxic mechanisms in play.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.

ABSTRACT
As the HIV-1 epidemic enters its fourth decade, HIV-1 associated neurological disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of anti-retroviral therapy. Advancing age and increased life expectancy of the HIV-1 infected population have been shown to increase the risk of cognitive dysfunction. Over the past 10 years, there has been a significant progress in our understanding of the mechanisms and the risk factors involved in the development of HAND. Key events that lead up to neuronal damage in HIV-1 infected individuals can be categorized based on the interaction of HIV-1 with the various cell types, including but not limited to macrophages, brain endothelial cells, microglia, astrocytes and the neurons. This review attempts to decipher these interactions, beginning with HIV-1 infection of macrophages and ultimately resulting in the release of neurotoxic viral and host products. These include: interaction with endothelial cells, resulting in the impairment of the blood brain barrier; interaction with the astrocytes, leading to metabolic and neurotransmitter imbalance; interactions with resident immune cells in the brain, leading to release of toxic cytokines and chemokines. We also review the mechanisms underlying neuronal damage caused by the factors mentioned above. We have attempted to bring together recent findings in these areas to help appreciate the viral and host factors that bring about neurological dysfunction. In addition, we review host factors and viral genotypic differences that affect phenotypic pathological outcomes, as well as recent advances in treatment options to specifically address the neurotoxic mechanisms in play.

No MeSH data available.


Related in: MedlinePlus