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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

Contribution of the dicysteine motif in Tat to neuropathogenesis. (1) Tat is secreted by infected macrophages and microglia in the vincity of the blood brain barrier resulting in damage to the integrity of the barrier. Dicysteine Tat can act as a ligand on certain chemokine receptors expressed by circulating monocytes (i.e. CCR2, CCR3, CCR5), and promote monocyte migration across the BBB into the CNS [148]. Clade C Tat lacking the intact dicysteine motif fails to attract monocytes in a two chamber migration assay [149]. (2) Dicysteine Tat (TatB but not TatC) also induces higher expression of CCL2 and activation marker CD40 in microglial cells than non-dicysteine Tat [150]. (3) When applied to astrocytes, dicysteine Tat induces higher levels of CCL2 [149] and in HIVE SCID Mouse model astrogliosis is more pronounced in the presence of HIV-1 with an intact dicysteine motif [151]. (4) In neurons, it has been proposed that the Cys31 in the Tat dicysteine motif specifically disrupts the disulfide bond between Cys 744 and Cys 798 on the NR1 subunit of the NMDA receptor, leading to persistent activation of the NMDA receptor [152]. The increase in Tat-mediated apoptosis in dicysteine Tat is also seen in human primary neurons (mediated by increased levels of cleaved caspase-3), in addition to higher levels of ROS and increased levels of mitochondrial depolarization [149]. Primary Human neurons exposed to viral supernatants from HIV-1 with intact dicysteine motif exhibit neuronal apoptosis and HIV-1 SCID mice exposed to the same supernatants have cognitive dysfunction [151].
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Figure 4: Contribution of the dicysteine motif in Tat to neuropathogenesis. (1) Tat is secreted by infected macrophages and microglia in the vincity of the blood brain barrier resulting in damage to the integrity of the barrier. Dicysteine Tat can act as a ligand on certain chemokine receptors expressed by circulating monocytes (i.e. CCR2, CCR3, CCR5), and promote monocyte migration across the BBB into the CNS [148]. Clade C Tat lacking the intact dicysteine motif fails to attract monocytes in a two chamber migration assay [149]. (2) Dicysteine Tat (TatB but not TatC) also induces higher expression of CCL2 and activation marker CD40 in microglial cells than non-dicysteine Tat [150]. (3) When applied to astrocytes, dicysteine Tat induces higher levels of CCL2 [149] and in HIVE SCID Mouse model astrogliosis is more pronounced in the presence of HIV-1 with an intact dicysteine motif [151]. (4) In neurons, it has been proposed that the Cys31 in the Tat dicysteine motif specifically disrupts the disulfide bond between Cys 744 and Cys 798 on the NR1 subunit of the NMDA receptor, leading to persistent activation of the NMDA receptor [152]. The increase in Tat-mediated apoptosis in dicysteine Tat is also seen in human primary neurons (mediated by increased levels of cleaved caspase-3), in addition to higher levels of ROS and increased levels of mitochondrial depolarization [149]. Primary Human neurons exposed to viral supernatants from HIV-1 with intact dicysteine motif exhibit neuronal apoptosis and HIV-1 SCID mice exposed to the same supernatants have cognitive dysfunction [151].

Mentions: Our laboratory previously investigated whether genetic differences between the circulating isolates are responsible for the wide variation in incidence of HAD in different geographic regions. We reported that a majority (88%) of HIV-1 subtype C isolates worldwide have a Tat protein with a Cys31Ser polymorphism that disrupts a dicysteine motif, which is a key element of Tat protein’s homology to β-chemokines [147] (Figure 4). In contrast, the Tat proteins encoded by 99% of non-subtype C HIV-1 isolates maintained a C31 residue at that position. We demonstrated that Tat protein of subtype C HIV-1 isolates with a C31S polymorphism is defective for monocyte chemotaxis function in vitro [147]. As the infiltration of monocytic cells to the brain is a hallmark of HAD and plays a central role in triggering the inflammatory onslaught on neurons, we hypothesized that the C31S polymorphism in Tat protein of subtype C HIV-1 isolates contributes to the mechanistic basis for low incidence of HAD reported in India, as fewer monocytic cells would migrate to brain and result in little neuronal damage.


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

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

Contribution of the dicysteine motif in Tat to neuropathogenesis. (1) Tat is secreted by infected macrophages and microglia in the vincity of the blood brain barrier resulting in damage to the integrity of the barrier. Dicysteine Tat can act as a ligand on certain chemokine receptors expressed by circulating monocytes (i.e. CCR2, CCR3, CCR5), and promote monocyte migration across the BBB into the CNS [148]. Clade C Tat lacking the intact dicysteine motif fails to attract monocytes in a two chamber migration assay [149]. (2) Dicysteine Tat (TatB but not TatC) also induces higher expression of CCL2 and activation marker CD40 in microglial cells than non-dicysteine Tat [150]. (3) When applied to astrocytes, dicysteine Tat induces higher levels of CCL2 [149] and in HIVE SCID Mouse model astrogliosis is more pronounced in the presence of HIV-1 with an intact dicysteine motif [151]. (4) In neurons, it has been proposed that the Cys31 in the Tat dicysteine motif specifically disrupts the disulfide bond between Cys 744 and Cys 798 on the NR1 subunit of the NMDA receptor, leading to persistent activation of the NMDA receptor [152]. The increase in Tat-mediated apoptosis in dicysteine Tat is also seen in human primary neurons (mediated by increased levels of cleaved caspase-3), in addition to higher levels of ROS and increased levels of mitochondrial depolarization [149]. Primary Human neurons exposed to viral supernatants from HIV-1 with intact dicysteine motif exhibit neuronal apoptosis and HIV-1 SCID mice exposed to the same supernatants have cognitive dysfunction [151].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Contribution of the dicysteine motif in Tat to neuropathogenesis. (1) Tat is secreted by infected macrophages and microglia in the vincity of the blood brain barrier resulting in damage to the integrity of the barrier. Dicysteine Tat can act as a ligand on certain chemokine receptors expressed by circulating monocytes (i.e. CCR2, CCR3, CCR5), and promote monocyte migration across the BBB into the CNS [148]. Clade C Tat lacking the intact dicysteine motif fails to attract monocytes in a two chamber migration assay [149]. (2) Dicysteine Tat (TatB but not TatC) also induces higher expression of CCL2 and activation marker CD40 in microglial cells than non-dicysteine Tat [150]. (3) When applied to astrocytes, dicysteine Tat induces higher levels of CCL2 [149] and in HIVE SCID Mouse model astrogliosis is more pronounced in the presence of HIV-1 with an intact dicysteine motif [151]. (4) In neurons, it has been proposed that the Cys31 in the Tat dicysteine motif specifically disrupts the disulfide bond between Cys 744 and Cys 798 on the NR1 subunit of the NMDA receptor, leading to persistent activation of the NMDA receptor [152]. The increase in Tat-mediated apoptosis in dicysteine Tat is also seen in human primary neurons (mediated by increased levels of cleaved caspase-3), in addition to higher levels of ROS and increased levels of mitochondrial depolarization [149]. Primary Human neurons exposed to viral supernatants from HIV-1 with intact dicysteine motif exhibit neuronal apoptosis and HIV-1 SCID mice exposed to the same supernatants have cognitive dysfunction [151].
Mentions: Our laboratory previously investigated whether genetic differences between the circulating isolates are responsible for the wide variation in incidence of HAD in different geographic regions. We reported that a majority (88%) of HIV-1 subtype C isolates worldwide have a Tat protein with a Cys31Ser polymorphism that disrupts a dicysteine motif, which is a key element of Tat protein’s homology to β-chemokines [147] (Figure 4). In contrast, the Tat proteins encoded by 99% of non-subtype C HIV-1 isolates maintained a C31 residue at that position. We demonstrated that Tat protein of subtype C HIV-1 isolates with a C31S polymorphism is defective for monocyte chemotaxis function in vitro [147]. As the infiltration of monocytic cells to the brain is a hallmark of HAD and plays a central role in triggering the inflammatory onslaught on neurons, we hypothesized that the C31S polymorphism in Tat protein of subtype C HIV-1 isolates contributes to the mechanistic basis for low incidence of HAD reported in India, as fewer monocytic cells would migrate to brain and result in little neuronal damage.

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