Limits...
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 gp120 neurotoxicity. (1) gp120 can bind to the NMDA receptor and lead to excessive opening of NMDAR-gated cation channels, allowing the influx of calcium ions to toxic levels [54]. (2) gp120 can directly bind to either CCR5 or CXCR4, activating an p38-MAPK mediated signaling cascade that leads to neuronal apoptosis [56]. The gp120-CXCR4 binding also up-regulates the expression of the nicotinic receptor α7, which increases cellular permeability to [Ca2+] influx and contributes to cell death [61].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Mechanisms of gp120 neurotoxicity. (1) gp120 can bind to the NMDA receptor and lead to excessive opening of NMDAR-gated cation channels, allowing the influx of calcium ions to toxic levels [54]. (2) gp120 can directly bind to either CCR5 or CXCR4, activating an p38-MAPK mediated signaling cascade that leads to neuronal apoptosis [56]. The gp120-CXCR4 binding also up-regulates the expression of the nicotinic receptor α7, which increases cellular permeability to [Ca2+] influx and contributes to cell death [61].

Mentions: The two major viral proteins that interact with the above receptors to cause neuronal injury are gp120 and Tat. Both monomeric and oligomeric gp120 have neurotoxic capabilities [52], and transgenic mice expressing gp120 have a spectrum of neuronal and glial changes resembling abnormalities in brains of HIV-1-infected humans [53]. HIV-1 gp120 directly binds NMDAR on human embryonic neurons and can cause a lethal influx of calcium ions [54] (Figure 2). HIV-1 gp120 can bind to either CCR5 or CXCR4 and induce death in neuroblastoma cells [52,55] (Figure 2). This apoptosis apparently takes place through a p38-MAPK-mediated signaling cascade [56]. Cognitive testing of gp120 transgenic mice showed age-dependent deficits in open field activity and spatial reference memory tests [57]. The natural ligands of both CCR5 (eg. CCL5, CCL3) and CXCR4 (CXCL12) were found to be neuroprotective against gp120 neurotoxicity [52,55,58,59]. However, CXCL12 displays neurotoxicity [56] after the N-terminal cleavage of a tetrapeptide in CXCL12 by MMP-2 [60]. Another factor up-regulated by the interaction of gp120 with CXCR4 is the neuronal nicotinic receptor α7, which increases cellular permeability to [Ca2+] influx and contributes to cell death [61].


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

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

Mechanisms of gp120 neurotoxicity. (1) gp120 can bind to the NMDA receptor and lead to excessive opening of NMDAR-gated cation channels, allowing the influx of calcium ions to toxic levels [54]. (2) gp120 can directly bind to either CCR5 or CXCR4, activating an p38-MAPK mediated signaling cascade that leads to neuronal apoptosis [56]. The gp120-CXCR4 binding also up-regulates the expression of the nicotinic receptor α7, which increases cellular permeability to [Ca2+] influx and contributes to cell death [61].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Mechanisms of gp120 neurotoxicity. (1) gp120 can bind to the NMDA receptor and lead to excessive opening of NMDAR-gated cation channels, allowing the influx of calcium ions to toxic levels [54]. (2) gp120 can directly bind to either CCR5 or CXCR4, activating an p38-MAPK mediated signaling cascade that leads to neuronal apoptosis [56]. The gp120-CXCR4 binding also up-regulates the expression of the nicotinic receptor α7, which increases cellular permeability to [Ca2+] influx and contributes to cell death [61].
Mentions: The two major viral proteins that interact with the above receptors to cause neuronal injury are gp120 and Tat. Both monomeric and oligomeric gp120 have neurotoxic capabilities [52], and transgenic mice expressing gp120 have a spectrum of neuronal and glial changes resembling abnormalities in brains of HIV-1-infected humans [53]. HIV-1 gp120 directly binds NMDAR on human embryonic neurons and can cause a lethal influx of calcium ions [54] (Figure 2). HIV-1 gp120 can bind to either CCR5 or CXCR4 and induce death in neuroblastoma cells [52,55] (Figure 2). This apoptosis apparently takes place through a p38-MAPK-mediated signaling cascade [56]. Cognitive testing of gp120 transgenic mice showed age-dependent deficits in open field activity and spatial reference memory tests [57]. The natural ligands of both CCR5 (eg. CCL5, CCL3) and CXCR4 (CXCL12) were found to be neuroprotective against gp120 neurotoxicity [52,55,58,59]. However, CXCL12 displays neurotoxicity [56] after the N-terminal cleavage of a tetrapeptide in CXCL12 by MMP-2 [60]. Another factor up-regulated by the interaction of gp120 with CXCR4 is the neuronal nicotinic receptor α7, which increases cellular permeability to [Ca2+] influx and contributes to cell death [61].

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