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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

Invasion of the blood brain barrier. HIV-1 infected immune cells release toxic viral products and inflammatory cytokines leading to degradation of tight junction proteins, oxidative stress and up-regulation of adhesion molecules. This results in the increased permeability of the blood brain barrier and increased migration of immune cells across the barrier. HIV-1 infiltrates the BBB early after infection [29] using HIV-infected monocytic cells as a “Trojan horse” for entry into brain [30].
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Figure 1: Invasion of the blood brain barrier. HIV-1 infected immune cells release toxic viral products and inflammatory cytokines leading to degradation of tight junction proteins, oxidative stress and up-regulation of adhesion molecules. This results in the increased permeability of the blood brain barrier and increased migration of immune cells across the barrier. HIV-1 infiltrates the BBB early after infection [29] using HIV-infected monocytic cells as a “Trojan horse” for entry into brain [30].

Mentions: HIV-1 proteins Tat and gp120 both directly damage the BBB (Figure 1). Tat is a non-structural viral protein secreted by infected cells [33]. Tat mRNA [34], Tat protein [35] and antibodies to Tat [36] are detectable in the CNS of HIV-infected patients. Brain endothelial cells, when exposed to HIV-1 Tat, have been shown to alter the expression and distribution of tight junction proteins (claudins & occludins) [37]. Tat treatment of HBMECs in vitro up-regulates matrix metallopeptidase-9 (MMP-9), which in turn increases the permeability of brain endothelial cells by degrading occludins [38]. In vitro two-chamber models with HBMECs and astrocytes have also shown HIV-1 Tat causes dysregulation of nitric oxide production in brain endothelial cells [39] and induces secretion of CCL2, a key chemokine responsible for migration of immune cells [40].


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

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

Invasion of the blood brain barrier. HIV-1 infected immune cells release toxic viral products and inflammatory cytokines leading to degradation of tight junction proteins, oxidative stress and up-regulation of adhesion molecules. This results in the increased permeability of the blood brain barrier and increased migration of immune cells across the barrier. HIV-1 infiltrates the BBB early after infection [29] using HIV-infected monocytic cells as a “Trojan horse” for entry into brain [30].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Invasion of the blood brain barrier. HIV-1 infected immune cells release toxic viral products and inflammatory cytokines leading to degradation of tight junction proteins, oxidative stress and up-regulation of adhesion molecules. This results in the increased permeability of the blood brain barrier and increased migration of immune cells across the barrier. HIV-1 infiltrates the BBB early after infection [29] using HIV-infected monocytic cells as a “Trojan horse” for entry into brain [30].
Mentions: HIV-1 proteins Tat and gp120 both directly damage the BBB (Figure 1). Tat is a non-structural viral protein secreted by infected cells [33]. Tat mRNA [34], Tat protein [35] and antibodies to Tat [36] are detectable in the CNS of HIV-infected patients. Brain endothelial cells, when exposed to HIV-1 Tat, have been shown to alter the expression and distribution of tight junction proteins (claudins & occludins) [37]. Tat treatment of HBMECs in vitro up-regulates matrix metallopeptidase-9 (MMP-9), which in turn increases the permeability of brain endothelial cells by degrading occludins [38]. In vitro two-chamber models with HBMECs and astrocytes have also shown HIV-1 Tat causes dysregulation of nitric oxide production in brain endothelial cells [39] and induces secretion of CCL2, a key chemokine responsible for migration of immune cells [40].

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