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Molecular mechanisms of neuroinvasion by monocytes-macrophages in HIV-1 infection.

Gras G, Kaul M - Retrovirology (2010)

Bottom Line: The blood-brain-barrier plays a critical role in this never stopping neuroinvasion, although it appears unaltered until the late stage of HIV encephalitis.HIV flux that moves toward the brain thus relies on hijacking and exacerbating the physiological mechanisms that govern blood brain barrier crossing rather than barrier disruption.This review will summarize the recent data describing neuroinvasion by HIV with a focus on the molecular mechanisms involved.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Emerging Diseases and Innovative Therapies, Division of Immuno-Virology, CEA, 18 Route du Panorama, F92265 Fontenay-aux Roses, France. gabriel.gras@cea.fr

ABSTRACT
HIV associated neurocognitive disorders and their histopathological correlates largely depend on the continuous seeding of the central nervous system with immune activated leukocytes, mainly monocytes/macrophages from the periphery. The blood-brain-barrier plays a critical role in this never stopping neuroinvasion, although it appears unaltered until the late stage of HIV encephalitis. HIV flux that moves toward the brain thus relies on hijacking and exacerbating the physiological mechanisms that govern blood brain barrier crossing rather than barrier disruption. This review will summarize the recent data describing neuroinvasion by HIV with a focus on the molecular mechanisms involved.

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Related in: MedlinePlus

Mechanistic model of HIV-1 neuroinvasion. (1) The physiological expression of chemokines by brain cells, among which are soluble fractalkine (Fkn) and CXCL12, supports a slow but continuous entry of monocytes and macrophages into the central nervous system. Due to their expression of CX3CR1, CD16 positive, activated monocytes are the preferential targets for such attraction. These CD16 positive monocytes are the main reservoir of monocyte/macrophage-harbored virus and are thus likely to be the predominant cell type carrying HIV into the brain. (2) Infiltrated HIV-infected monocytes locally produce HIV and inflammatory mediators in perivascular areas. This activates neighbouring astrocytes as well as the blood brain barrier (BBB) endothelium. (3) In response, endothelial cells up-regulate adhesion molecules, enhancing monocyte recruitment. However, membrane-bound Fkn is also induced on endothelial cells and can arrest CD16 positive monocytes at the endothelium thus inhibiting their further infiltration. (4) CCL2 is overexpressed by infected, HIV-stimulated macrophages and activated astrocytes, attracting CD16 negative, CCR2 positive monocytes toward the perivascular area. (5) Both CXCL12 and nerve growth factor (NGF) are overexpressed in the inflamed brain. NGF increases CXCR4 expression and promotes uninfected monocyte attraction by CXCL12. At the same time it limits entry of infected monocytes into the brain. (6) Activated uninfected perivascular macrophages may be targets for de novo infection by locally produced HIV, amplifying the activation - attraction - infection cycle. (7) Local inflammation as well as HIV products induce tight junction disorganization and lead to breaches in the BBB. Toxic serum proteins and free virions may enter the brain, favouring more infection and further amplifying inflammation.
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Figure 1: Mechanistic model of HIV-1 neuroinvasion. (1) The physiological expression of chemokines by brain cells, among which are soluble fractalkine (Fkn) and CXCL12, supports a slow but continuous entry of monocytes and macrophages into the central nervous system. Due to their expression of CX3CR1, CD16 positive, activated monocytes are the preferential targets for such attraction. These CD16 positive monocytes are the main reservoir of monocyte/macrophage-harbored virus and are thus likely to be the predominant cell type carrying HIV into the brain. (2) Infiltrated HIV-infected monocytes locally produce HIV and inflammatory mediators in perivascular areas. This activates neighbouring astrocytes as well as the blood brain barrier (BBB) endothelium. (3) In response, endothelial cells up-regulate adhesion molecules, enhancing monocyte recruitment. However, membrane-bound Fkn is also induced on endothelial cells and can arrest CD16 positive monocytes at the endothelium thus inhibiting their further infiltration. (4) CCL2 is overexpressed by infected, HIV-stimulated macrophages and activated astrocytes, attracting CD16 negative, CCR2 positive monocytes toward the perivascular area. (5) Both CXCL12 and nerve growth factor (NGF) are overexpressed in the inflamed brain. NGF increases CXCR4 expression and promotes uninfected monocyte attraction by CXCL12. At the same time it limits entry of infected monocytes into the brain. (6) Activated uninfected perivascular macrophages may be targets for de novo infection by locally produced HIV, amplifying the activation - attraction - infection cycle. (7) Local inflammation as well as HIV products induce tight junction disorganization and lead to breaches in the BBB. Toxic serum proteins and free virions may enter the brain, favouring more infection and further amplifying inflammation.

Mentions: HIV enters the CNS very early after infection, and then maintains its presence in the brain throughout the individual's life. Interestingly, major alterations of the BBB occur only late in HIV-CNS disease and thus initial seeding likely reflects the hijacking of physiological mechanisms of BBB crossing, such as the Trojan horse strategy initially proposed by Narayan and colleagues [137,138]. A model of the multistep, multifactorial process of CNS invasion by HIV-1, is illustrated in figure 1. It has for years remained unclear whether the infected CNS constituted, after its initial seeding, a viral sanctuary independent of the periphery or just reflected infection features outside the brain. The introduction of HAART challenged our vision of the brain as an independent sanctuary of HIV infection because the lower incidence of HAD in treated patients, despite low brain penetration of the molecules, strongly suggested that HIV induced CNS disorders do require continuous immune activation in the brain and neuroinvasion of activated and/or infected leukocytes.


Molecular mechanisms of neuroinvasion by monocytes-macrophages in HIV-1 infection.

Gras G, Kaul M - Retrovirology (2010)

Mechanistic model of HIV-1 neuroinvasion. (1) The physiological expression of chemokines by brain cells, among which are soluble fractalkine (Fkn) and CXCL12, supports a slow but continuous entry of monocytes and macrophages into the central nervous system. Due to their expression of CX3CR1, CD16 positive, activated monocytes are the preferential targets for such attraction. These CD16 positive monocytes are the main reservoir of monocyte/macrophage-harbored virus and are thus likely to be the predominant cell type carrying HIV into the brain. (2) Infiltrated HIV-infected monocytes locally produce HIV and inflammatory mediators in perivascular areas. This activates neighbouring astrocytes as well as the blood brain barrier (BBB) endothelium. (3) In response, endothelial cells up-regulate adhesion molecules, enhancing monocyte recruitment. However, membrane-bound Fkn is also induced on endothelial cells and can arrest CD16 positive monocytes at the endothelium thus inhibiting their further infiltration. (4) CCL2 is overexpressed by infected, HIV-stimulated macrophages and activated astrocytes, attracting CD16 negative, CCR2 positive monocytes toward the perivascular area. (5) Both CXCL12 and nerve growth factor (NGF) are overexpressed in the inflamed brain. NGF increases CXCR4 expression and promotes uninfected monocyte attraction by CXCL12. At the same time it limits entry of infected monocytes into the brain. (6) Activated uninfected perivascular macrophages may be targets for de novo infection by locally produced HIV, amplifying the activation - attraction - infection cycle. (7) Local inflammation as well as HIV products induce tight junction disorganization and lead to breaches in the BBB. Toxic serum proteins and free virions may enter the brain, favouring more infection and further amplifying inflammation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2864195&req=5

Figure 1: Mechanistic model of HIV-1 neuroinvasion. (1) The physiological expression of chemokines by brain cells, among which are soluble fractalkine (Fkn) and CXCL12, supports a slow but continuous entry of monocytes and macrophages into the central nervous system. Due to their expression of CX3CR1, CD16 positive, activated monocytes are the preferential targets for such attraction. These CD16 positive monocytes are the main reservoir of monocyte/macrophage-harbored virus and are thus likely to be the predominant cell type carrying HIV into the brain. (2) Infiltrated HIV-infected monocytes locally produce HIV and inflammatory mediators in perivascular areas. This activates neighbouring astrocytes as well as the blood brain barrier (BBB) endothelium. (3) In response, endothelial cells up-regulate adhesion molecules, enhancing monocyte recruitment. However, membrane-bound Fkn is also induced on endothelial cells and can arrest CD16 positive monocytes at the endothelium thus inhibiting their further infiltration. (4) CCL2 is overexpressed by infected, HIV-stimulated macrophages and activated astrocytes, attracting CD16 negative, CCR2 positive monocytes toward the perivascular area. (5) Both CXCL12 and nerve growth factor (NGF) are overexpressed in the inflamed brain. NGF increases CXCR4 expression and promotes uninfected monocyte attraction by CXCL12. At the same time it limits entry of infected monocytes into the brain. (6) Activated uninfected perivascular macrophages may be targets for de novo infection by locally produced HIV, amplifying the activation - attraction - infection cycle. (7) Local inflammation as well as HIV products induce tight junction disorganization and lead to breaches in the BBB. Toxic serum proteins and free virions may enter the brain, favouring more infection and further amplifying inflammation.
Mentions: HIV enters the CNS very early after infection, and then maintains its presence in the brain throughout the individual's life. Interestingly, major alterations of the BBB occur only late in HIV-CNS disease and thus initial seeding likely reflects the hijacking of physiological mechanisms of BBB crossing, such as the Trojan horse strategy initially proposed by Narayan and colleagues [137,138]. A model of the multistep, multifactorial process of CNS invasion by HIV-1, is illustrated in figure 1. It has for years remained unclear whether the infected CNS constituted, after its initial seeding, a viral sanctuary independent of the periphery or just reflected infection features outside the brain. The introduction of HAART challenged our vision of the brain as an independent sanctuary of HIV infection because the lower incidence of HAD in treated patients, despite low brain penetration of the molecules, strongly suggested that HIV induced CNS disorders do require continuous immune activation in the brain and neuroinvasion of activated and/or infected leukocytes.

Bottom Line: The blood-brain-barrier plays a critical role in this never stopping neuroinvasion, although it appears unaltered until the late stage of HIV encephalitis.HIV flux that moves toward the brain thus relies on hijacking and exacerbating the physiological mechanisms that govern blood brain barrier crossing rather than barrier disruption.This review will summarize the recent data describing neuroinvasion by HIV with a focus on the molecular mechanisms involved.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Emerging Diseases and Innovative Therapies, Division of Immuno-Virology, CEA, 18 Route du Panorama, F92265 Fontenay-aux Roses, France. gabriel.gras@cea.fr

ABSTRACT
HIV associated neurocognitive disorders and their histopathological correlates largely depend on the continuous seeding of the central nervous system with immune activated leukocytes, mainly monocytes/macrophages from the periphery. The blood-brain-barrier plays a critical role in this never stopping neuroinvasion, although it appears unaltered until the late stage of HIV encephalitis. HIV flux that moves toward the brain thus relies on hijacking and exacerbating the physiological mechanisms that govern blood brain barrier crossing rather than barrier disruption. This review will summarize the recent data describing neuroinvasion by HIV with a focus on the molecular mechanisms involved.

Show MeSH
Related in: MedlinePlus