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Macrophage signaling in HIV-1 infection.

Herbein G, Gras G, Khan KA, Abbas W - Retrovirology (2010)

Bottom Line: Furthermore HIV-1 proteins, e.g., gp120, may exert their effects by interacting with cell surface membrane receptors, especially chemokine co-receptors.By activating the signaling pathways such as NF-kappaB, MAP kinase (MAPK) and JAK/STAT, HIV-1 proteins promote viral replication by stimulating transcription from the long terminal repeat (LTR) in infected macrophages; they are also involved in macrophage-mediated bystander T cell apoptosis.The role of HIV-1 proteins in the modulation of macrophage signaling will be discussed in regard to the formation of viral reservoirs and macrophage-mediated T cell apoptosis during HIV-1 infection.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Virology, UPRES 4266 Pathogens and Inflammation, IFR 133 INSERM, University of Franche-Comté, CHU Besançon, F-25030 Besançon, France. georges.herbein@univ-fcomte.fr

ABSTRACT
The human immunodeficiency virus-1 (HIV-1) is a member of the lentivirus genus. The virus does not rely exclusively on the host cell machinery, but also on viral proteins that act as molecular switches during the viral life cycle which play significant functions in viral pathogenesis, notably by modulating cell signaling. The role of HIV-1 proteins (Nef, Tat, Vpr, and gp120) in modulating macrophage signaling has been recently unveiled. Accessory, regulatory, and structural HIV-1 proteins interact with signaling pathways in infected macrophages. In addition, exogenous Nef, Tat, Vpr, and gp120 proteins have been detected in the serum of HIV-1 infected patients. Possibly, these proteins are released by infected/apoptotic cells. Exogenous accessory regulatory HIV-1 proteins are able to enter macrophages and modulate cellular machineries including those that affect viral transcription. Furthermore HIV-1 proteins, e.g., gp120, may exert their effects by interacting with cell surface membrane receptors, especially chemokine co-receptors. By activating the signaling pathways such as NF-kappaB, MAP kinase (MAPK) and JAK/STAT, HIV-1 proteins promote viral replication by stimulating transcription from the long terminal repeat (LTR) in infected macrophages; they are also involved in macrophage-mediated bystander T cell apoptosis. The role of HIV-1 proteins in the modulation of macrophage signaling will be discussed in regard to the formation of viral reservoirs and macrophage-mediated T cell apoptosis during HIV-1 infection.

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A model of HIV-1 pathogenesis based on interactions between macrophages and T cells which account for increased immune suppression and cellular virion reservoirs. a) Viral glycoprotein gp120 activates the production of pro-inflammatory cytokines and chemokines by macrophages, attracting T cells in the vicinity of macrophages, thereby increasing the number of infected cells and fueling the viral reservoirs. HIV-1 proteins Nef, Tat, and Vpr activate the long terminal repeat (LTR) of HIV-1, resulting in sustained viral growth while also activating anti-apoptotic pathways that favor viral persistence and formation of viral reservoir. b) Viral protein Tat participates in CD4+ T cell death through TRAIL secretion by HIV-1 infected macrophages. Viral gp120 glycoproteins increase the expression of TNF and TNFR on macrophages and T cells, leading to CD8+ T cell apoptosis. Thus, macrophage signaling using viral proteins accounts for both viral persistence and immune suppression during HIV-1 infection.
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Figure 2: A model of HIV-1 pathogenesis based on interactions between macrophages and T cells which account for increased immune suppression and cellular virion reservoirs. a) Viral glycoprotein gp120 activates the production of pro-inflammatory cytokines and chemokines by macrophages, attracting T cells in the vicinity of macrophages, thereby increasing the number of infected cells and fueling the viral reservoirs. HIV-1 proteins Nef, Tat, and Vpr activate the long terminal repeat (LTR) of HIV-1, resulting in sustained viral growth while also activating anti-apoptotic pathways that favor viral persistence and formation of viral reservoir. b) Viral protein Tat participates in CD4+ T cell death through TRAIL secretion by HIV-1 infected macrophages. Viral gp120 glycoproteins increase the expression of TNF and TNFR on macrophages and T cells, leading to CD8+ T cell apoptosis. Thus, macrophage signaling using viral proteins accounts for both viral persistence and immune suppression during HIV-1 infection.

Mentions: In macrophages, Nef has been shown to activate multiple cellular pathways, possibly leading to increased infection of adjacent T cells through bystander mechanisms involving T cell activation (Figure 2). It has been shown that Nef-expressing macrophages enhance resting CD4+ T cell permissiveness through a complex cellular and soluble interaction involving macrophages, B cells, and CD4+ T cells [29]. Nef expression within macrophages via adenoviral vectors has been shown to induce the secretion of soluble CD23 and ICAM, resulting in up-regulation of costimulatory B cell receptors, including CD22, CD54, CD58, and CD80. This leads to T cell activation upon interaction with B cells via these costimulatory receptors, thus enabling the generation of non-productive or productive reservoirs, depending on the interactions [29].


Macrophage signaling in HIV-1 infection.

Herbein G, Gras G, Khan KA, Abbas W - Retrovirology (2010)

A model of HIV-1 pathogenesis based on interactions between macrophages and T cells which account for increased immune suppression and cellular virion reservoirs. a) Viral glycoprotein gp120 activates the production of pro-inflammatory cytokines and chemokines by macrophages, attracting T cells in the vicinity of macrophages, thereby increasing the number of infected cells and fueling the viral reservoirs. HIV-1 proteins Nef, Tat, and Vpr activate the long terminal repeat (LTR) of HIV-1, resulting in sustained viral growth while also activating anti-apoptotic pathways that favor viral persistence and formation of viral reservoir. b) Viral protein Tat participates in CD4+ T cell death through TRAIL secretion by HIV-1 infected macrophages. Viral gp120 glycoproteins increase the expression of TNF and TNFR on macrophages and T cells, leading to CD8+ T cell apoptosis. Thus, macrophage signaling using viral proteins accounts for both viral persistence and immune suppression during HIV-1 infection.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2865443&req=5

Figure 2: A model of HIV-1 pathogenesis based on interactions between macrophages and T cells which account for increased immune suppression and cellular virion reservoirs. a) Viral glycoprotein gp120 activates the production of pro-inflammatory cytokines and chemokines by macrophages, attracting T cells in the vicinity of macrophages, thereby increasing the number of infected cells and fueling the viral reservoirs. HIV-1 proteins Nef, Tat, and Vpr activate the long terminal repeat (LTR) of HIV-1, resulting in sustained viral growth while also activating anti-apoptotic pathways that favor viral persistence and formation of viral reservoir. b) Viral protein Tat participates in CD4+ T cell death through TRAIL secretion by HIV-1 infected macrophages. Viral gp120 glycoproteins increase the expression of TNF and TNFR on macrophages and T cells, leading to CD8+ T cell apoptosis. Thus, macrophage signaling using viral proteins accounts for both viral persistence and immune suppression during HIV-1 infection.
Mentions: In macrophages, Nef has been shown to activate multiple cellular pathways, possibly leading to increased infection of adjacent T cells through bystander mechanisms involving T cell activation (Figure 2). It has been shown that Nef-expressing macrophages enhance resting CD4+ T cell permissiveness through a complex cellular and soluble interaction involving macrophages, B cells, and CD4+ T cells [29]. Nef expression within macrophages via adenoviral vectors has been shown to induce the secretion of soluble CD23 and ICAM, resulting in up-regulation of costimulatory B cell receptors, including CD22, CD54, CD58, and CD80. This leads to T cell activation upon interaction with B cells via these costimulatory receptors, thus enabling the generation of non-productive or productive reservoirs, depending on the interactions [29].

Bottom Line: Furthermore HIV-1 proteins, e.g., gp120, may exert their effects by interacting with cell surface membrane receptors, especially chemokine co-receptors.By activating the signaling pathways such as NF-kappaB, MAP kinase (MAPK) and JAK/STAT, HIV-1 proteins promote viral replication by stimulating transcription from the long terminal repeat (LTR) in infected macrophages; they are also involved in macrophage-mediated bystander T cell apoptosis.The role of HIV-1 proteins in the modulation of macrophage signaling will be discussed in regard to the formation of viral reservoirs and macrophage-mediated T cell apoptosis during HIV-1 infection.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Virology, UPRES 4266 Pathogens and Inflammation, IFR 133 INSERM, University of Franche-Comté, CHU Besançon, F-25030 Besançon, France. georges.herbein@univ-fcomte.fr

ABSTRACT
The human immunodeficiency virus-1 (HIV-1) is a member of the lentivirus genus. The virus does not rely exclusively on the host cell machinery, but also on viral proteins that act as molecular switches during the viral life cycle which play significant functions in viral pathogenesis, notably by modulating cell signaling. The role of HIV-1 proteins (Nef, Tat, Vpr, and gp120) in modulating macrophage signaling has been recently unveiled. Accessory, regulatory, and structural HIV-1 proteins interact with signaling pathways in infected macrophages. In addition, exogenous Nef, Tat, Vpr, and gp120 proteins have been detected in the serum of HIV-1 infected patients. Possibly, these proteins are released by infected/apoptotic cells. Exogenous accessory regulatory HIV-1 proteins are able to enter macrophages and modulate cellular machineries including those that affect viral transcription. Furthermore HIV-1 proteins, e.g., gp120, may exert their effects by interacting with cell surface membrane receptors, especially chemokine co-receptors. By activating the signaling pathways such as NF-kappaB, MAP kinase (MAPK) and JAK/STAT, HIV-1 proteins promote viral replication by stimulating transcription from the long terminal repeat (LTR) in infected macrophages; they are also involved in macrophage-mediated bystander T cell apoptosis. The role of HIV-1 proteins in the modulation of macrophage signaling will be discussed in regard to the formation of viral reservoirs and macrophage-mediated T cell apoptosis during HIV-1 infection.

Show MeSH
Related in: MedlinePlus