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HIV-1 Infection of T Lymphocytes and Macrophages Affects Their Migration via Nef.

Vérollet C, Le Cabec V, Maridonneau-Parini I - Front Immunol (2015)

Bottom Line: The human immunodeficiency virus (HIV-1) disseminates in the body and is found in several organs and tissues.HIV-1-infected macrophages exhibit a reduced amoeboid migration but an enhanced mesenchymal migration, via the viral protein Nef.In conclusion, HIV infection of host target cells modifies their migration capacity; we infer that HIV-1 enhances virus spreading in confined environments by reducing T cells migration, and facilitates virus dissemination into different organs and tissues of the human body by enhancing macrophage mesenchymal migration.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR 5089, Institut de Pharmacologie et de Biologie Structurale (IPBS) , Toulouse , France ; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université Toulouse III - Paul Sabatier , Toulouse , France.

ABSTRACT
The human immunodeficiency virus (HIV-1) disseminates in the body and is found in several organs and tissues. Although HIV-1 mainly targets both CD4(+) T lymphocytes and macrophages, it has contrasting effects between these cell populations. HIV-1 infection namely reduces the viability of CD4(+) T cells, whereas infected macrophages are long-lived. In addition, the migration of T cells is reduced by the infection, whereas HIV-1 differentially modulates the migration modes of macrophages. In 2-dimensions (2D) assays, infected macrophages are less motile compared to the control counterparts. In 3D environments, macrophages use two migration modes that are dependent on the matrix architecture: amoeboid and mesenchymal migration. HIV-1-infected macrophages exhibit a reduced amoeboid migration but an enhanced mesenchymal migration, via the viral protein Nef. Indeed, the mesenchymal migration involves podosomes, and Nef stabilizes these cell structures through the activation of the tyrosine kinase Hck, which in turn phosphorylates the Wiskott-Aldrich syndrome protein (WASP). WASP is a key player in actin remodeling and cell migration. The reprogramed motility of infected macrophages observed in vitro correlates in vivo with enhanced macrophage infiltration in experimental tumors in Nef-transgenic mice compared to control mice. In conclusion, HIV infection of host target cells modifies their migration capacity; we infer that HIV-1 enhances virus spreading in confined environments by reducing T cells migration, and facilitates virus dissemination into different organs and tissues of the human body by enhancing macrophage mesenchymal migration.

No MeSH data available.


Related in: MedlinePlus

By targeting podosomes, HIV-1 Nef inhibits 2D migration and enhances the 3D mesenchymal migration mode of macrophages. HIV-1 infection of macrophages increases the size and stability of podosomes, compared to non-infected cells. The molecular mechanisms responsible for this process involve the interaction of the viral protein Nef with Hck, and WASP phosphorylation. Increase in podosome size correlates with (1) increase in cell adhesion and inhibition of 2D migration and (2) increase in matrix degradation, enhancement of 3D mesenchymal migration and thus macrophage infiltration in tissues.
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Figure 2: By targeting podosomes, HIV-1 Nef inhibits 2D migration and enhances the 3D mesenchymal migration mode of macrophages. HIV-1 infection of macrophages increases the size and stability of podosomes, compared to non-infected cells. The molecular mechanisms responsible for this process involve the interaction of the viral protein Nef with Hck, and WASP phosphorylation. Increase in podosome size correlates with (1) increase in cell adhesion and inhibition of 2D migration and (2) increase in matrix degradation, enhancement of 3D mesenchymal migration and thus macrophage infiltration in tissues.

Mentions: Podosomes are constitutively formed in few cell types, including macrophages, immature dendritic cells, and osteoclasts when adhering on stiff substrates. These structures are involved in cell adhesion, proteolytic degradation of the ECM, mechanosensing, and mesenchymal migration. They are not formed in cells that use the amoeboid migration, such as T lymphocytes (8, 20–27, 29). When macrophages are plated on coverslips, podosomes assemble at the ventral plasma membrane and are oriented perpendicularly to the substrate. They are constituted of an F-actin core surrounded by a ring of adhesion proteins, and concentrate most of the cellular F-actin. The organization of podosomes into super-structures called “podosome rosettes” is related to an increase in ECM degradation (45, 46) (Figure 1). In HIV-1-infected cells, podosomes become bigger, they assemble into podosome rosettes and the ECM degradation is enhanced, phenomena which are not observed in macrophages infected with Δnef HIV-1. In Nef-expressing macrophages, podosomes are more stable, their life span is doubled, and they degrade very actively the ECM, possibly as a result of their increased lifetime and their rosette organization. Interestingly, Nef accumulates in the podosome area, suggesting that it could interact with a podosome effector regulating the stability of these cell structures. In 3D environments, podosomes assemble at the tip of cell protrusions; they are called 3D podosomes (28). Interestingly, HIV-1-infected cells and Nef-expressing macrophages form more 3D podosomes than control cells (8). The regulation of podosomes by Nef can explain two aspects of the modified migration of macrophages by HIV-1 (Figure 2). First, podosomes that are adhesion cell structures are more stable and bigger, thus explaining the increased cell adhesion observed in HIV-1-infected macrophages (8). Actually, modifications in cell adhesion are known to result in altered 2D cell motility (47, 48). For example, the maturation of dendritic cells, which induces the dissolution of podosomes, allows these cells to undergo the transition from an adhesive to a highly migratory phenotype (49, 50). By contrast, increased cell adhesion by more stable podosomes should decrease 2D migration of HIV-1-infected macrophages. Second, 3D mesenchymal migration correlates with podosome stability and an increase in ECM proteolytic activity (45, 46), two parameters increased by HIV-1 infection (8). Therefore, by affecting podosomes, HIV-1 reduces the macrophage 2D migration and enhances 3D mesenchymal migration. This is the first pathogen known to target podosomes to control the migration of host cells.


HIV-1 Infection of T Lymphocytes and Macrophages Affects Their Migration via Nef.

Vérollet C, Le Cabec V, Maridonneau-Parini I - Front Immunol (2015)

By targeting podosomes, HIV-1 Nef inhibits 2D migration and enhances the 3D mesenchymal migration mode of macrophages. HIV-1 infection of macrophages increases the size and stability of podosomes, compared to non-infected cells. The molecular mechanisms responsible for this process involve the interaction of the viral protein Nef with Hck, and WASP phosphorylation. Increase in podosome size correlates with (1) increase in cell adhesion and inhibition of 2D migration and (2) increase in matrix degradation, enhancement of 3D mesenchymal migration and thus macrophage infiltration in tissues.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4594015&req=5

Figure 2: By targeting podosomes, HIV-1 Nef inhibits 2D migration and enhances the 3D mesenchymal migration mode of macrophages. HIV-1 infection of macrophages increases the size and stability of podosomes, compared to non-infected cells. The molecular mechanisms responsible for this process involve the interaction of the viral protein Nef with Hck, and WASP phosphorylation. Increase in podosome size correlates with (1) increase in cell adhesion and inhibition of 2D migration and (2) increase in matrix degradation, enhancement of 3D mesenchymal migration and thus macrophage infiltration in tissues.
Mentions: Podosomes are constitutively formed in few cell types, including macrophages, immature dendritic cells, and osteoclasts when adhering on stiff substrates. These structures are involved in cell adhesion, proteolytic degradation of the ECM, mechanosensing, and mesenchymal migration. They are not formed in cells that use the amoeboid migration, such as T lymphocytes (8, 20–27, 29). When macrophages are plated on coverslips, podosomes assemble at the ventral plasma membrane and are oriented perpendicularly to the substrate. They are constituted of an F-actin core surrounded by a ring of adhesion proteins, and concentrate most of the cellular F-actin. The organization of podosomes into super-structures called “podosome rosettes” is related to an increase in ECM degradation (45, 46) (Figure 1). In HIV-1-infected cells, podosomes become bigger, they assemble into podosome rosettes and the ECM degradation is enhanced, phenomena which are not observed in macrophages infected with Δnef HIV-1. In Nef-expressing macrophages, podosomes are more stable, their life span is doubled, and they degrade very actively the ECM, possibly as a result of their increased lifetime and their rosette organization. Interestingly, Nef accumulates in the podosome area, suggesting that it could interact with a podosome effector regulating the stability of these cell structures. In 3D environments, podosomes assemble at the tip of cell protrusions; they are called 3D podosomes (28). Interestingly, HIV-1-infected cells and Nef-expressing macrophages form more 3D podosomes than control cells (8). The regulation of podosomes by Nef can explain two aspects of the modified migration of macrophages by HIV-1 (Figure 2). First, podosomes that are adhesion cell structures are more stable and bigger, thus explaining the increased cell adhesion observed in HIV-1-infected macrophages (8). Actually, modifications in cell adhesion are known to result in altered 2D cell motility (47, 48). For example, the maturation of dendritic cells, which induces the dissolution of podosomes, allows these cells to undergo the transition from an adhesive to a highly migratory phenotype (49, 50). By contrast, increased cell adhesion by more stable podosomes should decrease 2D migration of HIV-1-infected macrophages. Second, 3D mesenchymal migration correlates with podosome stability and an increase in ECM proteolytic activity (45, 46), two parameters increased by HIV-1 infection (8). Therefore, by affecting podosomes, HIV-1 reduces the macrophage 2D migration and enhances 3D mesenchymal migration. This is the first pathogen known to target podosomes to control the migration of host cells.

Bottom Line: The human immunodeficiency virus (HIV-1) disseminates in the body and is found in several organs and tissues.HIV-1-infected macrophages exhibit a reduced amoeboid migration but an enhanced mesenchymal migration, via the viral protein Nef.In conclusion, HIV infection of host target cells modifies their migration capacity; we infer that HIV-1 enhances virus spreading in confined environments by reducing T cells migration, and facilitates virus dissemination into different organs and tissues of the human body by enhancing macrophage mesenchymal migration.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR 5089, Institut de Pharmacologie et de Biologie Structurale (IPBS) , Toulouse , France ; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université Toulouse III - Paul Sabatier , Toulouse , France.

ABSTRACT
The human immunodeficiency virus (HIV-1) disseminates in the body and is found in several organs and tissues. Although HIV-1 mainly targets both CD4(+) T lymphocytes and macrophages, it has contrasting effects between these cell populations. HIV-1 infection namely reduces the viability of CD4(+) T cells, whereas infected macrophages are long-lived. In addition, the migration of T cells is reduced by the infection, whereas HIV-1 differentially modulates the migration modes of macrophages. In 2-dimensions (2D) assays, infected macrophages are less motile compared to the control counterparts. In 3D environments, macrophages use two migration modes that are dependent on the matrix architecture: amoeboid and mesenchymal migration. HIV-1-infected macrophages exhibit a reduced amoeboid migration but an enhanced mesenchymal migration, via the viral protein Nef. Indeed, the mesenchymal migration involves podosomes, and Nef stabilizes these cell structures through the activation of the tyrosine kinase Hck, which in turn phosphorylates the Wiskott-Aldrich syndrome protein (WASP). WASP is a key player in actin remodeling and cell migration. The reprogramed motility of infected macrophages observed in vitro correlates in vivo with enhanced macrophage infiltration in experimental tumors in Nef-transgenic mice compared to control mice. In conclusion, HIV infection of host target cells modifies their migration capacity; we infer that HIV-1 enhances virus spreading in confined environments by reducing T cells migration, and facilitates virus dissemination into different organs and tissues of the human body by enhancing macrophage mesenchymal migration.

No MeSH data available.


Related in: MedlinePlus