HIV‐1 Nef triggers Vav‐mediated signaling pathway leading to functional and morphological differentiation of dendritic cells

Quaranta, Maria Giovanna; Mattioli, Benedetta; Spadaro, Francesca; Straface, Elisabetta; Giordani, Luciana; Ramoni, Carlo; Malorni, Walter; Viora, Marina

doi:10.1096/fj.03-0272com

Cited by 68 publications

(63 citation statements)

References 65 publications

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“…16,17 It also activates the Rho GTPase exchange factor Vav in both T cells 18 and dendritic cells. 19 This is similar to the observations made on larger intracellular pathogens that utilize various mechanisms to breach the cortical actin barrier. For instance, Salmonella injects bacterial proteins such as SopE into host cells at the site of invasion.…”

Section: Actin Cytoskeleton and Hiv Infectionsupporting

confidence: 83%

Human immunodeficiency virus (HIV)-1 proteins and cytoskeleton: partners in viral life and host cell death

Matarrese

Malorni

2005

Cell Death Differ

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Cytoskeletal components play a major role in the human immunodeficiency virus-1 (HIV-1) infection. A wide variety of molecules belonging to the microfilament system, including actin filaments and actin binding proteins, as well as microtubules have a key role in regulating both cell life and death. Cell shape maintenance, cell polarity and cell movements as well as cytoplasmic trafficking of molecules determining cell fate, including apoptosis, are in fact instructed by the cytoskeleton components. HIV infection and viral particle production seem to be controlled by cytoskeleton as well. Furthermore, HIV-associated apoptosis failure can also be regulated by the actin network function. In fact, HIV protein gp120 is able to induce cytoskeleton-driven polarization, thus sensitizing T cells to CD95/Fas-mediated apoptosis. The microfilament system seems thus to be a sort of cytoplasmic supervisor of the viral particle, the host cell and the bystander cell's very fate. Cell Death and Differentiation (2005) 12, 932-941.

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Section: Actin Cytoskeleton and Hiv Infectionsupporting

confidence: 83%

Human immunodeficiency virus (HIV)-1 proteins and cytoskeleton: partners in viral life and host cell death

Matarrese

Malorni

2005

Cell Death Differ

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“…It was shown that soluble Nef enters MF or dendritic cells and accumulates in perinuclear regions (41,42) through endocytosis, pinocytosis, or as-yet-unknown mechanisms (26). Of importance, we found that FITC-labeled Nef entered M2-MF more rapidly than it entered M1-MF (Fig.…”

Section: Rapid Uptake Of Nef By M2-mfmentioning

confidence: 64%

HIV-1 Proteins Preferentially Activate Anti-Inflammatory M2-Type Macrophages

Chihara

Hashimoto

Osman

et al. 2012

The Journal of Immunology

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HIV-1 proteins, including Tat, gp120, and Nef, activate macrophages (MΦ), which is consistent with the fact that HIV-1 infection is characterized by sustained immune activation. Meanwhile, MΦ are functionally classified into two types: proinflammatory M1-MΦ and anti-inflammatory M2-MΦ. We show that HIV-1 proteins, particularly Nef, preferentially activate M2-MΦ. Extracellular Tat, gp120, and Nef activated MAPK and NF-κB pathways in human peripheral blood monocyte-derived MΦ. However, the activation was marked in M-CSF–derived M2-MΦ but not GM-CSF–derived M1-MΦ. Nef was the most potent activator, and its signaling activation was comparable to that by TNF-α. Indeed, Nef was internalized more rapidly by M2-MΦ than by M1-MΦ. The myristoylation and proline-rich motif of Nef were responsible for the observed signaling activation. Consistent with the activation of MAPK/NF-κB pathways, Nef stimulated the production of a number of proinflammatory cytokines/chemokines by M2-MΦ. However, Nef reduced the expression of CD163 and phagocytosis, the characteristic markers of M2-MΦ, indicating that Nef drives an M2-like to M1-like phenotypic shift. Because the differentiation of most tissue MΦ depends on M-CSF and its receptor, which is the essential axis for the anti-inflammatory M2-MΦ phenotype, the current study reveals an efficient mechanism by which HIV-1 proteins, such as Nef, induce the proinflammatory MΦ.

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“…196,197 Also, through targeting of Vav and Rac1 signaling, recombinant Nef stimulates maturation of immature human DC and increased clustering with and activation of CD4+ T cells, which has been hypothesized to increase viral transmission. 198,199 On the other hand, in a murine DC line stably expressing Nef, the Nef-PAK2 connection was found to inhibit DC maturation and antigen presentation, which may impair development of antiviral immunity in vivo. 200 Clearly, although the molecular players are diverse and may depend on particular cell types, maturation stages or circumstances, HIV manipulates Rho GTPase signaling in DC in several ways to increase virus transmission to its primary target cell, the CD4+ T lymphocyte and to avoid the development of a potent antiviral immune response.…”

Section: Dendritic Cellsmentioning

confidence: 99%

Rho’ing in and out of cells

2014

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These authors contributed equally to this work Keywords: Rho GTPase, actin, egress, entry, gene expression, immune system, transformation, virus Rho GTPases are key regulators of actin and microtubule dynamics and organization. increasing evidence shows that many viruses have evolved diverse interactions with Rho GTPase signaling and manipulate them for their own benefit. in this review, we discuss how Rho GTPase signaling interferes with many steps in the viral replication cycle, especially entry, replication, and spread. Seen the diversity between viruses, it is not surprising that there is considerable variability in viral interactions with Rho GTPase signaling. However, several largely common effects on Rho GTPases and actin architecture and microtubule dynamics have been reported. For some of these processes, the molecular signaling and biological consequences are well documented while for others we just begin to understand them. A better knowledge and identification of common threads in the different viral interactions with Rho GTPase signaling and their ultimate consequences for virus and host may pave the way toward the development of new antiviral drugs that may target different viruses.©2014 Landes Bioscience. Do not distribute. e28318-2Small GTPases volume 5effector of ROCK, which phosphorylates and inhibits cofilin.14 Cofilin is an F-actin-severing protein. Mainly depending on the local availability of G-actin monomers, cofilin activity may lead to net actin depolymerization or increased actin polymerization and branching. Other RhoA effectors include members of the ezrin/radixin/moesin (ERM) proteins 15 . Rac1 is thought to release WAVE from an inhibited complex, thereby activating the actin-polymerizing complex Arp2/3. 16,17 Active Arp2/3 mediates branching and elongation of existing actin filaments, generating a meshwork. Cdc42 also activates Arp2/3 through a direct interaction with the Arp2/3 activators Wiskott-Aldrich syndrome protein (WASP) or N-WASP.18 Both Rac1 and Cdc42 also activate group I serine/threonine p21 activating kinases (PAK). These different signalization branches are interconnected. In general, RhoA pathway signaling counteracts the Rac1 and Cdc42 signaling axes and vice versa.Because Rho GTPase signaling is involved in a plethora of cellular processes, it is perhaps not surprising that several viral gene products have evolved to interfere with and modulate these signaling axes. Indeed, several viruses interfere with the actin cytoskeleton and Rho GTPase signaling during many steps of their replication cycle. During entry and egress, these interactions may allow or facilitate viral particle passage across the cortical actin barrier and to rearrange actin to conformations that promote virus infection and spread, while other viral processes, such as intracellular movement, gene expression and latency, but also interaction with the immune system or oncogenesis may also depend to some extent on Rho GTPase signaling and associated actin rearrangements. In this review, the current kno...

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HIV‐1 Nef triggers Vav‐mediated signaling pathway leading to functional and morphological differentiation of dendritic cells

Cited by 68 publications

References 65 publications

Human immunodeficiency virus (HIV)-1 proteins and cytoskeleton: partners in viral life and host cell death

Human immunodeficiency virus (HIV)-1 proteins and cytoskeleton: partners in viral life and host cell death

HIV-1 Proteins Preferentially Activate Anti-Inflammatory M2-Type Macrophages

Rho’ing in and out of cells

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