Nef does not inhibit F-actin remodelling and HIV-1 cell–cell transmission at the T lymphocyte virological synapse

Haller, Claudia; Tibroni, Nadine; Rudolph, Jochen M.; Grosse, Robert; Fackler, Oliver T.

doi:10.1016/j.ejcb.2010.09.010

Cited by 25 publications

(25 citation statements)

References 56 publications

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“…TSPANs thus negatively regulate events during virus production that impact the quality but not the quantity of viral progeny and thus the efficiency of subsequent rounds of virus replication (104,109,110). In particular, given that Nef and Vpu have been demonstrated to promote cell-cell transmission under certain experimental conditions (111)(112)(113), it is tempting to speculate that these effects are achieved, at least in part, via the deregulation of TSPAN localization and function. Similar to such effects at the virological synapse affecting cell-to-cell spread, modified TSPAN surface exposure might affect cell-cell communication across the immunological synapse, a process potently disrupted by Nef (34-36, 38, 114).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Nef and Vpu Are Functionally Redundant Broad-Spectrum Modulators of Cell Surface Receptors, Including Tetraspanins

Haller

Müller

Fritz

et al. 2014

J Virol

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IMPORTANCEIn this paper, we define that HIV-1 Nef and Vpu display a surprising functional overlap and affect the cell surface exposure of a previously unexpected breadth of cellular receptors. Our analyses furthermore identify the tetraspanin protein family as a previously unrecognized target of Nef and Vpu activity. These findings have implications for the interpretation of effects detected for these accessory gene products on individual host cell receptors and illustrate the coevolution of Nef and Vpu function.

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Section: Discussionmentioning

confidence: 99%

HIV-1 Nef and Vpu Are Functionally Redundant Broad-Spectrum Modulators of Cell Surface Receptors, Including Tetraspanins

Haller

Müller

Fritz

et al. 2014

J Virol

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“…Somewhat surprisingly, given its ability to disrupt triggered actin remodeling, Nef did not affect early steps of the TEM process, including shear-resistant attachment, crawling on the endothelial surface, and formation of potentially invasive and chemokine-sensing filopodia. Nef thus distinguishes between host cell protrusions to achieve simultaneous inhibition of sheet-like actinrich protrusions, such as lamellipodia (25) and promotion of filopodia formation (8,10). Of note, Murooka et al recently described that HIV-1-infected T cells in lymph nodes of humanized mice display reduced motility and form long filopodia-like cell protrusions or nanotubes that facilitate virus transfer to neighboring cells in a manner dependent on the HIV glycoprotein Env (29).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

Stolp

Imle

Coelho

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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HIV-1 negative factor (Nef) elevates virus replication and contributes to immune evasion in vivo. As one of its established in vitro activities, Nef interferes with T-lymphocyte chemotaxis by reducing host cell actin dynamics. To explore Nef’s influence on in vivo recirculation of T lymphocytes, we assessed lymph-node homing of Nef-expressing primary murine lymphocytes and found a drastic impairment in homing to peripheral lymph nodes. Intravital imaging and 3D immunofluorescence reconstruction of lymph nodes revealed that Nef potently impaired T-lymphocyte extravasation through high endothelial venules and reduced subsequent parenchymal motility. Ex vivo analyses of transendothelial migration revealed that Nef disrupted T-lymphocyte polarization and interfered with diapedesis and migration in the narrow subendothelial space. Consistently, Nef specifically affected T-lymphocyte motility modes used in dense environments that pose high physical barriers to migration. Mechanistically, inhibition of lymph node homing, subendothelial migration and cell polarization, but not diapedesis, depended on Nef’s ability to inhibit host cell actin remodeling. Nef-mediated interference with in vivo recirculation of T lymphocytes may compromise T-cell help and thus represents an important mechanism for its function as a HIV pathogenicity factor.

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“…Nonetheless, Nef significantly enhances viral replication in primary CD4 + T cells and macrophages that have been exposed to HIV-1 prior to their stimulation with mitogens [32], [33], a function of Nef that is likely determined by enhancement of the initial infection with cell-free HIV-1 [34]. In this regard, a compound that can reduce viral infectivity would be a valuable chemical probe for revealing the underlying mechanism of this function of Nef.…”

Section: Introductionmentioning

confidence: 99%

The Identification of a Small Molecule Compound That Reduces HIV-1 Nef-Mediated Viral Infectivity Enhancement

et al. 2011

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Nef is a multifunctional HIV-1 protein that accelerates progression to AIDS, and enhances the infectivity of progeny viruses through a mechanism that is not yet understood. Here, we show that the small molecule compound 2c reduces Nef-mediated viral infectivity enhancement. When added to viral producer cells, 2c did not affect the efficiency of viral production itself. However, the infectivity of the viruses produced in the presence of 2c was significantly lower than that of control viruses. Importantly, an inhibitory effect was observed with Nef+ wild-type viruses, but not with viruses produced in the absence of Nef or in the presence of proline-rich PxxP motif-disrupted Nef, both of which displayed significantly reduced intrinsic infectivity. Meanwhile, the overexpression of the SH3 domain of the tyrosine kinase Hck, which binds to a PxxP motif in Nef, also reduced viral infectivity. Importantly, 2c inhibited Hck SH3-Nef binding, which was more marked when Nef was pre-incubated with 2c prior to its incubation with Hck, indicating that both Hck SH3 and 2c directly bind to Nef and that their binding sites overlap. These results imply that both 2c and the Hck SH3 domain inhibit the interaction of Nef with an unidentified host protein and thereby reduce Nef-mediated infectivity enhancement. The first inhibitory compound 2c is therefore a valuable chemical probe for revealing the underlying molecular mechanism by which Nef enhances the infectivity of HIV-1.

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Nef does not inhibit F-actin remodelling and HIV-1 cell–cell transmission at the T lymphocyte virological synapse

Cited by 25 publications

References 56 publications

HIV-1 Nef and Vpu Are Functionally Redundant Broad-Spectrum Modulators of Cell Surface Receptors, Including Tetraspanins

HIV-1 Nef and Vpu Are Functionally Redundant Broad-Spectrum Modulators of Cell Surface Receptors, Including Tetraspanins

HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

The Identification of a Small Molecule Compound That Reduces HIV-1 Nef-Mediated Viral Infectivity Enhancement

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