The Nef Protein of Human Immunodeficiency Virus Establishes Superinfection Immunity by a Dual Strategy to Downregulate Cell-Surface CCR5 and CD4

Michel, Nico; Allespach, Ina; Venzke, Stephanie; Fackler, Oliver T.; Keppler, Oliver T.

doi:10.1016/j.cub.2005.02.058

Cited by 176 publications

(227 citation statements)

References 46 publications

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“…This scenario is consistent with a recent report on the Nef-mediated enhancement of TCR downstream effector functions, such as NF-B and NF-AT activation after stimulation with anti-CD3-coated latex beads (10). Moreover, the protein interaction surfaces of Nef required for full actin disruption activity also mediate the effects of Nef on cell surface receptors such as major histocompatibility class I and CCR5, as well as the ability of Nef to interfere with T-lymphocyte chemotaxis (15,32,53). Given the cardinal role of actin dynamics in vesicular transport and cell motility (45,54), the modulation of actin rearrangements mediated by N-Wasp might represent a general strategy of the HIV-1 pathogenicity factor Nef to optimize virus replication.…”

Section: Discussionsupporting

confidence: 91%

“…Expression Constructs-Most expression constructs for Nef.GFP fusion proteins and the bicistronic Nef expression vectors as well as the HIV-1 wild type and ⌬nef proviruses along with the vesicular stomatitis virus glycoprotein expression plasmid were described recently (32). The expression constructs for GFP fusion proteins for the ⌬12-39 and ⌬12-39/EDAA Nef variants were generated accordingly.…”

Section: Methodsmentioning

confidence: 99%

“…HIV-1 Production and Infection-Virus stocks were generated by co-transfection of proviral HIV plasmids into 293T cells as described (32). For infection of Jurkat cells, virus stocks were generated in the presence of the vesicular stomatitis virus G protein.…”

Section: Methodsmentioning

confidence: 99%

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The HIV-1 Pathogenicity Factor Nef Interferes with Maturation of Stimulatory T-lymphocyte Contacts by Modulation of N-Wasp Activity

Haller

Rauch

Michel

et al. 2006

Journal of Biological Chemistry

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148

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The Nef protein is a key determinant of human immunodeficiency virus (HIV) pathogenicity that, among other activities, sensitizes T-lymphocytes for optimal virus production. The initial events by which Nef modulates the T-cell receptor (TCR) cascade are poorly understood.TCRengagementtriggersactinrearrangementsthatcontrol receptor clustering for signal initiation and dynamic organization of signaling protein complexes to form an immunological synapse. Here we report that Nef potently interferes with cell spreading and formation of actin-rich circumferential rings in T-lymphocytes upon surface-supported TCR stimulation. These effects were conserved among Nef proteins from different lentiviruses and occurred in HIV-1-infected primary human T-lymphocytes. This novel Nef activity critically depended on its Src homology 3 domain binding motif and required efficient association with Pak2 activity. Notably, whereas overall signaling microcluster formation immediately following TCR engagement occurred normally in Nef-expressing cells, the viral protein inhibited the concomitant activation of the actin organizer N-Wasp. During the subsequent maturation phase of the stimulatory contact, Nef interfered with the translocation of N-Wasp to the cell periphery, the overall induction of tyrosine phosphorylation, and the selective recruitment of phosphorylated LAT to stimulatory contacts. Consistent with such a critical role of N-Wasp in this process, Nef also blocked morphological changes induced by the known N-Wasp regulators Rac1 and Cdc42. Together, our results demonstrate that Nef alters both the amount and composition of signaling microclusters. We propose modulation of actin dynamics as an important mechanism for Nef-induced alterations of TCR signaling.The Nef protein of the primate lentiviruses HIV-1/-2 2 and simian immunodeficiency virus is a crucial pathogenicity factor and substantially increases virus replication in vivo (1-4). Whereas the underlying molecular mechanisms remain to be fully elucidated, Nef facilitates immune evasion of infected cells and directly boosts virus spread. These effector functions probably reflect the ability of Nef to serve as a protein-interaction adaptor that modulates cellular vesicle transport and signal transduction machineries (5, 6). In CD4 ϩ T-lymphocytes, one of the major HIV-1 target cell populations in vivo, Nef lowers the threshold of TCR activation possibly to induce an intermediate activation state that is permissive for HIV-1 replication (7-12). Several protein assemblies, including the association with the Nef-associated kinase complex, the guanine exchange factors Vav and DOCK2-ELMO1, and the TCR chain, are involved in the modulation of TCR signaling by Nef (13-16). However, it has not been addressed how Nef affects early events of TCR signal initiation. Physiologically, TCR triggering occurs in the context of a close contact between a T-cell and antigenpresenting cell referred to as the immunological synapse (IS). Within this highly dynamic structure, spatial redistribut...

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The HIV-1 Pathogenicity Factor Nef Interferes with Maturation of Stimulatory T-lymphocyte Contacts by Modulation of N-Wasp Activity

Haller

Rauch

Michel

et al. 2006

Journal of Biological Chemistry

Self Cite

148

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“…Furthermore, accumulation of proteins such as MHC class I in the ER (15) or ER stress induction by IL-1␤ or NO impairs oligodendrocyte repair (19). Several retroviral envelope proteins induce ER stress, together with suppressing the cognate viral receptor (20). For example, infection by murine leukemia virus (MuLV) down-modulates expression of its cell surface receptor, mCAT-1 (21).…”

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

The Human Endogenous Retrovirus Envelope Glycoprotein, Syncytin-1, Regulates Neuroinflammation and Its Receptor Expression in Multiple Sclerosis: A Role for Endoplasmic Reticulum Chaperones in Astrocytes

Antony

Ellestad

Hammond

et al. 2007

The Journal of Immunology

123

125

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Retroviral envelopes are pathogenic glycoproteins which cause neuroinflammation, neurodegeneration, and endoplasmic reticulum stress responses. The human endogenous retrovirus (HERV-W) envelope protein, Syncytin-1, is highly expressed in CNS glia of individuals with multiple sclerosis (MS). In this study, we investigated the mechanisms by which Syncytin-1 mediated neuroimmune activation and oligodendrocytes damage. In brain tissue from individuals with MS, ASCT1, a receptor for Syncytin-1 and a neutral amino acid transporter, was selectively suppressed in astrocytes (p < 0.05). Syncytin-1 induced the expression of the endoplasmic reticulum stress sensor, old astrocyte specifically induced substance (OASIS), in cultured astrocytes, similar to findings in MS brains. Overexpression of OASIS in astrocytes increased inducible NO synthase expression but concurrently down-regulated ASCT1 (p < 0.01). Treatment of astrocytes with a NO donor enhanced expression of early growth response 1, with an ensuing reduction in ASCT1 expression (p < 0.05). Small-interfering RNA molecules targeting Syncytin-1 selectively down-regulated its expression, preventing the suppression of ASCT1 and the release of oligodendrocyte cytotoxins by astrocytes. A Syncytin-1-transgenic mouse expressing Syncytin-1 under the glial fibrillary acidic protein promoter demonstrated neuroinflammation, ASCT1 suppression, and diminished levels of myelin proteins in the corpus callosum, consistent with observations in CNS tissues from MS patients together with neurobehavioral abnormalities compared with wild-type littermates (p < 0.05). Thus, Syncytin-1 initiated an OASIS-mediated suppression of ASCT1 in astrocytes through the induction of inducible NO synthase with ensuing oligodendrocyte injury. These studies provide new insights into the role of HERV-mediated neuroinflammation and its contribution to an autoimmune disease.

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“…There is some debate regarding the sequential infection, as once a cell is infected, HIV downregulates the CD4 and CCR5 receptor molecules (Michel et al, 2005), and therefore simultaneous infection may be the primary mechanism involved. Interestingly, a study by Dang et al (2004) showed that dual infections of cells occurs at a much higher rate than predicted by chance, in both a T cell line, and primary T cells, regardless of how the virus was transmitted.…”

Section: Heterozygous Virions and Their Formationmentioning

confidence: 99%

HIV Recombination and Pathogenesis – Biological and Epidemiological Implications

Saksena¹,

Lau²,

Dwyer³

et al. 2011

HIV and AIDS - Updates on Biology, Immunology, Epidemiology and Treatment Strategies

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The Nef Protein of Human Immunodeficiency Virus Establishes Superinfection Immunity by a Dual Strategy to Downregulate Cell-Surface CCR5 and CD4

Cited by 176 publications

References 46 publications

The HIV-1 Pathogenicity Factor Nef Interferes with Maturation of Stimulatory T-lymphocyte Contacts by Modulation of N-Wasp Activity

The HIV-1 Pathogenicity Factor Nef Interferes with Maturation of Stimulatory T-lymphocyte Contacts by Modulation of N-Wasp Activity

The Human Endogenous Retrovirus Envelope Glycoprotein, Syncytin-1, Regulates Neuroinflammation and Its Receptor Expression in Multiple Sclerosis: A Role for Endoplasmic Reticulum Chaperones in Astrocytes

HIV Recombination and Pathogenesis – Biological and Epidemiological Implications

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