Interactions of HIV-1 NEF with cellular signal transducing proteins

G., Herma Renkema

doi:10.2741/renkema

Cited by 146 publications

(98 citation statements)

References 159 publications

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“…In part, this discrepancy may result from the use of different types of APCs: Raji B cells in the previous study (11) compared with primary DCs and macrophages in the present study. Although HIV-1 Nefs do not affect synapse formation, they certainly deregulate the communication between virally infected T cells and APCs by changing TCR-induced actin dynamics (13,14) and by modulating downstream TCR signaling pathways (54,55). Notably, we confirmed the previous finding (11) that HIV-1 Nef expression increased Lck accumulation in intracellular compartments ( Figure 3).…”

Section: Discussionsupporting

confidence: 81%

The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses

Arhel

Lehmann

Clauß³

et al. 2009

J. Clin. Invest.

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Section: Discussionsupporting

confidence: 81%

The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses

Arhel

Lehmann

Clauß³

et al. 2009

J. Clin. Invest.

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“…Nef could directly activate the CD4 ϩ T cells in which it is expressed. It has been shown that Nef expression can activate the proximal TCR machinery (25,51), allowing hyperphosphorylation of effectors such as LAT (23), which has been implicated in T-cell activation (71). On the other hand, the expansion of an activated Tg CD4 ϩ T-cell subset may represent a physiological response to the disease process.…”

Section: Discussionmentioning

confidence: 99%

CD4⁺T Cells from CD4C/HIV^NefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

Weng

Priceputu

Chrobák

et al. 2004

J Virol

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The cellular and molecular mechanisms of dysfunction and depletion of CD4 ؉ T lymphocytes over the course of human immunodeficiency virus type 1 (HIV-1) infection are still incompletely understood, but chronic immune activation is thought to play an important role in disease progression. We studied CD4 ؉ T-cell biology in CD4C/HIV transgenic (Tg) mice, in which Nef expression is sufficient to induce a severe AIDS-like disease including a preferential decrease of CD4 ؉ T cells. We show here that Nef-expressing Tg CD4 ؉ T cells exhibit an activated/memory-like phenotype which appears to be independent of antigenic stimulation, as documented in experiments involving breeding with AD10 TcR Tg mice. In addition, in vivo bromodeoxyuridine incorporation showed that a larger proportion of Tg than non-Tg CD4 ؉ T cells entered the S phase. However, in vitro, Tg CD4 ؉ T cells were found to have a very limited capacity to divide in response to stimulation with anti-CD3 and anti-CD28 or in allogeneic mixed leukocyte reactions. Interestingly, despite these observations, the deletion of Tg CD4 ؉ T cells had little impact on the development of other AIDS-like organ phenotypes. Thus, the Nef-induced chronic activation of CD4 ؉ T cells may exhaust the T-cell pool and may contribute to the thymic atrophy and the low number of CD4 ؉ T cells observed in these Tg mice.

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“…HIV-1-infected astrocytes remain mainly in a non-productive, chronically infected state, and express marginal viral structural proteins and high amounts of the HIV-1 Nef protein, suggesting a prominent role for Nef in the pathogenesis of HAD (Kohleisen et al, 1992;Kramer-Hammerle et al, 2005b;Ranki et al,HIV-1 Nef upregulates CCL2/MCP-1 expression Nef has been reported to interact with, and modulate, the activity of numerous molecules involved in intracellular signal transduction, including (1) members of the Src family of tyrosine kinases, (2) serine/threonine kinases, (3) phosphatidylinositol 3-kinase (PI 3-kinase), (4) guanine nucleotide exchange factor Vav, and (5) calmodulin (Greenway et al, 2003;Hayashi et al, 2002;Renkema and Saksela, 2000). Taken together, Nef is an excellent candidate for directing the expression of a soluble factor that attracts monocytes and/or T cells into the brain.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Nef upregulates CCL2/MCP-1 expression in astrocytes in a myristoylation- and calmodulin-dependent manner

Lehmann

Masanetz

Krämer

et al. 2006

Journal of Cell Science

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27 kDa accessory HIV and simian immunodeficiency virus (SIV) protein necessary for efficient virus replication and high viral load, has for several years been considered as a progression factor to AIDS (Greene and Peterlin, 2002). According to several excellent reviews, a variety of diverse functions including downregulation of cell-surface molecules have been assigned to the protein (Das and Jameel, 2005;Piguet and Trono, 1999;Roeth and Collins, 2006). Moreover, HIV-associated dementia (HAD) correlates with infiltration of monocytes into the brain. The accessory HIV-1 negative factor (Nef) protein, which modulates several signaling pathways, is constitutively present in persistently infected astroctyes. We demonstrated that monocytes responded with chemotaxis when subjected to cell culture supernatants of nef-expressing astrocytic U251MG cells. Using a protein array, we identified CC chemokine ligand 2/monocyte chemotactic protein-1 (CCL2/MCP-1) as a potential chemotactic factor mediating this phenomenon. CCL2/MCP-1 upregulation by Nef was further confirmed by ribonuclease protection assay, RT-PCR and ELISA. By applying neutralizing antibodies against CCL2/MCP-1 and using CCR2-deficient monocytes, we confirmed CCL2/MCP-1 as the exclusive factor secreted by nefexpressing astrocytes capable of attracting monocytes. Additionally, we showed that Nef-induced CCL2/MCP-1 expression depends on the myristoylation moiety of Nef and requires functional calmodulin. In summary, we suggest that Nef-induced CCL2/MCP-1 expression in astrocytes contributes to infiltration of monocytes into the brain, and thereby to progression of HAD.

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Interactions of HIV-1 NEF with cellular signal transducing proteins

Cited by 146 publications

References 159 publications

The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses

The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses

CD4⁺T Cells from CD4C/HIV^NefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

HIV-1 Nef upregulates CCL2/MCP-1 expression in astrocytes in a myristoylation- and calmodulin-dependent manner

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Interactions of HIV-1 NEF with cellular signal transducing proteins

Cited by 146 publications

References 159 publications

The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses

The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses

CD4+T Cells from CD4C/HIVNefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

HIV-1 Nef upregulates CCL2/MCP-1 expression in astrocytes in a myristoylation- and calmodulin-dependent manner

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Product

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CD4⁺T Cells from CD4C/HIV^NefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease