Role of Nef in primate lentiviral immunopathogenesis

Kirchhoff, Frank; Schindler, Michael; Specht, Anke; Arhel, Nathalie J.; Münch, Jan

doi:10.1007/s00018-008-8094-2

Cited by 113 publications

(116 citation statements)

References 172 publications

(168 reference statements)

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“…detection and elimination by the host immune system. It has been previously shown that the accessory HIV-1 Nef protein, which is required for effective viral persistence and greatly accelerates progression to AIDS (32), induces CD95L expression on T cells (33). HIV-1 also infects macrophages and DCs.…”

Section: Cd95 Triggering In Combination With Cd3/28 Activation Inducementioning

confidence: 99%

CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling

Strauß¹,

Lindquist²,

Arhel³

et al. 2009

J Cell Biol

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Section: Cd95 Triggering In Combination With Cd3/28 Activation Inducementioning

confidence: 99%

CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling

Strauß¹,

Lindquist²,

Arhel³

et al. 2009

J Cell Biol

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“…16 Delineating the mechanisms of Nef action has been hampered by the multitude of interactions with host T-cell proteins suggested to modulate various intracellular transport and signaling pathways. 17,18 This includes modulating exposure of cell-surface receptors such as MHC-I and II, CD4, and chemokine receptors to evade immune recognition and to prevent superinfection of infected cells, respectively (reviewed in Laguette et al 12 ). In addition, Nef affects the basal states of T-cell activation and the responsiveness of T lymphocytes to TCR signaling.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-Golgi network–associated Lck signaling

Pan

Rudolph

Abraham

et al. 2012

Blood

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IntroductionReplication of HIV-1 in primary human T lymphocytes is tightly coupled to their activation state. Whereas HIV-1 undergoes early replication events in quiescent CD4 ϩ T lymphocytes, subsequent steps in the viral life cycle require cell activation. 1 T lymphocyte activation is primarily governed by signaling through the TCR complex after engagement in a tight contact with APCs; this is referred to as the immunological synapse (IS).TCR engagement by specific MHC-presented peptides launches highly dynamic and coordinated transport events that recruit specific factors to the IS and exclude others from it. This signal initiation triggers a broad cascade of downstream signaling that include dynamic F-actin remodeling at the IS, tyrosine phosphorylation, release of calcium flux, and activation of transcription. These events increase production of the T-cell survival cytokine IL-2 and are coordinated by the TCR proximal tyrosine kinase Lck, a master switch of TCR signaling. Immediately after TCR engagement, active Lck is recruited to the IS. 2-4 Whereas signal diversification and enhancement occur at the plasma membrane (PM), subsequent TCR signaling is compartmentalized and also occurs at intracellular membranes. An important intracellular arm of the TCR response is regulated by the N-Ras GTPase that is activated at Golgi membranes downstream of Lck. [5][6][7][8][9] T-cell activation is thought to be beneficial to HIV-1 because it allows transcriptional activation of latent provirus and progression of the life cycle. However, activation-induced cell death after TCR engagement runs the risk of limiting the lifespan of productively infected cells and thus the amount of viral progeny produced.Consequently, HIV-1 encodes gene products such as Nef to fine-tune the activation states of infected T lymphocytes. 10,11 Nef is a 25-to 34-kDa myristoylated accessory protein encoded by HIV-1, HIV-2, and SIV. Ex vivo, Nef enhances the single-round infectivity of virus particles and moderately accelerates virus spread over multiple rounds. 12 In vivo, Nef strongly boosts virus replication, particularly during primary infection, when the presence of Nef can elevate virus titers by more than 2 logs, and is critical for rapid disease progression. [13][14][15] This role of Nef as a pathogenicity factor is also revealed in transgenic mice, in which Nef expression induces AIDS-like depletion of CD4 ϩ T lymphocytes. 16 Delineating the mechanisms of Nef action has been hampered by the multitude of interactions with host T-cell proteins suggested to modulate various intracellular transport and signaling pathways. 17,18 This includes modulating exposure of cell-surface receptors such as MHC-I and II, CD4, and chemokine receptors to evade immune recognition and to prevent superinfection of infected cells, respectively (reviewed in Laguette et al 12 ). In addition, Nef affects the basal states of T-cell activation and the responsiveness of T lymphocytes to TCR signaling. [19][20][21][22] Initial studies with overexpression strategies ...

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“…Lymphotropic viruses also modulate the responsiveness of virally infected T cells to stimulation by interacting APCs in a manner that renders them more permissive for viral replication (12)(13)(14). HIV-1 and other primate lentiviruses manipulate the function of the IS and T cell activation mainly by means of the accessory multifunctional Nef protein, which also impairs MHC Ag presentation and enhances viral infectivity and replication (14)(15)(16). Most importantly, Nef is required for efficient viral replication in vivo and greatly accelerates disease progression in HIV-1-infected individuals (17,18).…”

Section: Introductionmentioning

confidence: 99%

“…HIV-2 or SIV nef alleles that downmodulate CD3 block the responsiveness of virally infected primary T cells to TCR-mediated activation, whereas those of HIV-1 and its simian precursors fail to suppress T cell activation and programmed cell death (30). Besides host factors, these differences in Nef function may explain why high levels of chronic immune activation, associated with accelerated T cell turnover rates and apoptosis, are a hallmark of pathogenic HIV-1 infection but are absent in natural nonpathogenic SIV infections (15,31).…”

Section: Introductionmentioning

confidence: 99%

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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Role of Nef in primate lentiviral immunopathogenesis

Cited by 113 publications

References 172 publications

CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling

CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling

HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-Golgi network–associated Lck signaling

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

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