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

Arhel, Nathalie J.; Lehmann, Martin; Clauß, Karen; Nienhaus, G. Ulrich; Piguet, Vincent; Kirchhoff, Frank

doi:10.1172/jci38994

Cited by 44 publications

(61 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…25,27,28,30 Erk signaling is also targeted by Nef via an independent mechanism involving the NAKC complex that elevates HIV-1 transcription and exosome release. 48 Conceivably, the induction of TGN-associated Lck-Ras-Erk signaling represents a prerequisite for these subsequent functional Nef-Erk interactions.…”

Section: Discussionmentioning

confidence: 99%

“…11,30 In sharp contradiction to such elevated T-cell activation, Nef severely impairs the formation and organization of IS structures between Nef-expressing T lymphocytes and APCs by reducing the frequency of IS formation, blocking F-actin polarization at cell-cell contacts, and inducing mislocalization of the TCR itself and its effector kinase, Lck. 23,[30][31][32][33][34] These morphological alterations at the IS were accompanied by interference with early TCR signaling, such as induction of tyrosine phosphorylation. [32][33][34] How HIV-1 Nef induces this paradox scenario of enhanced downstream TCR signaling on disruption of signal initiation is unclear.…”

Section: Introductionmentioning

confidence: 99%

“…34 These effects are readily observed in virally infected primary T lymphocytes, and Nef is sufficient to induce rerouting of Lck. 30,31,33,34 In the present study, we sought to determine whether, in addition to removing the kinase from the IS, rerouting of Lck by HIV-1 Nef is actively involved in shaping TCR signaling responses of infected T lymphocytes. …”

mentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

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 ...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

show abstract

“…In contrast, HIV-1 Nef severely impairs the formation and organization of IS structures between Nef-expressing T lymphocytes and APCs by reducing the frequency of IS formation, blocking Factin polarization at cell-cell contacts, and inducing mislocalization of the TCR itself as well as its effector kinase Lck (28,(35)(36)(37)(38)(39). These morphological alterations at the IS were accompanied by interference with early TCR signaling such as induction of tyrosine phosphorylation (36,37,39).…”

mentioning

confidence: 99%

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

Abraham

Bankhead

Pan

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

Signal initiation by engagement of the TCR triggers actin rearrangements, receptor clustering, and dynamic organization of signaling complexes to elicit and sustain downstream signaling. Nef, a pathogenicity factor of HIV, disrupts early TCR signaling in target T cells. To define the mechanism underlying this Nef-mediated signal disruption, we employed quantitative single-cell microscopy following surface-mediated TCR stimulation that allows for dynamic visualization of distinct signaling complexes as microclusters (MCs). Despite marked inhibition of actin remodeling and cell spreading, the induction of MCs containing TCR-CD3 or ZAP70 was not affected significantly by Nef. However, Nef potently inhibited the subsequent formation of MCs positive for the signaling adaptor Src homology-2 domain-containing leukocyte protein of 76 kDa (SLP-76) to reduce MC density in Nef-expressing and HIV-1–infected T cells. Further analyses suggested that Nef prevents formation of SLP-76 MCs at the level of the upstream adaptor protein, linker of activated T cells (LAT), that couples ZAP70 to SLP-76. Nef did not disrupt pre-existing MCs positive for LAT. However, the presence of the viral protein prevented de novo recruitment of active LAT into MCs due to retargeting of LAT to an intracellular compartment. These modulations in MC formation and composition depended on Nef’s ability to simultaneously disrupt both actin remodeling and subcellular localization of TCR-proximal machinery. Nef thus employs a dual mechanism to disturb early TCR signaling by limiting the communication between LAT and SLP-76 and preventing the dynamic formation of SLP-76–signaling MCs.

show abstract

“…HIV also modulates the expression of MHC class I and II [64,110], resulting in impaired CD8+ and CD4+ T cells response, respectively. It is also demonstrated that the immunological synapse between T cells and HIV infected mφ are not disrupted [111]; though, there is significant reduction in the expression of MHC and co-stimulatory molecules (CD80/86) [110,112]. Mycobacterium tuberculosis bacilli inhibit the fusion of phagosome and lysosome, and survives in the mφ.…”

Section: Macrophagesmentioning

confidence: 99%

HIV induced suppression of host immunity: relevance to <i>Mycobacterium tuberculosis</i> infections

Kumar¹,

Mitra²

2017

HIV & AIDS Review

View full text Add to dashboard Cite

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

Abstract: Viruses that infect T cells, including

Cited by 44 publications

References 67 publications

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

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

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

HIV induced suppression of host immunity: relevance to <i>Mycobacterium tuberculosis</i> infections

Contact Info

Product

Resources

About