HIV-1 Nef: a multifaceted modulator of T cell receptor signaling

Abraham, Libin; Fackler, Oliver T.

doi:10.1186/1478-811x-10-39

Cited by 70 publications

(54 citation statements)

References 118 publications

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“…The precise mechanism by which Nef promotes TNT formation in MDMs in an M-Sec-dependent manner also remains to be determined. It has been demonstrated that Nef affects various aspects of host cell vesicular transport and cytoskeletal dynamics (41,42). Indeed, WT virusinfected MDMs, but not DNef virus-infected MDMs, exhibited protuberant shapes (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Potential Role of the Formation of Tunneling Nanotubes in HIV-1 Spread in Macrophages

Hashimoto

Bhuyan

Hiyoshi

et al. 2016

The Journal of Immunology

112

146

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Tunneling nanotubes (TNTs), the long membrane extensions connecting distant cells, have emerged as a novel form of cell-to-cell communication. However, it is not fully understood how and to what extent TNTs contribute to intercellular spread of pathogens including HIV-1. In this study, we show that HIV-1 promotes TNT formation per se via its protein Nef and a cellular protein M-Sec, which appears to mediate approximately half of viral spread among monocyte-derived macrophages (MDMs). A small compound that inhibits M-Sec–induced TNT formation reduced HIV-1 production by almost half in MDMs. Such inhibition was not observed with Nef-deficient mutant HIV-1 that fails to promote TNT formation and replicates less efficiently than the wild-type HIV-1 in MDMs. The TNT inhibitor–sensitive/Nef-promoting viral production was also observed in a T cell line ectopically expressing M-Sec, but not in another M-Sec− T cell line. Our results suggest the importance of TNTs in HIV-1 spread among MDMs and might answer the long-standing question how Nef promotes HIV-1 production in a cell type–specific manner.

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Section: Discussionmentioning

confidence: 99%

Potential Role of the Formation of Tunneling Nanotubes in HIV-1 Spread in Macrophages

Hashimoto

Bhuyan

Hiyoshi

et al. 2016

The Journal of Immunology

112

146

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“…This strategy allows Nef to optimize viral replication in CD4+ T lymphocytes and at the same time disturb efficient antiviral immunity. 192 Measles virus (MV), a single-stranded, negative-sense, enveloped RNA virus also interferes with actin remodeling in T-cells. CD3/CD28-induced activation of the PI3K/AKT kinase pathway and proliferation is impaired in T cells upon contact with the measles virus glycoprotein (gp) complex.…”

Section: Interactions With the Immune Systemmentioning

confidence: 99%

Rho’ing in and out of cells

2014

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These authors contributed equally to this work Keywords: Rho GTPase, actin, egress, entry, gene expression, immune system, transformation, virus Rho GTPases are key regulators of actin and microtubule dynamics and organization. increasing evidence shows that many viruses have evolved diverse interactions with Rho GTPase signaling and manipulate them for their own benefit. in this review, we discuss how Rho GTPase signaling interferes with many steps in the viral replication cycle, especially entry, replication, and spread. Seen the diversity between viruses, it is not surprising that there is considerable variability in viral interactions with Rho GTPase signaling. However, several largely common effects on Rho GTPases and actin architecture and microtubule dynamics have been reported. For some of these processes, the molecular signaling and biological consequences are well documented while for others we just begin to understand them. A better knowledge and identification of common threads in the different viral interactions with Rho GTPase signaling and their ultimate consequences for virus and host may pave the way toward the development of new antiviral drugs that may target different viruses.©2014 Landes Bioscience. Do not distribute. e28318-2Small GTPases volume 5effector of ROCK, which phosphorylates and inhibits cofilin.14 Cofilin is an F-actin-severing protein. Mainly depending on the local availability of G-actin monomers, cofilin activity may lead to net actin depolymerization or increased actin polymerization and branching. Other RhoA effectors include members of the ezrin/radixin/moesin (ERM) proteins 15 . Rac1 is thought to release WAVE from an inhibited complex, thereby activating the actin-polymerizing complex Arp2/3. 16,17 Active Arp2/3 mediates branching and elongation of existing actin filaments, generating a meshwork. Cdc42 also activates Arp2/3 through a direct interaction with the Arp2/3 activators Wiskott-Aldrich syndrome protein (WASP) or N-WASP.18 Both Rac1 and Cdc42 also activate group I serine/threonine p21 activating kinases (PAK). These different signalization branches are interconnected. In general, RhoA pathway signaling counteracts the Rac1 and Cdc42 signaling axes and vice versa.Because Rho GTPase signaling is involved in a plethora of cellular processes, it is perhaps not surprising that several viral gene products have evolved to interfere with and modulate these signaling axes. Indeed, several viruses interfere with the actin cytoskeleton and Rho GTPase signaling during many steps of their replication cycle. During entry and egress, these interactions may allow or facilitate viral particle passage across the cortical actin barrier and to rearrange actin to conformations that promote virus infection and spread, while other viral processes, such as intracellular movement, gene expression and latency, but also interaction with the immune system or oncogenesis may also depend to some extent on Rho GTPase signaling and associated actin rearrangements. In this review, the current kno...

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“…In particular, we hypothesized that HIV-1 Nef, an ϳ27-kDa accessory protein that enhances viral pathogenesis, may play an early role in determining HIV-1 control. Nef interacts with a number of host proteins and performs multiple functions (33), including downregulation of cell surface CD4 (34) and HLA class I (35), upregulation of HLA class II invariant chain (CD74) (36), enhancement of virion infectivity (37), stimulation of viral replication in peripheral blood mononuclear cells (PBMC) (38), and alteration of T cell receptor (TCR) signaling (39,40). Nef's relevance to pathogenesis is illustrated by the exceptionally slow disease progression exhibited by individuals infected with nef-deleted or nef-defective HIV-1 (41)(42)(43)(44).…”

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confidence: 99%

Impaired Nef Function Is Associated with Early Control of HIV-1 Viremia

Kuang

Anmole

et al. 2014

J Virol

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Host and viral factors influence the HIV-1 infection course. Reduced Nef function has been observed in HIV-1 controllers during the chronic phase, but the kinetics and mechanisms of Nef attenuation in such individuals remain unclear. We examined plasma RNA-derived Nef clones from 10 recently infected individuals who subsequently suppressed viremia to less than 2,000 RNA copies/ml within 1 year postinfection (acute controllers) and 50 recently infected individuals who did not control viremia (acute progressors). Nef clones from acute controllers displayed a lesser ability to downregulate CD4 and HLA class I from the cell surface and a reduced ability to enhance virion infectivity compared to those from acute progressors (all P < 0.01). HLA class I downregulation activity correlated inversely with days postinfection (Spearman's R ‫؍‬ ؊0.

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HIV-1 Nef: a multifaceted modulator of T cell receptor signaling

Cited by 70 publications

References 118 publications

Potential Role of the Formation of Tunneling Nanotubes in HIV-1 Spread in Macrophages

Potential Role of the Formation of Tunneling Nanotubes in HIV-1 Spread in Macrophages

Rho’ing in and out of cells

Impaired Nef Function Is Associated with Early Control of HIV-1 Viremia

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