Absence of Intact nef Sequences in a Long-Term Survivor with Nonprogressive HIV-1 Infection

Kirchhoff, Frank; Greenough, Thomas C.; Brettler, Doreen B.; Sullivan, John L.; Desrosiers, Ronald C.

doi:10.1056/nejm199501263320405

Cited by 951 publications

(650 citation statements)

References 20 publications

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“…Ex vivo, Nef enhances the single-round infectivity of virus particles and moderately accelerates virus spread over multiple rounds (17). In vivo, Nef strongly boosts virus replication particularly during primary infection and is critical for rapid disease progression (18)(19)(20). This role of Nef as a pathogenicity factor is also revealed in transgenic mice in which Nef expression induces AIDS-like depletion of CD4 + T lymphocytes (21).…”

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confidence: 80%

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

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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.

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mentioning

confidence: 80%

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

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“…Nef, an HIV-1 accessory protein, is expressed abundantly in the early stages of the viral life cycle and plays a key role in the progression of infection toward AIDS in primates (13)(14)(15). Among Nef functions, its ability to affect cell surface protein trafficking, including CD4 or MHC I molecules, has been well characterized (16).…”

mentioning

confidence: 99%

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

Vérollet

Zhang

Cabec

et al. 2010

The Journal of Immunology

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Macrophages are a major target of HIV-1 infection. HIV-1–infected macrophages form multinucleated giant cells (MGCs) using poorly elucidated mechanisms. In this study, we show that MGC formation was reduced when human macrophages were infected with nef-deleted HIV-1. Moreover, expression of Nef, an HIV-1 protein required in several aspects of AIDS, was sufficient to trigger the formation of MGCs in RAW264.7 macrophages. Among Nef molecular determinants, myristoylation was dispensable, whereas the polyproline motif was instrumental for this phenomenon. Nef has been shown to activate hematopoietic cell kinase (Hck), a Src tyrosine kinase specifically expressed in phagocytes, through a well-described polyproline–SH3 interaction. Knockdown approaches showed that Hck is involved in Nef-induced MGC formation. Hck is expressed as two isoforms located in distinct subcellular compartments. Although both isoforms were activated by Nef, only p61Hck mediated the effect of Nef on macrophage fusion. This process was abolished in the presence of a p61Hck kinase-dead mutant or when p61Hck was redirected from the lysosome membrane to the cytosol. Finally, lysosomal proteins including vacuolar adenosine triphosphatase and proteases participated in Nef-induced giant macrophage formation. We conclude that Nef participates in HIV-1–induced MGC formation via a p61Hck- and lysosomal enzyme-dependent pathway. This work identifies for the first time actors of HIV-1–induced macrophage fusion, leading to the formation of MGCs commonly found in several organs of AIDS patients.

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“…Although the complete function of Nef remains enigmatic, Nef has been shown to enhance viral infectivity and replication in primary cells (4,5), induce down-regulation of CD4 (6, 7) and major histocompatibility complex class I surface expression (8), and alter the activation of T cells (3,9,10). Deletions and mutations in the nef gene have been associated with long-term survival in patients infected with HIV (11,12). Further, simian immunodeficiency virus-infected macaques initially infected with nef(Ϫ) simian immunodeficiency virus are protected from subsequent infection by pathogenic nef(ϩ) simian immunodeficiency virus (13).…”

mentioning

confidence: 99%

Interleukin 10 is induced by recombinant HIV-1 Nef protein involving the calcium/calmodulin-dependent phosphodiesterase signal transduction pathway

Brigino

Haraguchi

Koutsonikolis

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Absence of Intact nef Sequences in a Long-Term Survivor with Nonprogressive HIV-1 Infection

Cited by 951 publications

References 20 publications

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-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-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

Interleukin 10 is induced by recombinant HIV-1 Nef protein involving the calcium/calmodulin-dependent phosphodiesterase signal transduction pathway

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