Importance of the nef gene for maintenance of high virus loads and for development of AIDS

Kestier, Harry W.; Ringler, Douglas J.; Mori, Kazuyasu; Panicali, Dennis; Sehgal, Prabhat K.; Daniel, Muthiah D.; Desrosiers, Ronald C.

doi:10.1016/0092-8674(91)90097-i

Cited by 1,530 publications

(1,116 citation statements)

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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: 78%

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

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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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confidence: 78%

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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“…Consistent with this Nef-enhanced virion infectivity in vitro, Nef has been shown to be essential for efficient viral replication in SCID-Hu mice in vivo [19]. Furthermore, Nef from a macaque strain of SIV, SIVmac239, is required for efficient virus replication and for induction of immunosuppressive disorders in rhesus monkeys [20]. Apart from its functional role in virus replication, several biologically important activities of HIV-1 Nef, such as the down-modulation of CD4 expression, have been documented [21].…”

Section: Introductionmentioning

confidence: 83%

Human immunodeficiency virus type 1 Nef protein on the cell surface is cytocidal for human CD4+ T cells

et al. 1996

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“…In vivo, Nef is at an m.o.i, of approximately 1.0 per cell and were cultured for 4 days. required for efficient virus replication and for induction of After culture, the cells were harvested and washed with PBS three times, and resuspended in 300 gl of lysis buffer (0.05% NP-40, immunosuppressive disorders in rhesus monkeys [8]. Nef pro-150 mM NaCI, 0.1 mM PMSF in 100 mM Tris-HCl), and then intein is necessary for efficient viral replication also in SCID-Hu cubated on ice for 10 min.…”

Section: Immunopreeipitation Analysis Of Nefproteinmentioning

confidence: 99%

Clustered localization of oligomeric Nef protein of human immunodeficiency virus type 1 on the cell surface

et al. 1996

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One report has shown that Nef molecules expressed by Abstract We studied human immunodeficieney virus type 1 (HIV-1) Nef protein biochemically and histologically. HIV-1 bacterial and eukaryotic systems form oligomers [11], but Nef, derived from baculosystem and from cells infected with there is no information about the oligomerization of Nef in HIV-I, formed homomeric monomers, dimers, trimers, and HIV-l-infected T cells. To clarify the mechanism of Nef-defurther polymers. These oligomers were non-covalently assopendent cell killing, we studied the biochemical and histologiciated. In cells infected with HIV-1, Nefmolecules were clustered cal properties of Nef. In this report we show that the Nef at the cell surface as well as cytoplasm. Our previous results have molecules form oligomers and cluster on the surface of indicated that the Nef on the surface of cells infected with HIV-1 HIV-1-infected CD4+ cells. is cytotoxic against uninfected CD4+ T cells. Thus, it is very likely that the HIV-l-medlated cytotoxic reaction is due, at least in part, to the clustered localization of oligomeric Nef on the cell 2. Materials and methods surface. Cells and antibodies

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Importance of the nef gene for maintenance of high virus loads and for development of AIDS

Cited by 1,530 publications

References 41 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

Human immunodeficiency virus type 1 Nef protein on the cell surface is cytocidal for human CD4+ T cells

Clustered localization of oligomeric Nef protein of human immunodeficiency virus type 1 on the cell surface

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