Association of simian immunodeficiency virus Nef with the T-cell receptor (TCR) zeta chain leads to TCR down-modulation.

Bell, Ian M.; Ashman, Claire; Maughan, J; Hooker, Erika; Cook, Fiona C.; Reinhart, Todd A.

doi:10.1099/0022-1317-79-11-2717

Cited by 93 publications

(85 citation statements)

References 49 publications

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“…The observed disruption of interactions between infected T cells and APCs is concordant with the previously reported downmodulation of surface CD3 and CD28 by HIV-2 and SIV (27)(28)(29)(30). Still, although HIV-1 Nef does not reduce TCR-CD3 surface expression (27)(28)(29)(30) and is only poorly effective in downmodulating CD28 (20,21), a previous study suggested that it also impairs IS formation (11).…”

Section: Discussionsupporting

confidence: 78%

“…While it remains debatable whether HIV-1 Nefs reduce or enhance the responsiveness of virally infected T cells to stimulation, it is clear that the effects of most primate lentiviral Nef proteins on TCR signaling and potentially also on the formation of the IS are much more severe than those of HIV-1 Nef proteins, because they also downmodulate TCR-CD3 and are substantially more effective in removing CD28 from the cell surface (20,21,(27)(28)(29)(30). Notably, the ability of Nef to downmodulate TCR-CD3 was specifically lost in the primate lentiviral lineage that gave rise to HIV-1: SIVcpz, its direct precursor from chimpanzees and some closely related SIVs from Cercopithecus monkeys (30).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 78%

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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“…It was recently shown that HIV-1 and its simian ancestor, SIVcpz, have one distinctive characteristic that may contribute to pathogenesis. In contrast to the Nef proteins of other immunodeficiency viruses, HIV-1 and SIVcpz Nef proteins are unable to downregulate the T-cell receptor (TCR) from the surfaces of infected cells (1,22). Schindler and colleagues proposed that TCR downregulation protects the host from the impact of chronic immune activation (22), which is increasingly thought to play a major role in HIV-1 disease progression (7).…”

mentioning

confidence: 99%

Downregulation of the T-Cell Receptor by Human Immunodeficiency Virus Type 2 Nef Does Not Protect against Disease Progression

Feldmann

Leligdowicz

Jaye

et al. 2009

J Virol

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Chronic immune activation is thought to play a major role in human immunodeficiency virus (HIV) pathogenesis, but the relative contributions of multiple factors to immune activation are not known. One proposed mechanism to protect against immune activation is the ability of Nef proteins from some HIV and simian immunodeficiency virus strains to downregulate the T-cell receptor (TCR)-CD3 complex of the infected cell, thereby reducing the potential for deleterious activation. HIV type 1 (HIV-1) Nef has lost this property. In contrast to HIV-1, HIV-2 infection is characterized by a marked disparity in the disease course, with most individuals maintaining a normal life span. In this study, we examined the relationship between the ability of HIV-2 Nef proteins to downregulate the TCR and immune activation, comparing progressors and nonprogressors. Representative Nef variants were isolated from 28 HIV-2-infected individuals. We assessed their abilities to downregulate the TCR from the surfaces of CD4 T cells. In the same individuals, the activation of peripheral lymphocytes was evaluated by measurement of the expression levels of HLA-DR and CD38. We observed a striking correlation of the TCR downregulation efficiency of HIV-2 Nef variants with immune activation in individuals with a low viral load. This strongly suggests that Nef expression can influence the activation state of the immune systems of infected individuals. However, the efficiency of TCR downregulation by Nef was not reduced in progressing individuals, showing that TCR downregulation does not protect against progression in HIV-2 infection.

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“…Protein G-coupled agarose beads (Amersham Biosciences, 50 l) were then added, and the pellets were washed three times with the KEB buffer and once with kinase activation buffer (1% Triton, 100 mM NaCl, 50 mM Tris-HCl, pH 8.0, 5 mM MgCl 2 , and 2 mM sodium orthovanadate). The IVKA reaction were performed in 50 l containing 10 Ci of [␥- 32 P]ATP for 5 min at room temperature, and the pellets were washed once with KEB and resuspended in 2ϫ SDS-loading buffer. The samples were separated by SDS-PAGE, and phosphorylated proteins were visualized by autoradiography.…”

Section: Transgene Construction and Generation Of Tg Mice-the Nefmentioning

confidence: 99%

Activation of p21-activated Kinase 2 and Its Association with Nef Are Conserved in Murine Cells but Are Not Sufficient to Induce an AIDS-like Disease in CD4C/HIV Transgenic Mice

Vincent

Priceputu

Kay

et al. 2006

Journal of Biological Chemistry

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A well conserved feature of human immunodeficiency virus, type 1 (HIV-1) and simian immunodeficiency virus (SIV) Nef is the interaction with and activation of the human p21-activated kinase 2 (PAK2). The conservation of this interaction in other species and its significance for Nef pathogenesis in vivo are poorly documented. In the present study, we measured these parameters in Nef-expressing thymocytes, macrophages, and dendritic cells of a transgenic (Tg) mouse model of AIDS (CD4C/HIV). We found that Nef binds to and activates PAK2, but not PAK1 and -3, in these three cell subsets. Nef associates with only a small fraction of PAK2. The Nef-PAK2 complex also comprises ␤-PIX-COOL. The impact of the Nef-PAK2 association on disease development was also analyzed in Tg mice expressing 10 different Nef mutant alleles. CD4C/HIV Tg mice expressing Nef alleles defective in Nef-PAK2 association (P69A, P72A/P75A, R105A/R106A, ⌬56 -66, or G2A (myristoylation site)) failed to develop disease of the non-lymphoid organs (kidneys and lungs). Among these, only Tg mice expressing Nef P69A and Nef G2Ashowed some depletion of CD4 ؉ T cells, although a down-regulation of the CD4 surface protein was documented in all these Tg lines, except those expressing Nef ⌬56 -66 . Among other Tg mice expressing Nef mutants having conserved the Nef-PAK2 association (RD35AA, D174K, P147A/P150A, ⌬8 -17, and ⌬25-65), only Tg mice expressing Nef ⌬8 -17 develop kidney and lung diseases, but all showed partial CD4 ؉ T cell depletion despite some being defective for CD4 down-regulation (RD35AA and D174K). Therefore, Nef can activate murine PAK2 and associate with a small fraction of it, as in human cells. Such activation and binding of PAK2 is clearly not sufficient but may be required to induce a multiorgan AIDS-like disease in Tg mice.

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Association of simian immunodeficiency virus Nef with the T-cell receptor (TCR) zeta chain leads to TCR down-modulation.

Cited by 93 publications

References 49 publications

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

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

Downregulation of the T-Cell Receptor by Human Immunodeficiency Virus Type 2 Nef Does Not Protect against Disease Progression

Activation of p21-activated Kinase 2 and Its Association with Nef Are Conserved in Murine Cells but Are Not Sufficient to Induce an AIDS-like Disease in CD4C/HIV Transgenic Mice

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