Evidence that the murine AIDS defective virus does not encode a superantigen

Doyon, Louise; Simard, C; Sékaly, Rafick‐Pierre; Jolicoeur, Paul

doi:10.1128/jvi.70.1.1-9.1996

Cited by 13 publications

(7 citation statements)

References 58 publications

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“…We next studied whether c-Abl associates with Pr60 gag in vivo, by coimmunoprecipitation. We used a nonproducer B-cell line (CST-B5) established from a MAIDS virus-infected mouse (10), in which Pr60 gag could be overexpressed. We isolated two clones (SB19 and SB21) which overexpressed Pr60 gag at levels 10-to 15-fold higher than those produced by the parental CST-B5 cells (Fig.…”

Section: Maids-binding Site For Sh3 [Mb3-1] [Lipskppksr] Mb3-2 [Enlpmentioning

confidence: 99%

The murine AIDS virus Gag precursor protein binds to the SH3 domain of c-Abl

Dupraz

Rebaï

Klein

et al. 1997

J Virol

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The Pr60 gag protein of the murine AIDS (MAIDS) defective virus promotes the proliferation of the infected target B cells and is responsible for inducing a severe immunodeficiency disease. Using the yeast two-hybrid system, we identified the SH3 domain of c-Abl as interacting with the proline-rich p12 domain of Pr60 gag. The two proteins were shown to associate in vitro and in vivo in MAIDS virus-infected B cells. Overexpression of Pr60 gag in these cells led to a detectable increase of the levels of c-Abl protein and to its translocation at the membrane. These results suggest that this viral protein serves as a docking site for signaling molecules and that c-Abl may be involved in the proliferation of infected B cells. Murine AIDS (MAIDS) is a severe immunodeficiency disease characterized by lymphadenopathy, splenomegaly, hypergammaglobulinemia, T-and B-cell dysfunctions, and late appearance of B-cell lymphomas and opportunistic infections (19, 23). This severe immune disease is caused by a defective strain of murine leukemia virus (MuLV) (2, 4). The main target cells of this defective virus appear to be peripheral B lymphocytes which are induced to proliferate after infection (17). The defective viral genome encodes a single Gag precursor (Pr60 gag) protein (15) whose p12 region is highly divergent from those of the p12 proteins of other helper MuLVs. Mutational analyses have confirmed that the Pr60 gag is necessary and sufficient for disease induction (14, 20, 25). In addition, myristylation-negative mutant MAIDS viruses were found to be nonpathogenic, indicating that myristylation and tight membrane association are required for Pr60 gag to be pathogenic (16). These results suggested that intact Pr60 gag may interact with some cellular effectors and possibly serve as a docking site at the membrane to initiate target cell expansion and pathogenesis. We searched for some proteins interacting with Pr60 gag and found that the c-Abl protein is one of these interacting proteins. MATERIALS AND METHODS Construction of plasmids for yeast two-hybrid screening. The construction of the clone encoding the complete Pr60 gag fused to the LexA DNA-binding domain (DB) (pBTM/DuGAG) was made by PCR site-directed mutagenesis using oligonucleotides 5Ј-CCGGAATTCATGGGACAGACCGTAACCACTC-3Ј (sense) and 5Ј-AGTACCATCTAGTGGCCACC-3Ј (antisense). An EcoRI site was introduced at nucleotide (nt) 970 from Du5H (2). The amplified fragment was digested with EcoRI and AatII (nt 1025) and subcloned into pBS-SK together with an AatII (nt 1025)-HindIII (nt 3264) fragment from plasmid pDu5Hneo (2) to generate Du5H R1-970 , which was sequenced. Digestion with EcoRI and SalI (of pBS-SK) from Du5H R1-970 generated a fragment which was cloned into pBTM116 to generate pBTM/DuGAG. Plasmids pBTM/DuGAG/⌬CA, pBTM/DuGAG/⌬12, and pBTM/DuGAG/⌬MA were constructed by swapping the AatII-HindIII fragment of plasmid Du5H R1-970 with those of plasmids pDu5H-A, pDu5H-B, and pDu5H-C, encoding Pr60 gag deletion mutants described previously (14), before subcloning into pB...

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Section: Maids-binding Site For Sh3 [Mb3-1] [Lipskppksr] Mb3-2 [Enlpmentioning

confidence: 99%

The murine AIDS virus Gag precursor protein binds to the SH3 domain of c-Abl

Dupraz

Rebaï

Klein

et al. 1997

J Virol

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“…In addition, both this report and several others (Hugin et. al, 1991;Muralidhar et al, 1992;Gilmore at al., 1993;McCarty et al, 1996;Doyon et al, 1996;Hayashi and Kanagawa, 1999) have argued against the presence of a SAg in MAIDS, particularly the one proposed early on as expressed on a terminal B-cell lymphoma line from a B6 mouse with end-stage MAIDS (Hugin at al., 1991).…”

Section: Discussionmentioning

confidence: 99%

“…If TCR is indeed engaged, then it would follow that a viral peptide, induced self peptide, or superantigen (SAg) complexed with MHC class II would be the TCR ligand driving Signal 1 propagation. However, as no LP-BM5 virusencoded or -associated peptide, or SAg, has yet been defined that could provide the ligand for the CD4 TCR in the context of MAIDS (Hugin et al, 1991;Muralidhar et al, 1992;Gilmore at al., 1993;McCarty et al, 1996;Doyon et al, 1996;Hayashi and Kanagawa, 1999), the question of a requirement for CD4 TCR engagement in MAIDS can not be approached using antibody or other reagents to block the ligation of the TCR by these putative peptide or SAg -MHC complexes. Also, it is not possible to study the need for the TCR by use of TCR -/mice because the required CD4 T cells will not be present.…”

Section: Introductionmentioning

confidence: 99%

Murine AIDS requires CD154/CD40L expression by the CD4 T cells that mediate retrovirus-induced disease: Is CD4 T cell receptor ligation needed?

Green

2007

Virology

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LP-BM5, a retroviral isolate, induces a disease featuring an acquired immunodeficiency syndrome termed murine AIDS (MAIDS). Many of the features of the LP-BM5-initiated disease are shared with HIV/AIDS. Our lab has shown that the interaction of B and CD4 T cells that is central to MAIDS pathogenesis requires ligation of CD40 on B cells by CD154 on CD4 T cells. Despite this strict requirement for CD154 expression, whether CD4 T cell receptor (TCR) occupancy is essential for the induction of MAIDS is unknown. To block TCR engagement, Tg mouse strains with monoclonal TCR of irrelevant peptide/MHC specificities, all on MAIDS-susceptible genetic backgrounds, were tested: the study of a panel of TCR Tg CD4 T cells controlled for the possibility of serendipitous crossreactive recognition of virus-associated or induced-self peptide, or superantigen, MHC complexes by a given TCR. The results argue that TCR engagement is not necessary for the induction of MAIDS.

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“…Since it is unlikely that the viral genome encodes conventional superantigens [12,16] or other antigens responsible for the polyclonal activation of T-and B-cells, and since the T-cell dysfunction involves both naive and memory CD4 + T-cells [17], antigenindependent mechanisms may be crucial in the pathogenesis. We have recently reported that the intracellular level of cAMP is strongly increased in T-cells from MAIDS mice leading to constitutive activation of PKA (protein kinase A) type I [18].…”

Section: Introductionmentioning

confidence: 99%

Cyclo-oxygenase type 2-dependent prostaglandin E2 secretion is involved in retrovirus-induced T-cell dysfunction in mice

Rahmouni

Aandahl

Nayjib

et al. 2004

Biochemical Journal

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MAIDS (murine AIDS) is caused by infection with the murine leukaemia retrovirus RadLV-Rs and is characterized by a severe immunodeficiency and T-cell anergy combined with a lymphoproliferative disease affecting both B- and T-cells. Hyperactivation of the cAMP-protein kinase A pathway is involved in the T-cell dysfunction of MAIDS and HIV by inhibiting T-cell activation through the T-cell receptor. In the present study, we show that MAIDS involves a strong and selective up-regulation of cyclo-oxygenase type 2 in the CD11b+ subpopulation of T- and B-cells of the lymph nodes, leading to increased levels of PGE2 (prostaglandin E2). PGE2 activates the cAMP pathway through G-protein-coupled receptors. Treatment with cyclo-oxygenase type 2 inhibitors reduces the level of PGE2 and thereby reverses the T-cell anergy, restores the T-cell immune function and ameliorates the lymphoproliferative disease.

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Evidence that the murine AIDS defective virus does not encode a superantigen

Cited by 13 publications

References 58 publications

The murine AIDS virus Gag precursor protein binds to the SH3 domain of c-Abl

The murine AIDS virus Gag precursor protein binds to the SH3 domain of c-Abl

Murine AIDS requires CD154/CD40L expression by the CD4 T cells that mediate retrovirus-induced disease: Is CD4 T cell receptor ligation needed?

Cyclo-oxygenase type 2-dependent prostaglandin E2 secretion is involved in retrovirus-induced T-cell dysfunction in mice

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