Severe immunodeficiency disease induced by a defective murine leukaemia virus

Aziz, Douglas C.; Hanna, Zaher; Jolicoeur, Paul

doi:10.1038/338505a0

Cited by 241 publications

(204 citation statements)

References 24 publications

Supporting

Mentioning

202

Contrasting

Order By: Relevance

“…In this report, we employ a novel approach to identify genes that collaborate with HOX11 in tumorigenesis in a mature B-lymphocyte target population by using the Du5H murine AIDS (mAIDS) virus (Aziz et al, 1989;Chattopadhyay et al, 1989) to accelerate lymphoma development in IgHm-HOX11 Tg animals. Most cells infected by the Du5H-defective virus are mature IgM þ IgD þ B-cells where the virus has been shown to be capable of functioning as an insertional mutagen (Huang et al, 1991(Huang et al, , 1995.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-transgenic mice

et al. 2006

View full text Add to dashboard Cite

Dysregulated expression of the homeobox gene, HOX11 is a frequent etiologic event in T-cell acute lymphoblastic leukemias. HOX11-transgenic mice (IgHl-HOX11 Tg )-expressing HOX11 in the B-cell compartment develop B-cell lymphomas with extended latency. The latency suggests that additional genetic events are required prior to the onset of malignant lymphoma. We report the identification of 17 HOX11 collaborating genes, revealed through their propensity to be targeted in a proviral insertional mutagenesis screen. Seven integrations disrupted genes in mitotic spindle checkpoint control, suggesting that cells with elevated HOX11 expression are especially sensitive to dysregulation of chromosome segregation during mitosis. IgHl-HOX11 Tg primary B-lymphocyte cultures exposed to the aneugenic agents, colchicine and colcemid, exhibited increased incidences of chromosome missegregation as assessed by cytokinesisblock micronucleus assays. Additionally, IgHl-HOX11 Tg cultures were shown to exhibit aberrant bypass of spindle checkpoint arrest, as assessed by the increased presence of cycling cells determined by assessment of DNA content and by BrdU immunolabelling. Western immunoblotting revealed elevated expression of the mitotic effector molecules, cyclin A, cyclin B1 and cdc20 in IgHl-HOX11 Tg cultures. Moreover, spontaneously arising lymphoid neoplasms in IgHl-HOX11 Tg mice frequently exhibit aberrant expression of mitotic regulators, concomitant with increased development of micronuclei, abnormal mitotic checkpoint control and increased incidences of abnormal karyotypes when expanded in culture. Collectively, these findings indicate that abnormal regulation of spindle checkpoint control as a result of HOX11 overexpression leads to a heightened predisposition for development of aneuploidy, contributing to oncogenesis.

show abstract

Section: Introductionmentioning

confidence: 99%

Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-transgenic mice

et al. 2006

View full text Add to dashboard Cite

show abstract

“…The HIV Gag protein p6 gag , the C-terminal polypeptide of the precursor Pr55 gag , contains a P-X-X-P sequence which is required for e cient virus particle production (Huang et al, 1995) and may function by binding to an SH3 domain-containing protein. Another example of Gag protein participation in pathogenesis is that of the murine acquired de®ciency syndrome (MAIDS) virus, whose causative agent is a defective MuLV encoding a truncated Gag protein p60 gag (Aziz et al, 1989;Morse et al, 1992), which is similar to p58 gag . In one hypothesis proposed to explain the pathogenic e ects of MAIDS, p60 gag is assumed to interact with one or more cellular signal transduction pathways to induce an oncogenic type response (Aziz et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

c-Src association with and phosphorylation of p58gag, a membrane- and microfilament-associated retroviral Gag-like protein in a xenotransplantable rat mammary tumor

Huang

Zhang

et al. 1999

Oncogene

View full text Add to dashboard Cite

The retroviral Gag-like protein p58 gag expressed in a highly metastatic ascites rat mammary adenocarcinoma has been implicated in cell surface changes contributing to xenotransplantability. p58 gag is present in the cells in a plasma membrane-and micro®lament-associated signal transduction particle containing Src and is phosphorylated on tyrosine. Overlay analyses and a nity chromatography with glutathione S-transferase (GST) fusion proteins of Src homology-3 (SH3) domains showed direct binding of the Src but not the Crk SH3 domain to p58 gag . This association was con®rmed by coimmunoprecipitation of partially puri®ed p58 gag from ascites cell lysates with platelet Src. Further, a GSTp58 gag fusion protein bound full length c-Src from either platelets or c-Src-expressing insect cells. The GST-p58 gag fusion protein, but not GST, was phosphorylated by platelet or insect cell-expressed c-Src, but not by a kinase negative c-Src variant. The binding of GST-p58 gag to c-Src was almost completely abolished by a 50-fold excess of the GST-SH3 domain of Src, and a parallel decrease in tyrosine phosphorylation of p58 gag was observed. These results demonstrate that p58 gag is tyrosine-phosphorylated as a consequence of its speci®c association with c-Src via its SH3 domain. These observations suggest a mechanism by which Gag proteins may contribute to retroviral maturation or pathogenesis through binding and relocalization of SH3 domaincontaining proteins such as Src-like tyrosine kinases to sites of association of micro®laments with the plasma membrane.

show abstract

“…Inbred female C57BL/6 (B6; H_2 b ; susceptible to LP-BM5-induced disease) mice were obtained from IFFA Credo (I'Arbresle, France). Mice were injected at the age of 4 weeks intraperitoneally with 0.1 mL of LP-BM5 MuLV stock containing a replication-defective component as described [2,5,6] and ---10 ffu/rnl, MCF (mink cell focus-inducing) virus and 103.8-10 5 pfu/ml, ectropic MuLV.…”

Section: Methodsmentioning

confidence: 99%

“…Third, combined treatment had an additive, protective effect on lymphocyte proliferative capacity. This successful dual therapeutic strategy in a mouse model has potential applicability for similar approaches in treating human immunodeficiency virus infection.The LP-BM5 murine leukemia viruses (MuLV) induce an immunodeficiency disease in susceptible murine strains [1][2][3][4][5][6]. The disorder has a natural history in many ways comparable to human immunodeficiency virus (HIV-l )-induced AIDS in humans and has therefore been termed murine AIDS (MAIDS) [3].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Effect of Cyclosporin A and Zidovudine on Immune Abnormalities Observed in the Murine Acquired Immunodeficiency Syndrome

Cerny¹,

Merino²,

Fossati³

et al. 1992

Journal of Infectious Diseases

View full text Add to dashboard Cite

Two therapeutic modalities, zidovudine (targeting retroviral replication) and cyclosporin A (targeting immunopathologic consequences of retroviral expression) were evaluated in a murine model of AIDS. In previous studies, cyclosporin A treatment (40 or 60 rug/kg/day) before and after infection with LP-BM5 murine leukemia viruses protected against the development of immunodeficiency disease. The present study extends these findings. First, a low dose of cyclosporin A (20 rug/kg/day) was ineffective, and treatment initiated 5 days after infection did not protect against virus-induced lymphoproliferation and hypergammaglobulinemia. Second, zidovudine added to drinking water (0.1 mg initiated 5 days after infection and continued for 8 weeks) was more effective than 0.2 mg/ml, given day 5-12 after infection. This treatment reduced lymph node size, disease severity as determined histologically, retrovirus-induced gp70 expression, and IgE (but not IgM and IgG) levels. Third, combined treatment had an additive, protective effect on lymphocyte proliferative capacity. This successful dual therapeutic strategy in a mouse model has potential applicability for similar approaches in treating human immunodeficiency virus infection.The LP-BM5 murine leukemia viruses (MuLV) induce an immunodeficiency disease in susceptible murine strains [1][2][3][4][5][6]. The disorder has a natural history in many ways comparable to human immunodeficiency virus (HIV-l )-induced AIDS in humans and has therefore been termed murine AIDS (MAIDS) [3]. Dysfunction of CD4+ T cells is a key feature in both conditions and precedes a numerical reduction of this T cell subset even though the LP-BM5 viruses have no selective tropism for CD4+ T cells [7].Previous studies of mice with MAIDS demonstrated that interactions between CD4+ T cells and B cells are central to the pathogenesis of this syndrome; infected mice depleted in vivo of CD4+ T cells had phenotypically and functionally normal B cells [8], while infected mice depleted of mature B cells had phenotypically and functionally normal CD4+ and CD8+ T cells [9]. Indirect evidence suggests that B cell-de-

show abstract

Severe immunodeficiency disease induced by a defective murine leukaemia virus

Cited by 241 publications

References 24 publications

Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-transgenic mice

Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-transgenic mice

c-Src association with and phosphorylation of p58gag, a membrane- and microfilament-associated retroviral Gag-like protein in a xenotransplantable rat mammary tumor

Effect of Cyclosporin A and Zidovudine on Immune Abnormalities Observed in the Murine Acquired Immunodeficiency Syndrome

Contact Info

Product

Resources

About