Biomedical subjects

Mariola Sadowska

Publications and source records attributed to Mariola Sadowska.

5 recordsLinked to original sources

PubMed2005

Indirubin-3'-monoxime, a derivative of a Chinese antileukemia medicine, inhibits P-TEFb function and HIV-1 replication.

OBJECTIVE: To evaluate the effects of the cyclin dependent kinase (CDK) inhibitor Indirubin-3'-monoxime (IM) on Tat-mediated transactivation function, a step of the HIV-1 cycle that is not currently targeted in antiviral therapy. METHODS: The effects of IM on CDK implicated in HIV-1 Tat transactivation function were evaluated by kinase assays, transfection experiments, RNase protection assay and RT-PCR analysis of viral transcripts. The antiviral effect of IM was investigated in cells from HIV-1 infected individuals as well as in cell lines, primary lymphocytes and monocyte-derived macrophages. The antiviral activity of IM was also tested against drug-resistant HIV-1. RESULTS: IM inhibits the kinase activity of CDK9 [50% inhibitory concentration (IC50) of 0.05 microM], the catalytic subunit of Positive transcription elongation factor b (P-TEFb). Inhibition of CDK9 activity by IM results in abrogation of Tat-induced expression of HIV-1 RNA in cell lines. In addition, IM inhibits the replication of HIV-1 in both peripheral blood mononuclear cells (IC50 of 1 microM) and macrophages (IC50 of 0.5 microM). IM is effective against primary and drug-resistant strains of HIV-1. Importantly, the antiviral effects of the drug were seen at concentrations that did not affect cell proliferation. CONCLUSIONS: Non-toxic concentrations of IM inhibit HIV-1 by blocking viral gene expression mediated by the cellular factor P-TEFb. The drug is effective against wild-type and drug-resistant strains of HIV-1. IM may help control replication of HIV-1 in patients by disrupting a step of the HIV-1 cycle that is not being targeted in current antiretroviral treatments.

Cyclin-Dependent Kinases↗

PubMed2005

The proline-rich homeodomain (PRH/HEX) protein is down-regulated in liver during infection with lymphocytic choriomeningitis virus.

The proline-rich homeodomain protein, PRH/HEX, participates in the early development of the brain, thyroid, and liver and in the later regenerative processes of damaged liver, vascular endothelial, and hematopoietic cells. A virulent strain of lymphocytic choriomeningitis virus (LCMV-WE) that destroys hematopoietic, vascular, and liver functions also alters the transcription and subcellular localization of PRH. A related virus (LCMV-ARM) that does not cause disease in primates can infect cells without affecting PRH. Biochemical experiments demonstrated the occurrence of binding between the viral RING protein (Z) and PRH, and genetic experiments mapped the PRH-suppressing phenotype to the large (L) segment of the viral genome, which encodes the Z and polymerase genes. The Z protein is clearly involved with PRH, but other viral determinants are needed to relocate PRH and to promote disease. By down-regulating PRH, the arenavirus is able to eliminate the antiproliferative effects of PRH and to promote liver cell division. The interaction of an arenavirus with a homeodomain protein suggests a mechanism for viral teratogenic effects and for the tissue-specific manifestations of arenavirus disease.

Animals↗

PubMed2004

HIV-1 transgenic rats develop T cell abnormalities.

HIV-1 infection leads to impaired antigen-specific T cell proliferation, increased susceptibility of T cells to apoptosis, progressive impairment of T-helper 1 (Th1) responses, and altered maturation of HIV-1-specific memory cells. We have identified similar impairments in HIV-1 transgenic (Tg) rats. Tg rats developed an absolute reduction in CD4+ and CD8+ T cells able to produce IFN-gamma following activation and an increased susceptibility of T cells to activation-induced apoptosis. CD4+ and CD8+ effector/memory (CD45RC- CD62L-) pools were significantly smaller in Tg rats compared to non-Tg controls, although the converse was true for the naïve (CD45RC+ CD62L+) T cell pool. Our interpretation is that the HIV transgene causes defects in the development of T cell effector function and generation of specific effector/memory T cell subsets, and that activation-induced apoptosis may be an essential factor in this process.

Animals↗

PubMed2004

Tumorigenesis by human herpesvirus 8 vGPCR is accelerated by human immunodeficiency virus type 1 Tat.

Human herpesvirus 8 (HHV-8), also called Kaposi's sarcoma (KS) herpesvirus, can cause KS but is inefficient. Untreated human immunodeficiency virus type 1 (HIV-1) coinfection is a powerful risk factor. The HHV-8 chemokine receptor, vGPCR (ORF74), activates NF-kappaB and NF-AT, and their levels of activation are synergistically increased by HIV-1 Tat. Transgenic vGPCR mice develop KS-like tumors. A cell line derived from one such tumor expresses vGPCR and forms tumors in nude mice. Here we show that transfection of DNA encoding HIV-1 tat (but not a transactivation-defective mutant) into these tumor cells increases NF-kappaB and NF-AT activation levels and accelerates tumor formation. Tumorigenesis was also accelerated when Tat DNA was transfected into normal cells and the transfected cells were mixed with the tumor cells and injected into a single site. Tumorigenesis was also increased when the two cell types were injected at separate sites, suggesting that tumorigenesis is accelerated by Tat through soluble factors.

Animals↗

PubMed2003

Kaposi's sarcoma-like tumors in a human herpesvirus 8 ORF74 transgenic mouse.

The product of human herpesvirus 8 (HHV-8) open reading frame 74 (ORF74) is related structurally and functionally to cellular chemokine receptors. ORF74 activates several cellular signaling pathways in the absence of added ligands, and NIH 3T3 cells expressing ORF74 are tumorigenic in nude mice. We have generated a line of transgenic (Tg) mice with ORF74 driven by the simian virus 40 early promoter. A minority (approximately 30%) of the Tg mice, including the founder, developed tumors resembling Kaposi's sarcoma (KS) lesions, which occurred most typically on the tail or legs. The tumors were highly vascularized, had a spindle cell component, expressed VEGF-C mRNA, and contained a majority of CD31(+) cells. CD31 and VEGF-C are typically expressed in KS. Tumors generally (but not always) occurred at single sites and most were relatively indolent, although several mice developed large visceral tumors. ORF74 was expressed in a minority of cells in the Tg tumors and in a few other tissues of mice with tumors; mice without tumors did not express detectable ORF74 in any tissues tested. Cell lines established from tumors expressed ORF74 in a majority of cells, expressed VEGF-C mRNA, and were tumorigenic in nude mice. The resultant tumors grew rapidly, metastasized, and continued to express ORF74. Cell lines established from these secondary tumors also expressed ORF74 and were tumorigenic. These data strongly suggest that ORF74 plays a role in the pathology of KS and confirm and extend previous findings on the tumorigenic potential of ORF74.

Animals↗