Summary. -Despite the success of highly active antiretroviral therapy, AIDS still remains as one of the most important world health problems. Toxicity of current available drugs and inevitable emergence of multi-drug resistant strains makes things worse. In the present study a series of novel Biginelli-type pyrimidine compounds were evaluated as potential anti-human immunodefi ciency virus (HIV)-1 agents using green fl uorescence protein (GFP) reporter single round HIV-1 infection assay. Th e rate of infected cells was monitored by fl owcytometry. Th e eff ect of compounds on the cellular proliferation was considered as the cyotoxicity. Th e anti-HIV-1 active compounds were selected for HIV-1 replication and syncytium formation assays. Th e antiretroviral activity of compounds was measured against luciferase reporter A murine leukemia virus (AMLV) virions as the retrovirus control. Compounds 2, 5, 6, 8, 11, 12, 13, 17, 18, 20, and 21 were the most potent against HIV-1. Compound 8 had the 50% inhibitory concentration (IC 50 ) of 100 nmol/l for inhibiting HIV-1 replication and 50% cytotoxic concentration (CC 50 ) was up to 100 μmol/l (therapeutic index (TI) >1000). Results show that the active compounds were able to inhibit the retrovirus control as well. Analysis of structure of the studied compounds proved relationships with their anti-HIV-1 eff ects. Some of the studied compounds seem to be promising anti-HIV-1 drug candidates. Structural manipulation based on the well-defi ned structure-activity relationships might propose some new leads for anti-HIV-1 drug discovery programs.Keywords: antivirals; HIV-1; Biginelli-type pyrimidines * Co-corresponding authors. E-mail: fassihi@pharm.mui.ac.ir, mrasadeghi@pasteur.ac.ir; phone: +98-311-7922562, +98-21 66468765.Abbreviations: AMLV = A murine leukemia virus; DHPMs = 3,4-dihydropyrimidine-2(1H)-ones; ENV(s) = envelope glycoprotein(s); GFP = green fl uorescence protein; HAART = highly active antiretroviral therapy; HIV = human immunodefi ciency virus; IN = integrase; RT = reverse transcriptase; RTU = reverse transcriptase unit; SCR = single-cycle replicable; IC 50 = 50% inhibitory concentration; CC 50 = 50% cytotoxic concentration; SI = selectivity index (CC 25 / IC 25 ); TI = therapeutic index (CC 50 /IC 50 ); VSVG = vesicular stomatitis virus-glycoprotein

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Purpose: Although the complex structure of acute lymphoblastic leukemia (ALL) and involvement of diverse pathways in its pathogenesis have put an obstacle in the way of efficient treatments, identification of strategies to manipulate the genome of neoplastic cells has made the treatment prospective more optimistic. Methods: To evaluate whether the transduction of Apoptin __a gene encoding a protein that participates in the induction of apoptosis__ could reduce the survival of leukemic cells, we generated recombinant lentivirus expressing Apoptin, and then, MTT assay, flow cytometric analysis of DNA content, western blotting, and qRT-PCR were applied. Results: Transduction of Apoptin into different leukemic cells was coupled with the reduction in the viability and proliferative capacity of the cells. Among all tested cell lines, Nalm-6 and C8166 were more sensitive to the anti-leukemic property of Apoptin. Moreover, we found that the transduction of Apoptin in the indicated cell lines not only induced G2/M cell cycle arrest but also induced apoptotic cell death by altering the balance between pro- and anti-apoptotic target genes. The efficacy of Apoptin transduction was not limited to these findings, as we reported for the first time that the overexpression of this gene could potentiate the anti-leukemic property of pan PI3K inhibitor BKM120. Conclusion: The results of this study showed that the transduction of Apoptin into lymphoblastic leukemia cell lines induced cytotoxic effects and enhanced therapeutic value of PI3K inhibition; however, further investigations are demanded to ascertain the safety and the efficacy of Apoptin transduction in patients with ALL.

Background: Hemophilia is a well-known bleeding disorder with worldwide distribution. Replacement therapy, using plasma-derived or recombinant coagulation factors, comprises a gold standard regimen for the treatment. Regardless of the advancements made in viral inactivation methods in the production of plasma-derived coagulation factors, the possibility of transmission of new viral infections remained as a noticeable concern yet. The aim of the current study was to investigate the status of parvovirus 4 (PARV4) in severe hemophilia A, von Willebrand disease (vWD), and healthy control. Materials and Methods: In the current case-control study, 76 patients with hemophilia and vWD and 60 individuals from their family members entered the study. Nested PCR used to determine the presence of PARV4 in study subjects (76 cases). To characterize the PARV4 genotype, positive samples subjected to sequencing and phylogenetic analysis. Results: PARV4 genome detected in 11 (14.47%) patients with bleeding disorders. Among whom, nine patients (14.75%) were with severe hemophilia A and two (13.33%) patients with vWD. Only five healthy controls (8.33%) were positive for PARV4. All PARV4 sequences were found to be genotype 1. Conclusion: PARV4 infection in patients with hemophilia and vWD was higher than the control group. While detection of PARV4 DNA in patients with bleeding disorders may not necessarily reflect a clinical urgency, future investigations are needed to define the clinical significance of PARV4. It seems the detection of the virus immune signature of PARV4 infection, particularly in the context of acute and persistent infections, needs to focus on cellular and tissue targets.