Biomedical subjects

Zoltán Beck

Publications and source records attributed to Zoltán Beck.

13 recordsLinked to original sources

PubMed2006

Effect of the extent of thiolation and introduction of phosphorothioate internucleotide linkages on the anti-HIV activity of Suligovir [(s4dU)35].

Suligovir is a 35-mer homo-oligonucleotide, containing exclusively 4-thio deoxyuridylate, proved to be a potent inhibitor of HIV entry. In this paper, we described the effect of extent of thiolation and the introduction of nuclease-resistant phosphorothioate linkages on the anti-HIV activity of Suligovir. We found that the decreased thiolated nucleotide content decreases the anti-HIV potency of the compound and the introduction of phosphorothioate linkages does not improve its antiviral activity.

Anti-HIV Agents↗

PubMed2006

[Expression of ZEBRA protein of Epstein-Barr virus in Hungarian patients with Hodgkin lymphoma: latent or lytic cycle?].

INTRODUCTION: Epstein-Barr virus is a ubiquitous human herpes virus in the Hungarian population. The virus is associated with an increasing number of lymphoid malignancies, such as Hodgkin and non-Hodgkin lymphomas. The ability of the virus to establish life-long persistent infection and induce growth transformation is related to the viral proteins that are variously expressed in both normal and malignant cells. Although the presence of ZEBRA protein induces lytic cycle, some lymphoma cases show this protein expression. AIM: In our present study we investigated the frequency of expression of ZEBRA protein in Hungarian patients with Hodgkin lymphoma associated with Epstein-Barr virus infection. The authors wanted to clarify whether this expression is specific to latency type II or occurs in some non-Hodgkin lymphoma cases with latency type III as well. Does the expression of ZEBRA protein have any effect on therapeutic response and survival rate of the patients? METHOD: 109 HL and 59 NHL were studied for the presence of the virus in the tumor and for expression of the latency proteins and ZEBRA by immunohistochemistry. RESULTS: 25 samples were evaluated successfully for ZEBRA of the 47 LMP1 positive HL samples. We detected the weak expression of ZEBRA protein in 13 of the 25 LMP1 positive Hodgkin lymphoma cases and in 6 of the 18 LMP1 positive non-Hodgkin lymphoma samples. The authors could not find correlation between the expression of ZEBRA protein and the type of latency. During the followed 120 months the total survival of patients with ZEBRA positivity proved to be significantly shorter as compared to that of ZEBRA negative cases. The authors could not find significant difference in the uneventful survival of these two groups. CONCLUSION: In the examined group of patients the ZEBRA positivity associated with a poor prognosis of the disease. Besides this relatively small number of cases, additional extensive studies are needed to conclude our observation. Elucidation of the switching mechanisms by which Epstein-Barr virus induces lytic cycle may provide an efficacious therapeutic approach to the EBV-related malignancies.

Adult↗

PubMed2006

Human herpesvirus 6A decreases the susceptibility of macrophages to R5 variants of human immunodeficiency virus 1: possible role of RANTES and IL-8.

Human herpesvirus 6 (HHV-6) frequently reactivates in human immunodeficiency virus 1 (HIV-1) infected patients, and is thought to be a cofactor in AIDS progression. Macrophages are targets and reservoirs of HIV-1 and HHV-6; hence, they have an important role in dissemination and pathogenesis of these viruses. The present study examined the effects of HHV-6 A variant on replication of R5 variants of HIV-1 in macrophages. For this purpose, HIV-1 replication was investigated in macrophages infected with HIV-1 alone or along with HHV-6A. Our results demonstrated that HHV-6A significantly suppressed HIV-1 replication in coinfected cultures. HHV-6A infection resulted in increased secretion of RANTES and IL-8. Experiments with exogenous RANTES and IL-8 revealed that these chemokines also significantly suppressed HIV-1 replication in infected macrophages. RANTES is able to induce desensitization and internalization of CCR5, the chemokine coreceptor of R5 variants. In addition, IL-8 receptor activation results in cross-desensitization and cross-internalization of CCR5. We found that CCR5 sensitivity and expression level is diminished in HHV-6A-infected macrophage cultures compared with uninfected cells. Taken together, our results indicate that HHV-6A infection decreases the susceptibility of macrophages to R5 variants of HIV-1 in which the HHV-6A induced RANTES and IL-8 may have importance.

Cells, Cultured↗

PubMed2006

Effects of human papillomavirus type 16 oncoproteins on survivin gene expression.

Survivin has recently been identified as a novel member of the inhibitor of apoptosis (IAP) gene family. The product of this gene not only suppresses apoptosis but also controls cell division. Survivin is undetectable in most terminally differentiated normal tissues but is expressed in embryonic and fetal organs and is present in most malignant tumours. Human papillomaviruses (HPV) are thought to play an important role in the development of cervical cancer. By interfering in the cell cycle, the viral oncoproteins (E6 and E7) can induce the immortalization of the host cell. The transcriptional effects of the HPV-16 E6 and E7 proteins on the survivin promoter in transiently transfected cell lines using luciferase tests were examined. HPV-16 E6, but not E7, was found to significantly transactivate the survivin promoter. Experiments performed in different cancer cell lines and with different E6 mutants indicated that the effect of E6 on the survivin promoter is largely dependent on p53 status. In accordance with this, the p53 tumour suppressor protein downregulated the expression of survivin. As E6 is able to interact with p53 and induces its ubiquitin-dependent degradation, it appears that the transactivation effect of E6 on survivin is mediated by the p53 degradation pathway. Transduction of HPV-16 E6 and E7 into human embryonic fibroblast cells showed that the HPV oncoproteins can upregulate endogenous survivin mRNA. Importantly, cell cycle synchronization experiments showed that the effect of HPV-16 E6 on survivin transcription is independent of the cell cycle.

Apoptosis↗

PubMed2005

Nick-forming sequences may be involved in the organization of eukaryotic chromatin into approximately 50 kbp loops.

Phenomena involving the disassembly of chromosomes to approximately 50 kbp double-stranded fragments upon protein denaturing treatments of normal and apoptotic mammalian nuclei as well as yeast protoplasts may be an indication of special, hypersensitive regions positioned regularly at loop-size intervals in the eukaryotic chromatin. Here we show evidence in yeast cell systems that loop-size fragmentation can occur in any phase of the cell cycle and that the plating efficiency of these cells is approximately 100%. The possibility of sequence specificity was investigated within the breakpoint cluster region (bcr) of the human MLL gene, frequently rearranged in certain leukemias. Our data suggest that DNA isolated from yeast cultures or mammalian cell lines carry nicks or secondary structures predisposing DNA for a specific nicking activity, at non-random positions. Furthermore, exposure of MLL bcr-carrying plasmid DNA to S1 nuclease or nuclear extracts or purified topoisomerase II elicited cleavages at the nucleotide positions of nick formation on human genomic DNA. These data support the possibility that certain sequence elements are preferentially involved in the cleavage processes responsible for the en masse disassembly of chromatin to loop-size fragments upon isolation of DNA from live eukaryotic cells.

Apoptosis↗

PubMed2005

[Association of Hodgkin lymphoma with Epstein-Barr virus in Hungary].

INTRODUCTION: The occurrence of Epstein-Barr virus associated Hodgkin's lymphoma shows considerable variation from continent to continent and from country to country but in Hungary no such investigations have been performed so far. AIM: The authors analyse the presence of Epstein-Barr virus and the type of latency in histologic samples taken from Hodgkin's disease patients. METHOD: They have analyzed the presence of virus using PCR, in situ hybridisation and immunohistochemistry. RESULTS: Out of 109 cases, 61 patients (56%) showed virus positivity by PCR while latent membrane protein 1 positivity was found in 47 cases (43%). As regards to gender ratio, 53% female and 58% male patients were virus positive by PCR. Epstein-Barr virus association did not show any alteration in children (1-14 years) when compared to that of adults (out of the 10 children 6 were positive by PCR). As regards to the lifestyle of Epstein-Barr virus positive patients, the incidence of smoking and the ratio of poor social conditions were significantly higher. Mixed cell type was the most frequent (65%) in these patients and Epstein-Barr PCR virus positivity was highest in this type (60%), primarily in age groups 11-20 and over 51 years. Epstein-Barr virus PCR positivity was 52% in nodular sclerosis (negative cases cumulated in the age group 15-30 years), other histologic subtypes could not be evaluated due to the small number of cases. On examining Hodgkin's lymphoma and Epstein-Barr virus association disease models, they could not categorize their patients into any of them though characteristic patient groups could be more or less observed also in their material. This may be explained by the socioeconomic differences of the population living under different economic conditions. CONCLUSION: These results indicate that Epstein-Barr infection may play an important role in the development of Hodgkin's lymphoma in Hungary, too.

Adolescent↗

PubMed2005

Apoptotic response of uveal melanoma cells upon treatment with chelidonine, sanguinarine and chelerythrine.

The benzophenanthridine alkaloids sanguinarine, chelerythrine and chelidonine were reported previously to provoke cell death in a variety of tumor cells suggesting their potential application as anticancer agents. Here we tested their effects on a primary human uveal melanoma cell line, OCM-1. Flow cytometric analysis of annexin V binding/PI exclusion and DNA fragmentation disclosed that all these alkaloids could induce apoptosis in OCM-1 cells. Moreover, necrotic cell death was also observed upon alkaloid treatment. As it was also evidenced by light microscopic inspection of cellular morphology, chelidonine primarily caused apoptosis, while sanguinarine and chelerythrine were effective via a so-termed bimodal cell death (apoptosis and primary necrosis). The relative efficiencies of the two modes depended on the applied dose. This study is the first implication for the possible use of these alkaloids in the therapy of uveal melanomas, for which no really efficient therapeutic regimen is available so far.

Alkaloids↗

PubMed2005

Antibodies against heat shock proteins and cholesterol in HIV infection.

This review summarizes data on the presence and function of different heat shock proteins (Hsp) in the HIV virions and the infected cells. A 60 kD heat shock protein-like molecule is present in the envelope of the human immunodeficiency virus type 1 which can specifically interact with the transmembrane glycoprotein gp41. The role of cholesterol in the so-called cholesterol-rich lipid raft where HIV is budding from the infected cells as well as the consequential insertion of cholesterol into the envelope of HIV virion are also discussed. Natural antibodies against 60 kD (Hsp60) and 70 kD (Hsp70) families of Hsp and cholesterol can be detected in most healthy individuals. HIV infection results in a sharp increase in the serum concentration of anti-Hsp70 and cholesterol antibodies whereas no difference in the concentration of anti-Hsp60 antibodies can be detected. Highly active antiretroviral therapy leads to normalization of the levels of both anti-Hsp70 and anti-cholesterol antibodies.

Autoantibodies↗

PubMed2003

Significant decrease of the enhancement/neutralization index in HIV patients during highly active antiretroviral therapy (HAART).

Authors studied the effect of highly active antiretroviral therapy (HAART) on balance of the antibodies that enhance or neutralize growth of HIV-1(IIIB) strain in MT-4 cells in the presence or absence of human complement. Sequential serum samples were collected from 28 patients in advanced stage of HIV disease before and during HAART. The balance of the enhancing and neutralizing antibodies was expressed by an index value (E/N I). Samples with an E/N I of <0.5 (twofold decrease in virus production) were considered as neutralizing, whereas samples with an E/N I>2.0 (twofold increase in virus production) were considered as enhancing. At the beginning of HAART serum samples from eight patients enhanced, and samples from only two patients neutralized the virus in the presence of complement, median (25th-75th percentile) value of E/N I was 1.32 (0.79-2.29). E/N I significantly (P<0.0001) dropped to 0.37 (0.19-0.57) during the follow-up period of 18.5 (10.5-23.5) months under HAART. Similar changes were detected when serum samples were tested with no complement added. The E/N I values were also markedly decreased when cultures inoculated with mixtures of HIV and purified IgG prepared from serum pools taken before and during HAART, respectively, were compared. In the last samples of 20/28 patients, neutralization was measured even in the presence of complement while enhancement was found with none of these samples. These findings suggest that HAART results in disappearance of enhancing antibodies and switches the E/N I toward neutralization.

Antibodies, Blocking↗

PubMed2003

Differential patterns of human cytomegalovirus gene expression in various T-cell lines carrying human T-cell leukemia-lymphoma virus type I: role of Tax-activated cellular transcription factors.

Replication of human cytomegalovirus (HCMV) was investigated in various T-cell lines expressing the tax gene product of human T-cell leukemia-lymphoma virus type I (HTLV-I). Differential patterns of HCMV replication were found in HTLV-I-carrying cell lines. HCMV gene expression was restricted to the immediate-early genes in MT-2 and MT-4 cells, whereas full replication cycle of the virus was observed in C8166-45 cells. Productive HCMV infection induced a cytopathic effect resulting in the lysis of infected cells. The results of electrophoretic mobility shift assay (EMSA) showed high levels of NF-kappaB-, CREB/ATF-1-, and SRF-specific DNA binding activity in all Tax-positive cell lines. In contrast, SP1 activity could be detected only in C8166-45 cells. Using an inducible system (Jurkat cell line JPX-9), a dramatic increase in NF-kappaB, CREB/ATF-1, SRF, and SP1 binding activity, as well as productive HCMV infection, were observed upon Tax expression. Overexpression of SP1 in MT-2 and MT-4 cells converted HCMV infection from an abortive to a productive one. These data suggest that the stimulatory effect of Tax protein on HCMV in T cells is accomplished through at least five host-related transcription factor pathways. The results of this study provide possible mechanisms whereby HCMV infections might imply suppression of adult T-cell leukemia.

Cadmium Chloride↗

PubMed2002

[Study of pathogenetic role of Epstein-Barr virus in Hungarian patients with B-cell non-Hodgkin lymphomas].

INTRODUCTION: The Epstein-Barr virus is a member of herpesvirus family. It plays an important role in the etiopathogenesis of Burkitt lymphoma, other B-cell non-Hodgkin lymphomas, nasopharyngeal carcinoma, X chromosome-linked lymphoproliferative disease, Hodgkin lymphomas and a part of T-cell lymphomas. It has been suggested that association of Epstein-Barr virus with lymphomas and its pathological significance in disease varies in different geographical areas. The aim of our study was to reveal the role of Epstein-Barr virus in B-cell non-Hodgkin lymphomas diagnosed in Hungary. The authors asked: A) What is the frequency of the presence of virus genome in the biopsy specimen from B-cell non-Hodgkin patients? B) Which types of virus latency can be observed? PATIENTS AND METHODS: Genomic DNA and EBER-specific RNA of Epstein-Barr virus in paraffin-embedded specimens were detected by polymerase chain reaction and in situ hybridisation, respectively. RESULTS: Out of 36 B-cell non-Hodgkin lymphoma cases, 16 (45%) were found to be positive for Epstein-Barr virus by the above methods. Expression of latency genes, nuclear antigene-2 and latent membrane protein-1 was studied by immunohistochemical technique. The 16 virus-positive non-Hodgkin lymphoma cases showed Epstein-Barr virus latency types II. (37%) or III. (63%). CONCLUSIONS: The authors data suggest that Epstein-Barr virus may be associated with the development of B-cell non-Hodgkin lymphomas in Hungarian patients.

Base Sequence↗

PubMed2002

Human herpesvirus 6 variant a infects human term syncytiotrophoblasts in vitro and induces replication of human immunodeficiency virus type 1 in dually infected cells.

Human herpesvirus 6 (HHV-6) and human immunodeficiency virus type 1 (HIV-1) may interact during transplacental transmission of HIV-1. The placental syncytiotrophoblast layer serves as the first line of defense of the fetus against viruses. Patterns of replication of HHV-6 variant A (HHV-6A) and HIV-1 were analyzed in singly and dually infected human term syncytiotrophoblast cells cultured in vitro. For this purpose, the GS strain of HHV-6A and the Ba-L and IIIB strains of HIV-1 were used. HHV-6A replication was restricted at the level of early gene products in singly infected syncytiotrophoblasts, whereas no viral protein expression was found in cells infected with HIV-1 alone. Coinfection of syncytiotrophoblast cells with HHV-6A and HIV-1 resulted in production of infectious HIV-1. In contrast, no enhancement of HHV-6A expression was observed in cell cultures infected with both viruses. Uninfected syncytiotrophoblast cells were found to express CXCR4 and CCR3 but not CD4 or CCR5 receptors. Infection of syncytiotrophoblasts with HHV-6A did not induce CD4 expression and had no influence on chemokine receptor expression. Activation of HIV-1 from latency in coinfected cells was mediated by the immediate-early (IE)-A and IE-B gene products of HHV-6A. Open reading frames U86 and U89 of the IE-A region were able to activate HIV-1 replication in a synergistic manner. The data suggest that in vivo double infection of syncytiotrophoblast cells with HHV-6A and HIV-1 could contribute to the transplacental transmission of HIV-1 but not HHV-6A.

Cells, Cultured↗

PubMedDate not supplied

Frequent methylation of p16INK4A/p14ARF promoters in tumorigenesis of Epstein-Barr virus transformed lymphoblastoid cell lines.

BACKGROUND: The data that the p16INK4A gene is frequently inactivated in Burkitt lymphoma (BL) and that this event often accompanies the inactivation of p14ARF in several tumours prompted us to examine the genetic and methylation status of both genes in BL and B-lymphoblastoid cell lines (LCLs). MATERIALS AND METHODS: The existence of gene deletion, mutation and promoter methylation was investigated by single-strand conformational polymorphism, direct sequencing and methylation-specific PCR (MSP) analysis, respectively. RESULTS: Sequencing of each exon of both tumour suppressor genes revealed p16INK4A mutation only in 3 out of 11 BL, but 1 of them also affected the p14ARF gene. MSP analysis of promoters showed p16INK4A to be methylated and p14ARF not to be methylated in each Epstein-Barr virus-positive BL cell line. Primary B-cells and de novo established LCLs had no genetic changes or methylated promoter of either gene. LCLs achieving the stage of immortalization usually showed methylation of both p16INK4A and p14ARF promoters. CONCLUSION: Our results suggest that, in contrast to p161NK4A, inactivation of p14ARF by either genetic change or promoter methylation has no importance in the development of BL cell lines, while its methylation has a central role in the immortalization of LCLs.

B-Lymphocytes↗