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Berlin Brandenburg

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  • PMC (PubMed Central)  (5)
  • 1
    Language: English
    In: PLoS ONE, 2012, Vol.7(5), p.e36506
    Description: Oncolytic influenza A viruses with deleted NS1 gene (delNS1) replicate selectively in tumour cells with defective interferon response and/or activated Ras/Raf/MEK/ERK signalling pathway. To develop a delNS1 virus with specific immunostimulatory properties, we used an optimised technology to insert the interleukin-15 (IL-15) coding sequence into the viral NS gene segment (delNS1-IL-15). DelNS1 and delNS1-IL-15 exerted similar oncolytic effects. Both viruses replicated and caused caspase-dependent apoptosis in interferon-defective melanoma cells. Virus replication was required for their oncolytic activity. Cisplatin enhanced the oncolytic activity of delNS1 viruses. The cytotoxic drug increased delNS1 replication and delNS1-induced caspase-dependent apoptosis. Interference with MEK/ERK signalling by RNAi-mediated depletion or the MEK inhibitor U0126 did not affect the oncolytic effects of the delNS1 viruses. In oncolysis sensitive melanoma cells, delNS1-IL-15 (but not delNS1) infection resulted in the production of IL-15 levels ranging from 70 to 1140 pg/mL in the cell culture supernatants. The supernatants of delNS1-IL-15-infected (but not of delNS1-infected) melanoma cells induced primary human natural killer cell-mediated lysis of non-infected tumour cells. In conclusion, we constructed a novel oncolytic influenza virus that combines the oncolytic activity of delNS1 viruses with immunostimulatory properties through production of functional IL-15. Moreover, we showed that the oncolytic activity of delNS1 viruses can be enhanced in combination with cytotoxic anti-cancer drugs.
    Keywords: Research Article ; Biology ; Medicine ; Virology ; Infectious Diseases ; Molecular Biology ; Oncology ; Dermatology
    E-ISSN: 1932-6203
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  • 2
    Language: English
    In: PLoS ONE, 2011, Vol.6(5), p.e19705
    Description: Glycyrrhizin is known to exert antiviral and anti-inflammatory effects. Here, the effects of an approved parenteral glycyrrhizin preparation (Stronger Neo-Minophafen C) were investigated on highly pathogenic influenza A H5N1 virus replication, H5N1-induced apoptosis, and H5N1-induced pro-inflammatory responses in lung epithelial (A549) cells. Therapeutic glycyrrhizin concentrations substantially inhibited H5N1-induced expression of the pro-inflammatory molecules CXCL10, interleukin 6, CCL2, and CCL5 (effective glycyrrhizin concentrations 25 to 50 µg/ml) but interfered with H5N1 replication and H5N1-induced apoptosis to a lesser extent (effective glycyrrhizin concentrations 100 µg/ml or higher). Glycyrrhizin also diminished monocyte migration towards supernatants of H5N1-infected A549 cells. The mechanism by which glycyrrhizin interferes with H5N1 replication and H5N1-induced pro-inflammatory gene expression includes inhibition of H5N1-induced formation of reactive oxygen species and (in turn) reduced activation of NFκB, JNK, and p38, redox-sensitive signalling events known to be relevant for influenza A virus replication. Therefore, glycyrrhizin may complement the arsenal of potential drugs for the treatment of H5N1 disease.
    Keywords: Research Article ; Medicine ; Infectious Diseases ; Pharmacology
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Medical Microbiology and Immunology, 2009, Vol.198(3), pp.147-155
    Description: The human immunodeficiency virus (HIV) had spread unrecognized in the human population as sexually transmitted disease and was finally identified by its disease AIDS in 1981. Even after the isolation of the causative agent in 1983, the burden and death rate of AIDS accelerated worldwide especially in young people despite the confection of new drugs capable to inhibit virus replication since 1997. However, at least in industrialised countries, this trend could be reversed by the introduction of combination therapy strategies. The design of new drugs is on going; besides the inhibition of the three enzymes of HIV for replication and maturation (reverse transcriptase, integrase and protease), further drugs inhibits fusion of viral and cellular membranes and virus maturation. On the other hand, viral diagnostics had been considerably improved since the emergence of HIV. There was a need to identify infected people correctly, to follow up the course of immune reconstitution of patients by measuring viral load and CD4 cells, and to analyse drug escape mutations leading to drug resistance. Both the development of drugs and the refined diagnostics have been transferred to the treatment of patients infected with hepatitis B virus (HBV) and hepatitis C virus (HCV). This progress is not completed; there are beneficial aspects in the response of the scientific community to the HIV burden for the management of other viral diseases. These aspects are described in this contribution. Further aspects as handling a stigmatising disease, education of self-responsiveness within sexual relationships, and ways for confection of a protective vaccine are not covered.
    Keywords: HIV ; HBV ; HCV ; Diagnostics ; Therapy
    ISSN: 0300-8584
    E-ISSN: 1432-1831
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  • 4
    Language: English
    In: BMC Microbiology, 01 May 2007, Vol.7(1), p.49
    Description: Abstract Background West Nile virus (WNV) infection can cause severe meningitis and encephalitis in humans. Apoptosis was recently shown to contribute to the pathogenesis of WNV encephalitis. Here, we used WNV-infected glioma cells to study WNV-replication and WNV-induced apoptosis in human brain-derived cells. Results T98G cells are highly permissive for lytic WNV-infection as demonstrated by the production of infectious virus titre and the development of a characteristic cytopathic effect. WNV replication decreased cell viability and induced apoptosis as indicated by the activation of the effector caspase-3, the initiator caspases-8 and -9, poly(ADP-ribose)polymerase (PARP) cleavage and the release of cytochrome c from the mitochondria. Truncation of BID indicated cross-talk between the extrinsic and intrinsic apoptotic pathways. Inhibition of the caspases-8 or -9 inhibited PARP cleavage, demonstrating that both caspases are involved in WNV-induced apoptosis. Pan-caspase inhibition prevented WNV-induced apoptosis without affecting virus replication. Conclusion We found that WNV infection induces cell death in the brain-derived tumour cell line T98G by apoptosis under involvement of constituents of the extrinsic as well as the intrinsic apoptotic pathways. Our results illuminate the molecular mechanism of WNV-induced neural cell death.
    Keywords: Biology
    ISSN: 1471-2180
    E-ISSN: 1471-2180
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  • 5
    Language: English
    In: PLoS Medicine, 2006, Vol.3(7), p.e237
    Description: Experimental animal data show that protection against severe acute respiratory syndrome coronavirus (SARS-CoV) infection with human monoclonal antibodies (mAbs) is feasible. For an effective immune prophylaxis in humans, broad coverage of different strains of SARS-CoV and control of potential neutralization escape variants will be required. Combinations of virus-neutralizing, noncompeting mAbs may have these properties. ; Human mAb CR3014 has been shown to completely prevent lung pathology and abolish pharyngeal shedding of SARS-CoV in infected ferrets. We generated in vitro SARS-CoV variants escaping neutralization by CR3014, which all had a single P462L mutation in the glycoprotein spike (S) of the escape virus. In vitro experiments confirmed that binding of CR3014 to a recombinant S fragment (amino acid residues 318–510) harboring this mutation was abolished. We therefore screened an antibody-phage library derived from blood of a convalescent SARS patient for antibodies complementary to CR3014. A novel mAb, CR3022, was identified that neutralized CR3014 escape viruses, did not compete with CR3014 for binding to recombinant S1 fragments, and bound to S1 fragments derived from the civet cat SARS-CoV-like strain SZ3. No escape variants could be generated with CR3022. The mixture of both mAbs showed neutralization of SARS-CoV in a synergistic fashion by recognizing different epitopes on the receptor-binding domain. Dose reduction indices of 4.5 and 20.5 were observed for CR3014 and CR3022, respectively, at 100% neutralization. Because enhancement of SARS-CoV infection by subneutralizing antibody concentrations is of concern, we show here that anti-SARS-CoV antibodies do not convert the abortive infection of primary human macrophages by SARS-CoV into a productive one. ; The combination of two noncompeting human mAbs CR3014 and CR3022 potentially controls immune escape and extends the breadth of protection. At the same time, synergy between CR3014 and CR3022 may allow for a lower total antibody dose to be administered for passive immune prophylaxis of SARS-CoV infection. ; Late in 2002, severe acute respiratory syndrome (SARS) emerged in the Guangdong province of China. In February 2003, an infected doctor from the province carried this new viral threat to human health to Hong Kong. Here, people staying in the same hotel caught the disease and took it to other countries. SARS was on the move, hitching lifts with international travellers. Because the virus responsible for SARS—SARS-CoV—spread by close person-to-person contact and killed 10% of the people it infected, health experts feared a world-wide epidemic. This was avoided by the World Health Organization issuing a global alert and warning against unnecessary travel to affected areas and by public-health officials isolating patients and their close contacts. By July 2003, the first SARS epidemic was over. 8,098 people had been infected; 774 people had died. Since then, sporadic cases of SARS have been contained locally. ; The first epidemic of SARS was caused by an animal virus that became adapted to spread between people. There is no reason this process won't be repeated. If it is, stringent quarantine measures could again prevent a global epidemic, but at considerable economic cost. What is needed is a way to prevent SARS developing in healthy people who have been exposed to SARS-CoV and to treat sick people so that they are less infectious and can fight the virus. In this study, researchers have been investigating “passive immunization” as a way to limit SARS epidemics. In passive immunization, short-term protection against illness is achieved by injecting antibodies—proteins that recognize specific molecules (called antigens) on foreign organisms such as bacteria and viruses and prevent those organisms from causing disease. Antibodies for passive immunization can be isolated from blood taken from people who have had SARS, or they can be manufactured as so-called “human monoclonal antibodies” in a laboratory. One of these human monoclonal antibodies—CR3014—had been previously made and shown to prevent lung damage in ferrets infected with SARS-CoV and to stop the infected animals from infecting others. But for effective disease prevention in people, a single monoclonal antibody might not be enough. There are strains of SARS-CoV that CR3014 does not recognize and therefore cannot act against. Also, the virus can alter the antigen recognized by CR3014 when it is grown at a low antibody concentration, producing so-called escape variants; if this happens CR3014 can no longer prevent these escape variants from killing human cells. ; The researchers tested how well a combination of two monoclonal antibodies controlled SARS-CoV killing of human cells. First, they showed that CR3014 escape variants all had the same small change in a part of the virus surface that interacts with human cells. CR3014 blocked this interaction in the parent SARS-CoV strain but not in the escape variants. They then made a new monoclonal antibody—CR3022—that prevented both the parent SARS-CoV stain and the CR3014 escape viruses from killing human cells. The two antibodies bound to neighboring parts of the virus surface, and both of them could bind at the same time. CR3022 also bound to surfaces of SARS-CoV strains to which CR3014 does not bind. And when they tried, the researchers could not generate any viral escape variants to which CR3022 was unable to bind. Finally, the effect of the two antibodies together on inhibition of SARS-CoV killing of human cells was more than the sum of their individual effects. ; A combination of two (or more) human monoclonal antibodies that recognize different parts of the SARS-CoV surface that interacts with human cells might be a good way to immunize people passively against SARS-CoV. It might minimize the possibility of escape variants arising, broaden the range of virus strains against which protection is provided, and reduce the amount of antibody needed for effective protection. Before the approach is tried in people, it will have to be tested in animals—results from experiments done on human cells in dishes are not always replicated in whole animals or people. If the approach passes further tests, the hope is that passive immunization of people with SARS and their close contacts might reduce disease severity in infected people and reduce viral spread as effectively as dramatic quarantine measures. ; Please access these websites via the online version of this summary at . ; • Medline Plus pages on . ; • US Centers for Disease Control and Prevention information on . ; • US National Institute of Allergy and Infectious Diseases factsheet about . ; • Wikipedia page on and (note: Wikipedia is a free online encyclopedia that anyone can edit). ; Two human monoclonal antibodies that bind to different parts of the viral glycoprotein spike show synergistic effects in virus neutralization and suppress the emergence of resistant virus in vitro.
    Keywords: Research Article ; Biochemistry -- Drug Discovery ; Respiratory Medicine ; Drugs And Adverse Drug Reactions ; Infectious Diseases ; Immunology And Allergy ; Respiratory Medicine
    ISSN: 1549-1277
    E-ISSN: 1549-1676
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