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  • 1.
    Andersson, Emma K
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Adenovirus interactions with CD46 on transgenic mouse erythrocytes2010In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 402, no 1, p. 20-25Article in journal (Refereed)
    Abstract [en]

    Hemagglutination is an established method but has not been used previously to determine the efficacy of virus binding to a specific cellular receptor. Here we have utilized CD46-expressing erythrocytes from a transgenic mouse to establish whether and to what extent the species B adenoviruses (Ads) as well as Ad37 and Ad49 of species D can interact with CD46. A number of different agglutination patterns, and hence CD46 interactions, could be observed for the different adenovirus types. In this system Ad7p, Ad11a, and Ad14 did not agglutinate mouse erythrocytes at all. Hemagglutination of CD46 expressing erythrocytes with high efficiency was observed for the previously established CD46 users Ad11p and Ad35 as well as for the less investigated Ad34. Ad50 agglutinated with moderate efficiency. Ad16, Ad21 and Ad49 gave incomplete agglutination. Ad16 was the only adenovirus that could be eluted. No specific CD46 interaction could be observed for Ad3p or for Ad37.

  • 2.
    Arnberg, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kidd, Alistair H
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Edlund, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Pring-Åkerblom, Patricia
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Adenovirus type 37 binds to cell surface sialic acid through a charge-dependent interaction2002In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 302, no 1, p. 33-43Article in journal (Refereed)
    Abstract [en]

    Most adenoviruses use the coxsackie-adenovirus receptor (CAR) as a major cellular receptor. We have shown recently that adenovirus types 8, 19a, and 37, which are the major causes of epidemic keratoconjunctivitis, use sialic acid rather than CAR as a major cellular receptor. The predicted isoelectric point of the receptor-interacting knob domain in the adenovirus fiber protein is unusually high (9.0-9.1) in type 8, 19a, and 37. The pKa of sialic acid is low, 2.6, implying a possible involvement of charge in fiber knob-sialic acid interactions. Here we show that (i) positively charged adenovirus knobs require sialic acid for efficient cell membrane interactions; (ii) viral and knob interactions with immobilized sialic acid or cell-surface sialic acid are sensitive to increased ionic strength; (iii) negatively charged molecules such as sulfated glycosaminoglycans inhibit the binding of virions to target cells in a nonspecific, charge-dependent manner; and that (iv) the ability of adenovirus knobs to interact with sialic acid correlates with the overall charge on the top surface of the respective knobs as predicted by homology modeling. Taken together, the results presented provide strong evidence for a charge mechanism during the interaction between the Ad37 fiber knob and sialic acid.

  • 3.
    Arnberg, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mei, Ya Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Fiber genes of adenoviruses with tropism for the eye and the genital tract1997In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 227, no 1, p. 239-244Article in journal (Refereed)
    Abstract [en]

    We have characterized the fibergenes of adenovirus type 19p (Ad19p), Ad19a, and Ad37 by sequencing. The fiber genes of Ad19a and Ad37 are identical and only five amino acids differ comparing Ad19a/Ad37 with Ad19p. Based on the translated sequences we calculated the isoelectrical points (Ips) and found that the fiber knobs of Ad19p, Ad19a, and Ad37 together with Ad8 display the highest Ips of all so far characterized. Two regions within the fiber knob with unusually basic characteristics have been identified. Sequence alignments revealed that the corresponding regions in other fiber knobs are highly antigenic in pepscan analysis and of importance for hemagglutination. Only two positions differ in the knobs comparing Ad19a/Ad37 with Ad19p. Hence, either of these or both amino acid residues should be expected to be responsible for the observed differences in hemagglutination between Ad19p and Ad19a/Ad37. Moreover, we have found two amino acids (Ala227 and Lys252) that are unique in their respective position in Ad19p, Ad19a, Ad37, and Ad8. Three amino acids (Lys236, Lys240, and Asn251) are unique in their respective position in Ad19a and Ad37, that manifest a tropism for the genital tract. All five amino acids colocalize within one of the two basic regions.

  • 4. Blusch, Jürgen H
    et al.
    Deryckere, François
    Windheim, Mark
    Ruzsics, Zsolt
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Adrian, Thomas
    Burgert, Hans-Gerhard
    The novel early region 3 protein E3/49K is specifically expressed by adenoviruses of subgenus D: implications for epidemic keratoconjunctivitis and adenovirus evolution2002In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 296, no 1, p. 94-106Article in journal (Refereed)
    Abstract [en]

    The early transcription unit 3 (E3) of adenoviruses (Ads) encodes immunomodulatory functions. We previously described a novel gene of 49K within the E3 region of Ad19a, an Ad of subgenus D that is similar to Ad8 and Ad37 causes epidemic keratoconjunctivitis (EKC). Interestingly, 49K was reported not to be present in Ad9 and Ad17, other subgenus D Ads not causing EKC. Therefore, we investigated whether 49K is selectively expressed in EKC-causing Ads. Using specific DNA probes, we detect 49K-homologous genes in all subgenus D Ads tested. Moreover, 49K-specific antibodies recognize a high molecular weight protein in cells infected with all subgenus D serotypes irrespective of their ability to cause EKC. Sequencing of several 49K genes reveals a high homology without a distinct feature recognizable for those of EKC-associated Ad strains. Thus, E3/49K is a subgenus D specific E3 protein whose expression does not correlate with the EKC-causing phenotype and thus may rather be implicated in illnesses commonly caused by this subgenus. Interestingly, the 49K sequences of Ad19a and Ad37 are identical. To estimate the extent of the sequence identity between these two viruses, we initially sequenced the right ITR and the hexon. This analysis revealed that the right ITR of Ad19a is identical to Ad37, while the hexon sequence is Ad19p-like. This suggested that the region of identity is much larger and that Ad19a arose by recombination of Ad37 with an Ad19p-like Ad. Further sequencing mapped the crossover within the DNA binding protein. Thus, Ad19a contains a large sequence block ( approximately 13 kb), from the 100K gene to the right ITR, identical to Ad37. The implications of these findings in light of the temporal appearance of the EKC-causing Ad strains are discussed.

  • 5.
    Drobni, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mistry, Nitesh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    McMillan, Nigel
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Carboxy-fluorescein diacetate, succinimidyl ester labeled papillomavirus virus-like particles fluoresce after internalization and interact with heparan sulfate for binding and entry2003In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 310, no 1, p. 163-172Article in journal (Refereed)
    Abstract [en]

    Human papillomaviruses (HPVs) infect epithelial cells and are associated with genital carcinoma. Most epithelial cell lines express cell-surface glycosaminoglycans (GAGs) usually found attached to the protein core of proteoglycans. Our aim was to study how GAGs influenced HPV entry. Using a human keratinocyte cell line (HaCaT), preincubation of HPV virus-like particles (VLPs) with GAGs showed a dose-dependent inhibition of binding. The IC(50) (50% inhibition) was only 0.5 microg/ml for heparin, 1 microg/ml for dextran sulfate, and 5-10 microg/ml for heparan sulfate from mucosal origin. Mutated chinese hamster ovary (CHO) cell lines lacking heparan sulfate or all GAGs were unable to bind HPV VLPs. Here we also report a method to study internalization by using VLPs labeled with carboxy-fluorescein diacetate, succinimidyl ester, a fluorochrome that is only activated after cell entry. Pretreatment of labeled HPV VLPs with heparin inhibited uptake, suggesting a primary interaction between HPV and cell-surface heparan sulfate.

  • 6. Fineran, Peter C.
    et al.
    Charpentier, Emmanuelle
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Memory of viral infections by CRISPR-Cas adaptive immune systems: acquisition of new information2012In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 434, no 2, p. 202-209Article, review/survey (Refereed)
    Abstract [en]

    Multiple organisms face the threat of viral infections. To combat phage invasion, bacteria and archaea have evolved an adaptive mechanism of protection against exogenic mobile genetic elements, called CRISPR-Cas. In this defense strategy, phage infection is memorized via acquisition of a short invader sequence, called a spacer, into the CRISPR locus of the host genome. Upon repeated infection, the 'vaccinated' host expresses the spacer as a precursor RNA, which is processed into a mature CRISPR RNA (crRNA) that guides an endonuclease to the matching invader for its ultimate destruction. Recent efforts have uncovered molecular details underlying the crRNA biogenesis and interference steps. However, until recently the step of adaptation had remained largely uninvestigated. In this minireview, we focus on recent publications that have begun to reveal molecular insights into the adaptive step of CRISPR-Cas immunity, which is required for the development of the heritable memory of the host against viruses. 

  • 7.
    Gokumakulapalle, Madhuri
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Replication-competent human adenovirus 11p vectors can propagate in Vero cells2016In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 495, p. 42-51Article in journal (Refereed)
    Abstract [en]

    The use of continuous cell lines derived from the African green monkey kidney (AGMK) has led to major advances in virus vaccine development. However, to date, these cells have not been used to facilitate the creation of human adenoviruses because most human adenoviruses undergo abortive infections in them. Here, we report the susceptibility of AGMK-derived cells to adenovirus lip (Ad11p) infection. First, we showed that CD46 molecules, which act as receptors for Ad11p, are expressed in AGMK cells. We then monitored Ad11p replication by measuring GFP expression as an indicator of viral transcription. We found that AGMK-derived cells were as capable as carcinoma cells at propagating full-length replication competent Ad11p (RCAd11p) DNA. Of the AGMK cell lines tested, Vero cells had the greatest capacity for adenovirus production. Thus, AGMK cells can be used to evaluate RCAd11p-mediated gene delivery, and Vero cells can be used for the production of RCAd11pGFP vectors at relatively high yields.

  • 8.
    Gustafsson, Dan J
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Andersson, Emma K
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hu, Yan-Ling
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Marttila, Marko
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lindman, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Strand, Mårten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wang, Li
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Adenovirus 11p downregulates CD46 early in infection2010In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 405, no 2, p. 474-482Article in journal (Refereed)
    Abstract [en]

    Adenovirus 11 prototype (Ad11p), belonging to species B, uses CD46 as an attachment receptor. CD46, a complement regulatory molecule, is expressed on all human nucleated cells. We show here that Ad11p virions downregulate CD46 on the surface of K562 cells as early as 5min p.i. Specific binding to CD46 by the Ad11p fiber knob was required to mediate downregulation. The complement regulatory factors CD55 and CD59 were also reduced to a significant extent as a consequence of Ad11p binding to K562 cells. In contrast, binding of Ad7p did not result in downregulation of CD46 early in infection. Thus, the presumed interaction between Ad7p and CD46 did not have the same consequences as the Ad11p-CD46 interaction, the latter virus (Ad11p) being a promising gene therapy vector candidate. These findings may lead to a better understanding of the pathogenesis of species B adenovirus infections.

  • 9. Habjan, Matthias
    et al.
    Penski, Nicola
    Wagner, Valentina
    Spiegel, Martin
    Överby, Anna K
    Department of Virology, University of Freiburg, D-79008 Freiburg, Germany.
    Kochs, Georg
    Huiskonen, Juha T
    Weber, Friedemann
    Efficient production of Rift Valley fever virus-like particles: the antiviral protein MxA can inhibit primary transcription of bunyaviruses2009In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 385, no 2, p. 400-408Article in journal (Refereed)
    Abstract [en]

    Rift Valley fever virus (RVFV) is a highly pathogenic member of the family Bunyaviridae that needs to be handled under biosafety level (BSL) 3 conditions. Here, we describe reverse genetics systems to measure RVFV polymerase activity in mammalian cells and to generate virus-like particles (VLPs). Recombinant polymerase (L) and nucleocapsid protein (N), expressed together with a minireplicon RNA, formed transcriptionally active nucleocapsids. These could be packaged into VLPs by additional expression of viral glycoproteins. The VLPs resembled authentic virus particles and were able to infect new cells. After infection, VLP-associated nucleocapsids autonomously performed primary transcription, and co-expression of L and N in VLP-infected cells allowed subsequent replication and secondary transcription. Bunyaviruses are potently inhibited by a human interferon-induced protein, MxA. However, the affected step in the infection cycle is not entirely characterized. Using the VLP system, we demonstrate that MxA inhibits both primary and secondary transcriptions of RVFV. A set of infection assays distinguishing between virus attachment, entry, and subsequent RNA synthesis confirmed that MxA is able to target immediate early RNA synthesis of incoming RVFV particles. Thus, our reverse genetics systems are useful for dissecting individual steps of RVFV infection under non-BSL3 conditions.

  • 10. Hooper, J W
    et al.
    Kamrud, K I
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Custer, D
    Schmaljohn, C S
    DNA vaccination with hantavirus M segment elicits neutralizing antibodies and protects against seoul virus infection.1999In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 255, no 2, p. 269-78Article in journal (Refereed)
    Abstract [en]

    Seoul virus (SEOV) is one of four known hantaviruses causing hemorrhagic fever with renal syndrome (HFRS). Candidate naked DNA vaccines for HFRS were constructed by subcloning cDNA representing the medium (M; encoding the G1 and G2 glycoproteins) or small (S; encoding the nucleocapsid protein) genome segment of SEOV into the DNA expression vector pWRG7077. We vaccinated BALB/c mice with three doses of the M or S DNA vaccine at 4-week intervals by either gene gun inoculation of the epidermis or needle inoculation into the gastrocnemius muscle. Both routes of vaccination resulted in antibody responses as measured by ELISA; however, gene gun inoculation elicited a higher frequency of seroconversion and higher levels of antibodies in individual mice. We vaccinated Syrian hamsters with the M or S construct using the gene gun and found hantavirus-specific antibodies in five of five and four of five hamsters, respectively. Animals vaccinated with the M construct developed a neutralizing antibody response that was greatly enhanced in the presence of guinea pig complement. Immunized hamsters were challenged with SEOV and, after 28 days, were monitored for evidence of infection. Hamsters vaccinated with M were protected from infection, but hamsters vaccinated with S were not protected.

  • 11. Hultin, Emilie
    et al.
    Arroyo Mühr, Laila Sara
    Bzhalava, Zurab
    Hortlund, Maria
    Lagheden, Camilla
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Dillner, Joakim
    Viremia preceding multiple sclerosis: Two nested case-control studies2018In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 520, p. 21-29Article in journal (Refereed)
    Abstract [en]

    Infections have been suggested to be involved in Multiple Sclerosis (MS). We used metagenomic sequencing to detect both known and yet unknown microorganisms in 2 nested case control studies of MS. Two different cohorts were followed for MS using registry linkages. Serum samples taken before diagnosis as well as samples from matched control subjects were selected.

    In cohort1 with 75 cases and 75 controls, most viral reads were Anelloviridae-related and >95% detected among the cases. Among samples taken up to 2 years before MS diagnosis, Anellovirus species TTMV1, TTMV6 and TTV27 were significantly more common among cases. In cohort2, 93 cases and 93 controls were tested under the pre-specified hypothesis that the same association would be found. Although most viral reads were again related to Anelloviridae, no significant case-control differences were seen. We conclude that the Anelloviridae-MS association may be due to multiple hypothesis testing, but other explanations are possible.

  • 12. Kamrud, K I
    et al.
    Hooper, J W
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Schmaljohn, C S
    Comparison of the protective efficacy of naked DNA, DNA-based Sindbis replicon, and packaged Sindbis replicon vectors expressing Hantavirus structural genes in hamsters.1999In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 263, no 1, p. 209-19Article in journal (Refereed)
    Abstract [en]

    Seoul virus (SEOV) is a member of the Hantavirus genus (family Bunyaviridae) and an etiological agent of hemorrhagic fever with renal syndrome. The medium (M) and small (S) gene segments of SEOV encode the viral envelope glycoproteins and nucleocapsid protein, respectively. We compared the immunogenicity and protective efficacy of naked DNA (pWRG7077), DNA-based Sindbis replicon (pSIN2.5), and packaged Sindbis replicon vectors (pSINrep5), containing either the M or S gene segment of SEOV in Syrian hamsters. All of the vectors elicited an anti-SEOV immune response to the expressed SEOV gene products. Vaccinated hamsters were challenged with SEOV and monitored for evidence of infection. Protection from infection was strongly associated with M-gene vaccination. A small number of S-gene-vaccinated animals also were protected. Hamsters vaccinated with the pWRG7077 vector expressing the M gene demonstrated the most consistent protection from SEOV infection and also were protected from heterologous hantavirus (Hantaan virus) infection.

  • 13.
    Mei, Ya-Fang
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lindman, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Human adenoviruses of subgenera B, C, and E with various tropisms differ in both binding to and replication in the epithelial A549 and 293 cells2002In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 295, no 1, p. 30-43Article in journal (Refereed)
    Abstract [en]

    Adenoviruses of six subgenera, namely, adenovirus 31 (Ad31) (subgenus A), Ad3, Ad7, Ad11p, Ad11a, and Ad35 (subgenus B), Ad5v and Ad5p (subgenus C), Ad37 (subgenus D), Ad4 (subgenus E), and Ad41 (subgenus F), were studied. The relative binding properties of different adenoviruses to 293 (human kidney embryonic cells) and A549 (human lung carcinoma cells) cells were compared by flow cytometry. All analyzed adenoviruses bound to cells in a dose-dependent manner. The binding capacity showed that Ad11p, Ad35 (subgenus B:2) with kidney tropism, and Ad4 (subgenus E), which can cause adenopharyngoconjunctivitis, bound strongly to both A549 and 293 cells. The other members of subgenus B and Ad37 of subgenus D manifested an intermediate binding capacity. The analyzed adenoviruses of subgenera A, C, and F manifested a low affinity. Adenoviruses of subgenera B:2 and E manifested high binding affinity to preparations of cell membranes from the epithelial cell lines. Reciprocal competition experiments using Ad11p and Ad4 demonstrated that the two viruses did not block each other. Antibodies against alphavbeta3 and alphavbeta5 reduced the binding of Ad5v virions and slightly impaired the binding of Ad4 but did not affect Ad11p binding to the A549 cell surface. Recombinant fiber proteins of Ad11p and Ad35 reciprocally blocked the binding of both viruses to the epithelial cells but they could not block Ad4. The hexon protein expression of Ad11p and Ad4 was 100 times more efficient than that of the Ad5 vector (pFG140), whereas the infectivity of Ad11p and Ad4 was 40- to 200-fold that of the commonly used Ad5v vector. Taken together, our findings demonstrate that Ad11p and Ad4 bind different receptor molecules and that the fibers of these two viruses provide the predominant high degree of binding, which obviously is a requirement for subsequent internalization and efficacious expression.

  • 14.
    Mei, Ya-Fang
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Segerman, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lindman, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hörnsten, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Human hematopoietic (CD34+) stem cells possess high-affinity receptors for adenovirus type 11p2004In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 328, no 2, p. 198-207Article in journal (Refereed)
    Abstract [en]

    Gene transfer into human hematopoietic stem cells using Ad5 is inefficient due to lack of the primary receptor CAR and the secondary receptors alphavbeta3 integrin and alphavbeta5 integrin, and due to the high seroprevalence of Ad5 antibodies in most adults, resulting in diminished gene transduction. In the present study, we screened six species (species A-F) of adenovirus, displaying different tropisms for interaction with CD34+ cells, at the level of virus attachment and expression. Virus particles were biotinylated and their binding capacity was determined by FACS analysis using streptavidin-FITC. Ad11p, Ad35, and Ad3 (species B) showed high binding affinity, while Ad7, Ad11a (species B), and Ad37 (species D) displayed intermediate affinity. Virions of Ad4 (species E), Ad5 (species C), Ad31 (species A), and Ad41 (species F) hardly bound to hematopoietic progenitor cells. Using a double-labeling system, we demonstrated that adenoviruses bind to quiescent CD34+ cells. Ad11p virions showed the highest affinity among the adenoviruses detected. We further confirmed that virus fiber-specific receptors were present on the hematopoietic progenitor cell surface, because both recombinant fiber of Ad11p and specific antiserum against rfiber could block virus attachment. The ability of the adenoviruses to infect hematopoietic cells was studied by immunofluorescence staining. The adenoviruses from species B and Ad37 showed higher infectivity than Ad31, Ad5, Ad4, and Ad41. Among the studied species B adenoviruses, Ad11p manifested a superior infectivity. Thus, we have confirmed that these cells have high-affinity receptors for species B:2 human adenovirus, Ad11p, and this virus may be used as candidate vector to target therapeutic genes to hematopoietic stem cells.

  • 15.
    Mei, Ya-Fang
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wu, Haidong
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hultenby, Kjell
    Silver, Jim
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Complete replication-competent adenovirus 11p vectors with E1 or E3 insertions show improved heat stability2016In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 497, p. 198-210Article in journal (Refereed)
    Abstract [en]

    Conventional adenovirus vectors harboring E1 or E3 deletions followed by the insertion of an exogenous gene show considerably reduced virion stability. Here, we report strategies to generate complete replication-competent Ad11p(RCAd11p) vectors that overcome the above disadvantage. A GFP cassette was successfully introduced either upstream of E1A or in the E3A region. The resulting vectors showed high expression levels of the hexon and E1genes and also strongly induced the cytopathic effect in targeted cells. When harboring oversized genomes, the RCAd11pE1 and RCAd11pE3 vectors showed significantly improved heat stability in comparison to Ad11pwt; of the three, RCAd11pE3 was the most tolerant to heat treatment. Electron microscopy showed that RCAd11pE3, RCAd11pE1, Ad11pwt, and Ad11pE1 Delmanifested dominant, moderate, minimum, or no full virus particles after heat treatment at 47°C for 5 h. Our results demonstrated that both genome size and the insertion site in the viral genome affect virion stability.

  • 16.
    Näslund, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lagerqvist, Nina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Habjan, Matthias
    Department of Virology, University of Freiburg, D-79008 Freiburg, Germany.
    Lundkvist, Ake
    Swedish Institute for Infectious Disease Control, SE-171 82 Solna, Sweden.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Weber, Friedemann
    Department of Virology, University of Freiburg, D-79008 Freiburg, Germany.
    Bucht, Göran
    Swedish Defence Research Agency, Department of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Vaccination with virus-like particles protects mice from lethal infection of Rift Valley fever virus2009In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 385, no 2, p. 409-415Article in journal (Refereed)
    Abstract [en]

    Rift Valley Fever virus (RVFV) regularly accounts for severe and often lethal outbreaks among livestock and humans in Africa. Safe and effective veterinarian and human vaccines are highly needed. We present evidence that administration of RVF virus-like particles (VLPs) induces protective immunity in mice. In an accompanying paper, (Habjan, M., Penski, N., Wagner, V., Spiegel, M., Overby, A.K., Kochs, G., Huiskonen, J., Weber, F., 2009. Efficient production of Rift Valley fever virus-like particles: the antiviral protein MxA can inhibit primary transcription of Bunyaviruses. Virology 385, 400-408) we report the production of these VLPs in mammalian cells. After three subsequent immunizations with 1x10(6) VLPs/dose, high titers of virus-neutralizing antibodies were detected; 11 out of 12 mice were protected from challenge and only 1 out of 12 mice survived infection in the control groups. VLP vaccination efficiently suppressed replication of the challenge virus, whereas in the control animals high RNA levels and increasing antibody titers against the nucleocapsid protein indicated extensive viral replication. Our study demonstrates that the RVF VLPs are highly immunogenic and confer protection against RVFV infection in mice. In the test groups, the vaccinated mice did not exhibit any side effects, and the lack of anti-nucleocapsid protein antibodies serologically distinguished vaccinated animals from experimentally infected animals.

  • 17. Peña Cárcamo, José R.
    et al.
    Morell, María L.
    Vázquez, Cecilia A.
    Vatansever, Sezen
    Upadhyay, Arunkumar S.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Cordo, Sandra M.
    García, Cybele C.
    The interplay between viperin antiviral activity, lipid droplets and Junín mammarenavirus multiplication2018In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 514, p. 216-229Article in journal (Refereed)
    Abstract [en]

    Junín arenavirus infections are associated with high levels of interferons in both severe and fatal cases. Upon Junín virus (JUNV) infection a cell signaling cascade initiates, that ultimately attempts to limit viral replication and prevent infection progression through the expression of host antiviral proteins. The interferon stimulated gene (ISG) viperin has drawn our attention as it has been highlighted as an important antiviral protein against several viral infections. The studies of the mechanistic actions of viperin have described important functional domains relating its antiviral and immune-modulating actions through cellular lipid structures. In line with this, through silencing and overexpression approaches, we have identified viperin as an antiviral ISG against JUNV. In addition, we found that lipid droplet structures are modulated during JUNV infection, suggesting its relevance for proper virus multiplication. Furthermore, our confocal microscopy images, bioinformatics and functional results also revealed viperin-JUNV protein interactions that might be participating in this antiviral pathway at lipid droplet level. Altogether, these results will help to better understand the factors mediating innate immunity in arenavirus infection and may lead to the development of pharmacological agents that can boost their effectiveness thereby leading to new treatments for this viral disease.

  • 18.
    Segerman, Anna
    et al.
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Lindman, Kristina
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Mei, Ya-Fang
    Allard, Annika
    Wadell, Göran
    Adenovirus types 11p and 35 attach to and infect primary lymphocytes and monocytes, but hexon expression in T-cells requires prior activation.2006In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 349, no 1, p. 96-111Article in journal (Refereed)
    Abstract [en]

    Hematopoietic cells are attractive targets for gene therapy, but the conventional adenovirus (Ad) vectors, based on Ad5, transduce these cells inefficiently. One reason for low permissiveness of hematopoietic cells to infection by species C Ads appears to be inefficient attachment. Vectors pseudotyped with species B fibers are clearly more efficient at transducing hematopoietic cells than Ad5. To evaluate which Ad species B type(s) would be the most efficient vector(s) for primary T-cells, B-cells and monocytes, attachment to and entry of the species B1 serotypes 3p and 7p and the species B2 serotypes 11p and 35 into primary PBMCs was studied. Ad11p and Ad35 were the only serotypes to show efficient binding and for which uptake by PBMCs could be detected. Infection of PBMCs by Ad5, Ad11p and Ad35 was compared. Expression of Ad hexons was detected in stimulated PBMCs, most frequently in T-cells, and in unstimulated monocytes, although B-cells appear to be refractory to productive infection. Replication of Ad DNA was severely restricted in most PBMCs. Neither hexon expression nor genome replication could be detected in unstimulated lymphocytes, but FISH and a real-time PCR-based assay suggested that Ad11p and Ad35 DNA reach the nucleus. Activation thus appears to be required for T-cells to be permissive to Ad gene expression. In summary, there are substantial differences between Ad3p and Ad7p on the one hand and Ad11p and Ad35 on the other, in their ability to interact with PBMCs. Ad11p and Ad35 probably represent vectors of choice for these cell types.

  • 19. Vogt, Alexander
    et al.
    Scull, Margaret A
    Friling, Tamar
    Horwitz, Joshua A
    Donovan, Bridget M
    Dorner, Marcus
    Gerold, Gisa
    Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA.
    Labitt, Rachael N
    Rice, Charles M
    Ploss, Alexander
    Recapitulation of the hepatitis C virus life-cycle in engineered murine cell lines2013In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 444, no 1-2, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV) remains a major medical problem. In-depth study of HCV pathogenesis and immune responses is hampered by the lack of suitable small animal models. The narrow host range of HCV remains incompletely understood. We demonstrate that the entire HCV life-cycle can be recapitulated in mouse cells. We show that antiviral signaling interferes with HCV RNA replication in mouse cells. We were able to infect mouse cells expressing human CD81 and occludin (OCLN)-the minimal set of entry factor factors required for HCV uptake into mouse cells. Infected mouse cells sustain HCV RNA replication in the presence of miR122 and release infectious particles when mouse apoE is supplied. Our data demonstrate that the barriers of HCV interspecies transmission can be overcome by engineering a suitable cellular environment and provide a blue-print towards constructing a small animal model for HCV infection.

1 - 19 of 19
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