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  • 1.
    Andersson, S
    et al.
    Örebro University.
    Brave, A
    Swedish Institute for Infectious Disease Control.
    Kalbina, I
    Örebro University.
    Saevenstrand, H
    Örebro University.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Strid, A
    Örebro University.
    Feeding of Mice with Transgenic Arabidopsis Thaliana Expressing HIV-1 Subtype C p24 gives Rise to Systemic Immune Response2008In: AIDS RESEARCH AND HUMAN RETROVIRUSES, ISSN 0889-2229, vol 24, 2008, Vol. 24, p. 95-95Conference paper (Refereed)
  • 2. Boberg, Andreas
    et al.
    Bråve, Andreas
    Johansson, Susanne
    Wahren, Britta
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Rollman, Erik
    Murine models for HIV vaccination and challenge2008In: Expert Review of Vaccines, ISSN 1476-0584, E-ISSN 1744-8395, Vol. 7, no 1, p. 117-130Article in journal (Refereed)
    Abstract [en]

    HIV-1 only infects humans and chimpanzees. SIV or SHIV are, therefore, used as models for HIV in rhesus, cynomologus and pigtail macaques. Since conducting experiments in primate models does not fully mimic infection or vaccination against HIV-1 and is expensive, there is a great need for small-animal models in which it is possible to study HIV-1 infection, immunity and vaccine efficacy. This review summarizes the available murine models for studying HIV-1 infection with an emphasis on our experience of the HIV-1-infected-cell challenge as a model for evaluating candidate HIV-1 vaccines. In the cell-based challenge model, several important factors that, hopefully, can be related to vaccine efficacy in humans were discovered: the efficiency of combining plasmid DNA representing several of the viral genes originating from multiple clades of HIV-1, the importance of adjuvants activating innate and induced immunity and the enhanced HIV eradication by drug-conjugated antibody. © 2008 Future Drugs Ltd.

  • 3. Boberg, Andreas
    et al.
    Dominici, Sabrina
    Brave, Andreas
    Hallermalm, Kristian
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Magnani, Mauro
    Wahren, Britta
    Immunization with HIV protease peptides linked to syngeneic erythrocytes2007In: Infectious Agents and Cancer, ISSN 1750-9378, Vol. 2, no 1Article in journal (Refereed)
    Abstract [en]

    New potent vaccine adjuvants are desirable for increasing the efficacy of novel vaccine modalities such as DNA and peptides. We therefore tested if syngeneic erythrocytes could serve as delivery vectors for selected HIV peptides and compared the potency of these constructs to immunization with peptides in phosphate buffered saline or in incomplete Freunds adjuvant Immunization of mice with peptides in a low dose (5 ng) coupled to erythrocytes induced a weak immune response in mice. These peptides alone (5 μg) gave no immune responses, while formulating the peptides (50 μg) in IFA induced strong homologous immunity as well as prominent cross reactivity to a related mutant epitope. Thus, vaccine delivery using syngeneic erythrocytes, although attractive for clinical use, might be of limited value due to the low amount of antigen that can be loaded per erythrocyte.

  • 4.
    Boberg, Andreas
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Stålnacke, Alexandra
    Etvax AB, Solna, Sweden.
    Bråve, Andreas
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Wahren, Britta
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Carlin, Nils
    Etvax AB, Solna, Sweden.
    Receptor binding by cholera toxin B-subunit and amino acid modification improves minimal peptide immunogenecity2012In: ISRN Molecular Biology, ISSN 2090-7907, Vol. 2012, article id 170676Article in journal (Refereed)
    Abstract [en]

    We increase our understanding of augmenting a cellular immune response, by using an HIV-1 protease-derived epitope (PR7584), and variants thereof, coupled to the C-terminal, of the B subunit of cholera toxin (CTB). Fusion proteins were used for immunizations of HLA-A0201 transgenic C57BL/6 mice. We observed different capacities to elicit a cellular immune response by peptides with additions of five to ten amino acids to the PR epitope. There was a positive correlation between the magnitude of the elicited cellular immune response and the capacity of the fusion protein to bind GM-1. This binding capacity is affected by its ability to form natural pentamers of CTB. Our results suggest that functional CTB pentamers containing a foreign amino acid-modified epitope is a novel way to overcome the limited cellular immunogenicity of minimal peptide antigens. This way of using a functional assay as readout for improved cellular immunogenicity might become highly valuable for difficult immunogens such as short peptides (epitopes).

  • 5.
    Brave, Andreas
    et al.
    Karolinska Institute.
    Johansson, Ulrika
    Karolinska University.
    Hallengard, David
    Karolinska Institute.
    Heidari, Shirin
    Karolinska University.
    Gullberg, Hanna
    Karolinska University.
    Wahren, Britta
    Karolinska Institute.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Spetz, Anna-Lena
    Karolinska University.
    Induction of HIV-1-specific cellular and humoral immune responses following immunization with HIV-DNA adjuvanted with activated apoptotic lymphocytes2010In: VACCINE, ISSN 0264-410X, Vol. 28, no 9, p. 2080-2087Article in journal (Refereed)
    Abstract [en]

    Delivery of DNA encoding foreign antigens into mammalian cells can induce adaptive immune responses. There are currently many DNA-based vaccines in clinical trials against infectious diseases and cancer but there is a lack of adjuvants for improvement of responses to DNA-based vaccines. Here, we show augmented systemic and mucosa-associated B cell responses after immunization with a cocktail of seven different plasmids (3 env, 2 gag, 1 rev, 1 RT) combined with mitogen activated apoptotic syngeneic lymphocytes in mice. In addition we show that apoptotic cells can function as adjuvant for induction of cellular immune responses in a magnitude comparable to the cytokine adjuvant GM-CSF in mice. These data suggest that activated apoptotic lymphocytes can act independent as adjuvants to improve antigen-specific DNA vaccines.

  • 6.
    Bråve, Andreas
    et al.
    Swedish Institute for Infectious Disease Control & Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Sweden .
    Johansen, Kari
    Swedish Institute for Infectious Disease Control & Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Sweden .
    Palma, Paolo
    Division of Immunology and Infectious Diseases, Ospedale Pediatrico Bambino Gesù and Chair of Paediatrics, Department of Public Health, University of Rome Tor Vergata, Italy .
    Benthin, Reinhold
    Swedish Institute for Infectious Disease Control & Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Sweden .
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Maternal immune status influences HIV-specific immune responses in pups after DNA prime protein boost using mucosal adjuvant2008In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 26, no 47, p. 5957-5966Article in journal (Refereed)
    Abstract [en]

    This study was designed to determine the impact of maternal HIV-1 specific immunity on HIV-DNA immunization of 2 weeks old pups during the breast-feeding period.

    Adult female mice received intranasal or intradermal HIV DNA (gp160Env, p37Gag, Nef, Tat and Rev) prime and recombinant protein booster immunizations that induced mucosal and systemic HIV-1 specific B and T cell responses. Intranasal administration of the immunogens induced higher serum IgG titers to HIV antigens than the intradermal immunization. Furthermore, predominantly higher HIV-1 specific fecal IgA titers were obtained in nasally immunized mice. The capacity to respond to one single prime with DNA and one boost with recombinant protein was then compared in pups born to mothers displaying HIV-1-specific immune responses and in pups born to non-vaccinated mothers. Immune responses to the greatest number of antigens were detected in pups born to mothers having the highest HIV-1 specific immune responses. These data suggest that HIV-1 DNA-plasmid immunization during breast-feeding and recombinant protein boosting shortly thereafter enhances the breadth of the humoral HIV-1 specific immune responses.

  • 7. Bråve, Andreas
    et al.
    Hallengärd, David
    Schröder, Ulf
    Blomberg, Pontus
    Wahren, Britta
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Intranasal immunization of young mice with a multigene HIV-1 vaccine in combination with the N3 adjuvant induces mucosal and systemic immune responses2008In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 26, no 40, p. 5075-5078Article in journal (Refereed)
    Abstract [en]

    One of the major challenges for the development of an HIV vaccine is to induce potent virus-specific immune responses at the mucosal surfaces where transmission of virus occurs. Intranasal delivery of classical vaccines has been shown to induce good mucosal antibody responses, but so far for genetic vaccines the success has been limited. This study shows that young individuals are sensitive to nasal immunization with a genetic vaccine delivered in a formulation of a lipid adjuvant, the Eurocine N3. Intranasal delivery of a multiclade/multigene HIV-1 genetic vaccine gave rise to vaginal and rectal IgA responses as well as systemic humoral and cellular responses. As electroporation might become the preferred means of delivering genetic vaccines for systemic HIV immunity, nasal delivery by droplet formulation in a lipid adjuvant might become a means of priming or boosting the mucosal immunity. © 2008 Elsevier Ltd. All rights reserved.

  • 8.
    Buonaguro, L
    et al.
    Viral Oncogenesis and Immunotherapies & AIDS Reference Center, Italy.
    Devito, C
    Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Tornesello, ML
    Viral Oncogenesis and Immunotherapies & AIDS Reference Center, Italy.
    Schröder, U
    Eurocine Vaccines AB, Sweden.
    Wahren, B
    Karolinska Institute, Sweden.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Buonaguro, FM
    Viral Oncogenesis and Immunotherapies & AIDS Reference Center, Italy.
    DNA-VLP prime-boost intra-nasal immunization induces cellular and humoral anti-HIV-1 systemic and mucosal immunity with cross-clade neutralizing activity2007In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 25, no 32, p. 5968-5977Article in journal (Refereed)
    Abstract [en]

    The immune response to HIV-1 virus-like particles (VLPs), presenting a clade A Ugandan gp120, has been evaluated in a mouse model by intra-nasal (i.n.) administration by a VLP + VLP homologous or a DNA + VLP heterologous prime-boost immunization protocol, including a HIV-1 DNA gp160/rev plasmid. Furthermore, the effect of the Eurocine lipid-based mucosal L3 adjuvant on the VLP immunogenicity has been assessed as well. The designed heterologous protocol is able to increase the env-specific humoral and cellular immune response, compared to the homologous protocol, which is to some extent increased by the administration of L3-adjuvanted VLP boosting dose. The anti-gag response is statistically increased in both homologous and heterologous protocols, particularly when the VLP boosting dose is adjuvanted. Immune sera from immunized animals exhibit >50% ex vivo neutralizing activity against heterologous A and B-clade viral isolates. An envelope B-cell epitope mapping shows an enhanced response against V3 epitopes all across the C2-V5 region in the heterologous prime-boost immunization strategy. The induction of humoral immunity at mucosal sites, which represents the main port of entry for the HIV-1 infection, is extremely relevant. In this framework, the DNA-VLP heterologous prime-boost protocol appears a promising preventive vaccine approach which can significantly benefit from specific mucosal adjuvants, as the Eurocine L3. © 2007 Elsevier Ltd. All rights reserved.

  • 9.
    Buonaguro, L
    et al.
    NCI Fond Pascale, Naples.
    Tornesello, M
    NCI Fond Pascale, Naples.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Schroder, U
    Eurocine Vaccines AB.
    Wahren, B
    Karolinska Inst.
    Buonaguro, F M
    NCI Fond Pascale, Naples.
    Induction of Mucosal Immunity by HIV-1 VLPs Administered Intra-Nasally in Prime/Boost Protocols2008In: AIDS RESEARCH AND HUMAN RETROVIRUSES, ISSN 0889-2229, vol 24, 2008, Vol. 24, p. 88-88Conference paper (Refereed)
  • 10.
    Buonaguro, Luigi
    et al.
    Istituto Nazionale Tumori Fond. G. Pascale, Naples, Italy.
    Tagliamonte, Maria
    Istituto Nazionale Tumori Fond. G. Pascale, Naples, Italy.
    Visciano, Maria Luisa
    Istituto Nazionale Tumori Fond. G. Pascale, Naples, Italy.
    Andersen, Hanne
    Bioqual Inc., Rockville, Maryland, USA.
    Lewis, Mark
    Bioqual Inc., Rockville, Maryland, USA.
    Pal, Ranajit
    Advanced BioScience Laboratories, Inc., Kensington, Maryland, USA.
    Torneselloa, Maria Lina
    Istituto Nazionale Tumori Fond. G. Pascale, Naples, Italy.
    Schroeder, Ulf
    Karolinska Institutet Science Park, Stockholm, Sweden.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Wahren, Britta
    Swedish Institute for Infectious Disease Control, Stockholm, Sweden.
    Buonaguro, Franco M.
    Istituto Nazionale Tumori Fond. G. Pascale, Naples, Italy.
    Immunogenicity of HIV Virus-Like Particles in Rhesus Macaques by Intranasal Administration2012In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 19, no 6, p. 970-973Article in journal (Refereed)
    Abstract [en]

    Female rhesus macaques were immunized with HIV virus-like particles (HIV-VLPs) or HIV DNA administered as sequential combinations of mucosal (intranasal) and systemic (intramuscular) routes, according to homologous or heterologous prime-boost schedules. The results show that in rhesus macaques only the sequential intranasal and intramuscular administration of HIV-VLPs, and not the intranasal alone, is able to elicit humoral immune response at the systemic as well as the vaginal level.

  • 11.
    Chang, Chien-Hsing
    et al.
    Morris Plains, New Jersey, United States of America.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Loo, Meiyu
    Morris Plains, New Jersey, United States of America.
    Falkeborn, Tina
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Li, Rongxiu
    Morris Plains, New Jersey, United States of America.
    Cardillo, Thomas M.
    Morris Plains, New Jersey, United States of America.
    Rossi, Edmund A.
    Morris Plains, New Jersey, United States of America.
    Goldenberg, David M.
    Morris Plains, New Jersey, United States of America.
    Wahren, Britta
    Karolinska Institutet, Stockholm, Sweden.
    A Novel Class of Anti-HIV Agents with Multiple Copies of Enfuvirtide Enhances Inhibition of Viral Replication and Cellular Transmission In Vitro2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e41235-e41235Article in journal (Refereed)
    Abstract [en]

    We constructed novel HIV-1 fusion inhibitors that may overcome the current limitations of enfuvirtide, the first such therapeutic in this class. The three prototypes generated by the Dock-and-Lock (DNL) technology to comprise four copies of enfuvirtide tethered site-specifically to the Fc end of different humanized monoclonal antibodies potently neutralize primary isolates (both R5-tropic and X4-tropic), as well as T-cell-adapted strains of HIV-1 in vitro. All three prototypes show EC50 values in the subnanomolar range, which are 10- to 100-fold lower than enfuvirtide and attainable whether or not the constitutive antibody targets HIV-1. The potential of such conjugates to purge latently infected cells was also demonstrated in a cell-to-cell viral inhibition assay by measuring their efficacy to inhibit the spread of HIV-1LAI from infected human peripheral blood mononuclear cells to Jurkat T cells over a period of 30 days following viral activation with 100 nM SAHA (suberoylanilide hydroxamic acid). The IgG-like half-life was not significantly different from that of the parental antibody, as shown by the mean serum concentration of one prototype in mice at 72 h. These encouraging results provide a rationale to develop further novel anti-HIV agents by coupling additional antibodies of interest with alternative HIV-inhibitors via recombinantly-produced, self-assembling, modules.

  • 12.
    Che, Karlhans Fru
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Shankar, Esaki M
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Sundaram, Muthu
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Messmer, Davorka
    Moores Cancer Center, University of California San Diego, La Jolla, USA.
    Bhardwa, N
    New York University School of Medicine, New York, NY, USA.
    Lifson, Jeffrey D
    AIDS and Cancer Virus Program SAIC Frederick Inc., National Cancer Institute at Frederick, Maryland, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Cross Talk between P38MAPK and STAT3 Regulates Expression of Negative Costimulatory Molecules and Transcriptional Repressors in HIV-1 Primed T cellsManuscript (preprint) (Other academic)
    Abstract [en]

    HIV-1 infection enhances the expression of negative costimulatory molecules on T cellsleading to T cell impairment. The signaling pathway underlying the regulation ofinhibitory molecules and the subsequent onset of T cell impairment remains to beinvestigated. Herein, we showed that the T cells activated by HIV-pulsed dendritic cells(DCs) upregulated CTLA-4, TRAIL, LAG-3, TIM-3, and CD160 and suppressionassociated transcription factors BLIMP-1, DTX1, and FOXP3, leading to T cellsuppression. The induction of suppressor T cells was regulated by the signal transducerand activator of transcription 3 (STAT3) molecules as blockade of this pathwaysignificantly down regulates the expression of inhibitory molecules. The cytokines IL-6and IL-10 were not responsible for STAT3 activation as their neutralization could neitherrecover T cell proliferation nor decrease the expression of negative costimulatorymolecules. Contrarily, we demonstrated that the intracytoplasmic cross-talk of P38Mitogen-Activated Protein Kinase (MAPK) with STAT3 was responsible as blockade ofthe P38MAPK significantly impaired negative costimulatory molecular expression andthe subsequent recovery of T cell proliferation. Notably, the blockade of viral access toDC cytosol, via CD4 binding and fusion, significantly reduced the negative effects DCsimposed on the primed T cells. In conclusion, viral access to cytosol modulated theDCs- T cell priming to induce T cells with upreguled expression of negativecostimulatory molecules in a P38MAPK/STAT3 pathway dependent fashion

  • 13.
    Che, Karlhans Fru
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Shankar, Esaki Muthu
    University of Malaya, Malaysia .
    Muthu, Sundaram
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Messmer, Davorka
    University of California, San Diego, United States.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    p38 Mitogen-Activated Protein Kinase/Signal Transducer and Activator of Transcription-3 Pathway Signaling Regulates Expression of Inhibitory Molecules in T Cells Activated by HIV-1-Exposed Dendritic Cells2012In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 18, no 8, p. 1169-1182Article in journal (Refereed)
    Abstract [en]

    Human immunodeficiency virus type 1 (HIV-1) infection enhances the expression of inhibitory molecules on T cells, leading to T-cell impairment. The signaling pathways underlying the regulation of inhibitory molecules and subsequent onset of T-cell impairment remain elusive. We showed that both autologous and allogeneic T cells exposed to HIV-pulsed dendritic cells (DCs) upregulated cytotoxic T-lymphocyte antigen (CTLA-4), tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), lymphocyte-activation gene-3 (LAG3). T-cell immunoglobulin mucin-3 (TIM-3), CD160 and certain suppression-associated transcription factors, such as B-lymphocyte induced maturation protein-1 (BLIMP-1), deltex homolog 1 protein (DTX1) and forkhead box P3 (FOXP3), leading to T-cell suppression. This induction was regulated by p38 mitogen-activated protein kinase/signal transducer and activator of transcription-3 (P38MAPK/STAT3) pathways, because their blockade significantly abrogated expression of all the inhibitory molecules studied and a subsequent recovery in T-cell proliferation. Neither interleukin-6 (IL-6) nor IL-10 nor growth factors known to activate STAT3 signaling events were responsible for STAT3 activation. Involvement of the P38MAPK/STAT3 pathways was evident because these proteins had a higher level of phosphorylation in the HIV-1-primed cells. Furthermore, blockade of viral CD4 binding and fusion significantly reduced the negative effects DCs imposed on primed T cells. In conclusion, HIV-1 interaction with DCs modulated their functionality, causing them to trigger the activation of the P38MAPK/STAT3 pathway in T cells, which was responsible for the upregulation of inhibitory molecules. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00103

  • 14.
    Ellegård, Rada
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Crisci, Elisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Shankar, Esaki M.
    University of Malaya, Malaysia.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-12015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 4, p. 1698-1704Article in journal (Refereed)
    Abstract [en]

    Mucosa resident dendritic cells (DCs) may represent one of the first immune cells that HIV-1 encounters during sexual transmission. The virions in body fluids can be opsonized with complement factors because of HIV-mediated triggering of the complement cascade, and this appears to influence numerous aspects of the immune defense targeting the virus. One key attribute of host defense is the ability to attract immune cells to the site of infection. In this study, we investigated whether the opsonization of HIV with complement (C-HIV) or a mixture of complement and Abs (CI-HIV) affected the cytokine and chemokine responses generated by DCs, as well as their ability to attract other immune cells. We found that the expression levels of CXCL8, CXCL10, CCL3, and CCL17 were lowered after exposure to either C-HIV or CI-HIV relative to free HIV (F-HIV). DCs exposed to F-HIV induced higher cell migration, consisting mainly of NK cells, compared with opsonized virus, and the chemotaxis of NK cells was dependent on CCL3 and CXCL10. NK cell exposure to supernatants derived from HIV-exposed DCs showed that F-HIV induced phenotypic activation (e.g., increased levels of TIM3, CD69, and CD25) and effector function (e.g., production of IFN gamma and killing of target cells) in NK cells, whereas C-HIV and CI-HIV did not. The impairment of NK cell recruitment by DCs exposed to complement-opsonized HIV and the lack of NK activation may contribute to the failure of innate immune responses to control HIV at the site of initial mucosa infection.

  • 15.
    Ellegård, Rada
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Crisci, Elisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Burgener, Adam
    University of Manitoba, Winnipeg, Canada; Public Health Agency of Canada, Winnipeg, Canada.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Birse, Kenzie
    University of Manitoba, Winnipeg, Canada; Public Health Agency of Canada, Winnipeg, Canada.
    Westmacott, Garrett
    Public Health Agency of Canada, Winnipeg, Canada.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Lifson, Jeffrey D.
    Leidos Biomedical Research, Inc., Frederick, MD, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Complement Opsonization of HIV-1 Results in Decreased Antiviral and Inflammatory Responses in Immature Dendritic Cells via CR32014In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 9, p. 4590-4601Article in journal (Refereed)
    Abstract [en]

    Immature dendritic cells (iDCs) in genital and rectal mucosa may be one of the first cells to come into contact with HIV-1 during sexual transmission of virus. HIV-1 activates the host complement system, which results in opsonization of virus by inactivated complement fragments, for example, iC3b. We investigated antiviral and inflammatory responses induced in human iDCs after exposure to free HIV-1 (F-HIV), complement-opsonized HIV-1 (C-HIV), and complement and Ab-opsonized HIV-1 (CI-HIV). F-HIV gave rise to a significantly higher expression of antiviral factors such as IFN-beta, myxovirus resistance protein A, and IFN-stimulated genes, compared with C-HIV and CI-HIV. Additionally, F-HIV induced inflammatory factors such as IL-1 beta, IL-6, and TNF-alpha, whereas these responses were weakened or absent after C-HIV or CI-HIV exposure. The responses induced by F-HIV were TLR8-dependent with subsequent activation of IFN regulatory factor 1, p38, ERK, PI3K, and NF-kappa B pathways, whereas these responses were not induced by C-HIV, which instead induced activation of IFN regulatory factor 3 and Lyn. This modulation of TLR8 signaling was mediated by complement receptor 3 and led to enhanced infection. The impact that viral hijacking of the complement system has on iDC function could be an important immune evasion mechanism used by HIV-1 to establish infection in the host.

  • 16.
    Falkeborn, Tina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Asahara, Naomi
    Advanced Medical Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Japan.
    Hayashi, Masayuki
    Advanced Medical Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Japan.
    Arai, Masaaki
    Advanced Medical Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Japan.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Maltais, Anna-Karin
    Eurocine Vaccines AB, Karolinska Institutet Science Park, Solna, Sweden.
    Comparison of the mucosal adjuvant Endocine™ with two well-known adjuvants: cholera toxin and alum2015In: Jacobs Journal of Vaccine and Vaccination, ISSN 2381-2664, Vol. 1, no 1, article id 006Article in journal (Refereed)
    Abstract [en]

    To enable efficient mucosal vaccination with split or subunit antigens, an adjuvant is often needed. To date, no mucosal adjuvants are approved for human use, however, there are a variety of mucosal adjuvants in development, including the liposome-based adjuvant Endocine™. The aim of this study was to evaluate split influenza antigens together with Endocine™ and in order to assess the potency of Endocine™, the induction of humoral immune responses were compared to those following influenza vaccination with cholera toxin (CT) or aluminum salt (alum). We show that Endocine™ significantly enhances influenza-specific immune responses in intranasally immunized mice compared to nonadjuvanted vaccine. Furthermore, vaccines adjuvanted with Endocine™ evoked comparable serum IgG and virus neutralizing (VN) antibody titers as nasal vaccines adjuvanted with CT. Compared to parenteral vaccination with alum, Endocine™ triggered significantly higher mucosal and serum IgA titers, and similar VN titers. Taken together, these results support further development of Endocine™ as a mucosal adjuvant and as part of a nasal influenza vaccine candidate.

  • 17.
    Falkeborn, Tina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Brave, Andreas
    Swedish Institute Communicable Disease Control SMI, Sweden.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Åkerlind, Britt
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Microbiology.
    Schroder, Ulf
    Eurocine Vaccines AB, Sweden.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Endocine™, N3OA and N3OASq; Three Mucosal Adjuvants That Enhance the Immune Response to Nasal Influenza Vaccination2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8Article in journal (Refereed)
    Abstract [en]

    Annual outbreaks of seasonal influenza are controlled or prevented through vaccination in many countries. The seasonal vaccines used are either inactivated, currently administered parenterally, or live-attenuated given intranasally. In this study three mucosal adjuvants were examined for the influence on the humoral (mucosal and systemic) and cellular influenza A-specific immune responses induced by a nasally administered vaccine. We investigated in detail how the anionic Endocine™ and the cationic adjuvants N3OA and N3OASq mixed with a split inactivated influenza vaccine induced influenza A-specific immune responses as compared to the vaccine alone after intranasal immunization. The study showed that nasal administration of a split virus vaccine together with Endocine™ or N3OA induced significantly higher humoral and cell-mediated immune responses than the non-adjuvanted vaccine. N3OASq only significantly increased the cell-mediated immune response. Furthermore, nasal administration of the influenza vaccine in combination with any of the adjuvants; Endocine™, N3OA or N3OASq, significantly enhanced the mucosal immunity against influenza HA protein. Thus the addition of these mucosal adjuvants leads to enhanced immunity in the most relevant tissues, the upper respiratory tract and the systemic circulation. Nasal influenza vaccination with an inactivated split vaccine can therefore provide an important mucosal immune response, which is often low or absent after traditional parenteral vaccination.

  • 18.
    Falkeborn, Tina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Lindberg, Alf
    Eurocine Vaccines AB, Karolinska Institutet Science Park, Solna, Sweden.
    Maltais, Anna-Karin
    Eurocine Vaccines AB, Karolinska Institutet Science Park, Solna, Sweden.
    The mucosal adjuvant 1 Endocine™ increases immune responses to influenza antigen in aged miceManuscript (preprint) (Other academic)
    Abstract [en]

    More effective influenza vaccines for the elderly population is needed. The vaccines used today are less effective in elderly compared to in adults. It is more difficult to stimulate a protective immune response in elderly due to immunosenescence. Elderly people have a decline in both humoral and cell mediated immunity, which make them more susceptible to viral infections. The aim of this study was to evaluate the mucosal adjuvant Endocine™ together with split influenza antigen in different ages of BALB/c mice (15, 20 and 25 months old). The results from this study show that a nasal influenza vaccine  formulated with Endocine™ enhanced both systemic and mucosal immune responses compared to an unadjuvanted vaccine delivered subcutaneously or intra nasal in aged mice. However, in the 25 months old mice only a very modest immune response was detected. Although the influenza-specific immune responses in aged mice were not induced to the same levels as achieved in young mice, the results show that nasal vaccine formulated with Endocine™ could provide benefits for the elderly.

  • 19. Harila, Kirsi
    et al.
    Prior, Ian
    Sjöberg, Mathilda
    Salminen, Antti
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Suomalainen, Maarit
    Vpu and Tsg101 regulate intracellular targeting of the human immunodeficiency virus type 1 core protein precursor Pr55gag2006In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 80, no 8, p. 3765-3772Article in journal (Refereed)
    Abstract [en]

    Assembly of human immunodeficiency virus type 1 (HIV-1) is directed by the viral core protein Pr55gag. Depending on the cell type, Pr55 gag accumulates either at the plasma membrane or on late endosomes/multivesicular bodies. Intracellular localization of Pr55 gag determines the site of virus assembly, but molecular mechanisms that define cell surface or endosomal targeting of Pr55gag are poorly characterized. We have analyzed targeting of newly synthesized Pr55 gag in HeLa H1 cells by pulse-chase studies and subcellular fractionations. Our results indicated that Pr55gag was inserted into the plasma membrane and, when coexpressed with the viral accessory protein Vpu, Pr55gag remained at the plasma membrane and virions assembled at this site. In contrast, Pr55gag expressed in the absence of Vpu was initially inserted into the plasma membrane, but subsequently endocytosed, and virus assembly was partially shifted to internal membranes. This endocytosis of Pr55gag required the host protein Tsg101. These results identified a previously unknown role for Vpu and Tsg101 as regulators for the endocytic uptake of Pr55gag and suggested that the site of HIV-1 assembly is determined by factors that regulate the endocytosis of Pr55gag. Copyright © 2006, American Society for Microbiology. All Rights Reserved.

  • 20. Harila, Kirsi
    et al.
    Salminen, Antti
    Prior, Ian
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Suomalainen, Maarit
    The Vpu-regulated endocytosis of HIV-1 Gag is clathrin-independent2007In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 369, no 2, p. 299-308Article in journal (Refereed)
    Abstract [en]

    Recent results by us and others have shown that the accessory protein Vpu determines plasma membrane versus endosomal accumulation of the HIV-1 core protein Gag and progeny virions in the HeLa model of HIV-1 infection, since Vpu suppresses endocytosis of cell surface-associated Gag. In this report, we used pulse-chase studies and subcellular fractionations to investigate endocytosis of newly synthesized Gag in HeLa HI cells. The uptake of Gag in Delta Vpu-virus background was not blocked by inhibitors of clathrin-mediated endocytosis and macropinocytosis. The cholesterol-sequestering drug filipin inhibited the uptake, but only if the drug was applied before extensive multimerization of Gag had taken place. Thus, the uptake mechanism most likely is only indirectly dependent on cholesterol. Our results also indicated that targeting phenotype of Gag was different in confluent versus subconfluent cell cultures, which could perhaps explain some of the controversies in intracellular targeting of Gag. (c) 2007 Elsevier Inc. All rights reserved.

  • 21.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Clarification of how HIV-1 DNA and protein immunizations may be better used to obtain HIV-1-specific mucosal and systemic immunity2007In: Expert Review of Vaccines, ISSN 1476-0584, E-ISSN 1744-8395, Vol. 6, no 2, p. 203-212Article in journal (Refereed)
    Abstract [en]

    More focused research on a mucosal HIV-1 vaccine is needed urgently. An increasing amount of collected data, using heterologous multimodality prime-booster strategies, suggest that an efficient and protective HIV-1 vaccine must generate broad, long-lasting HIV-specific CD8+ cytotoxic T-lymphocyte and neutralizing antibody responses. In the mucosa, these responses would be most effective if a preferential stimulus of HIV-1 neutralizing secretory immunoglobulin A and G were obtained. The attractive property of mucosal immunization is the obtained mucosal and systemic immunity, whereas systemic immunization induces a more limited immunity, predominantly in systemic sites. These objectives will require new vaccine regimens, such as multiclade HIV DNA and protein vaccines (nef, tat, gag and env expressed in DNA plasmids) delivered onto mucosal surfaces with needle-free delivery methods, such as nasal drop, as well as oral and rectal/vaginal delivery, and should merit clinical trials. © 2007 Future Drugs Ltd.

  • 22.
    Hinkula, Jorma
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Hagbom, Marie
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Wahren, Britta
    Swedish Institute for Infectious Disease Control Microbiology and Tumorbiology Center Karolinska Institute, Solna.
    Schröder, Ulf
    Eurocine AB Karolinska Science Park, Stockholm.
    Safety and immunogenicity, after nasal application of HIV-1 DNA gagp37 plasmid vaccine in young mice2008In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 26, no 40, p. 5101-5106Article in journal (Refereed)
    Abstract [en]

    Background: There is a need for safe and potent adjuvants capable of delivering vaccine candidates over the mucosal barrier, with good capacity to stimulate both mucosal and systemic cell-mediated and humoral immunity. An adjuvant aimed for intranasal delivery should preferably deliver the antigen and minimize the transfer into the close proximity of the central nervous system, thus avoiding damage on the olfactory tissues. Advantages with a mucosal delivery route would be to provide mucosal and systemic immunity, requiring lower vaccine doses then when given parentally. The aim of this study was to study if the N3 adjuvant intranasally administered with HIV DNA plasmids would be transferred into the olfactory tissues and cause local inflammation and tissue damage. Results: The N3 adjuvant alone and when combined with HIV-1 DNA gag plasmid and delivered intranasally did not cause detectable damage to the nasal epithelium or the olfactory epithelium or bulb over a period of 3 days after delivery. The intranasal administration of HIV-1 gagp37 DNA induced both a humoral and a cell-mediated immunity against the gag antigen. Significantly higher HIV-1-specific humoral, but not cell-mediated immune responses were seen in DNA/N3-immunized mice in comparison with HIV-1 DNA/saline-immunized animals. Conclusions: A safe and convenient intranasal mode of HIV-1 DNA plasmid and adjuvant delivery was shown not to interfere with the tissues in close proximity to the central nervous system. The N3 adjuvant combined with HIV-1 plasmids enhances the HIV-1-specific immunogenicity and merits to be clinically tested. © 2008 Elsevier Ltd. All rights reserved.

  • 23.
    Hinkula, Jorma
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Walther-Jallow, Lilian
    Karolinska University Hospital .
    Lauren, Anna
    Lund University.
    Makitalo, Barbro
    Karolinska University Hospital .
    Oberg, Monica
    Lund University.
    Wahren, Britta
    Karolinska Institute.
    Fenyo, Eva-Maria
    Lund University.
    Spetz, Anna-Lena
    Karolinska University Hospital .
    Neutralizing activity and cellular immune responses induced in mice after immunization with apoptotic HIV-1/murine leukemia virus infected cells2009In: VACCINE, ISSN 0264-410X, Vol. 27, no 46, p. 6424-6431Article in journal (Refereed)
    Abstract [en]

    Dendritic cells present microbial antigens to T cells after uptake of apoptotic vesicles from infected cells. We previously reported that immunizations with apoptotic HIV-1/murine leukemia virus (MuLV) infected cells lead to induction of both cellular and humoral immune responses as well as resistance to mucosal challenge with live HIV-1/MuLV infected cells. Here we extended those studies and investigated whether apoptotic cells from HIV-1/MuLV infected cells stimulate the production of HIV-1 neutralizing activity. We compared different routes of administration and were able to induce p24- and Nef-specific cellular proliferation after intraperitoneal (i.p.), intranasal (i.n.), subcutaneous (s.c.) and intramuscular (i.m.) immunizations. Serum IgG and IgA antibodies directed against gp160, p24, or Nef were also produced regardless of immunization route used. However, the induction of mucosa-associated IgAs from faeces or vaginal secretions were detected only after either i.p. or i.n. immunizations. We were able to measure neutralizing activity in sera of mice after i.p. and i.n. immunization. Neutralizing reactivity was also detected after s.c. and i.m. immunizations in the presence of the cytokine adjuvant granulocyte macrophage-colony stimulating factor (GM-CSF). Conclusively we show induction of cellular and humoral immune responses including neutralizing activity after immunization with apoptotic HIV-1/MuLV infected cells in mice. The results from this study support further evaluations using apoptotic cells as antigen delivery system for vaccination against HIV-1 in other animal models.

  • 24.
    Ignatowicz, Lech
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Mazurek, Jolanta
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Leepiyasakulchai, Chaniya
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Sköld, Markus
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology.
    Källenius, Gunilla
    Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden.
    Pawlowski, Andrzej
    Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden.
    Mycobacterium tuberculosis infection interferes with HIV vaccination in mice.2012In: PloS one, ISSN 1932-6203, Vol. 7, no 7, p. e41205-Article in journal (Refereed)
    Abstract [en]

    Tuberculosis (TB) has emerged as the most prominent bacterial disease found in human immunodeficiency virus (HIV)-positive individuals worldwide. Due to high prevalence of asymptomatic Mycobacterium tuberculosis (Mtb) infections, the future HIV vaccine in areas highly endemic for TB will often be administrated to individuals with an ongoing Mtb infection. The impact of concurrent Mtb infection on the immunogenicity of a HIV vaccine candidate, MultiHIV DNA/protein, was investigated in mice. We found that, depending on the vaccination route, mice infected with Mtb before the administration of the HIV vaccine showed impairment in both the magnitude and the quality of antibody and T cell responses to the vaccine components p24Gag and gp160Env. Mice infected with Mtb prior to intranasal HIV vaccination exhibited reduced p24Gag-specific serum IgG and IgA, and suppressed gp160Env-specific serum IgG as compared to respective titers in uninfected HIV-vaccinated controls. Importantly, in Mtb-infected mice that were HIV-vaccinated by the intramuscular route the virus neutralizing activity in serum was significantly decreased, relative to uninfected counterparts. In addition mice concurrently infected with Mtb had fewer p24Gag-specific IFN-γ-expressing T cells and multifunctional T cells in their spleens. These results suggest that Mtb infection might interfere with the outcome of prospective HIV vaccination in humans.

  • 25. Istrate, C
    et al.
    Douagi, I
    Charpilienne, A
    McInnerney, GM
    Hidmark, Å
    Johansen, K
    Larsson, Marie
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Poncet, D
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Bone marrow dendritic cells internalize live RF-81 bovine rotavirus and rotavirus-like particles (RF 2/6-GFP-VLP and RF 8*2/6/7-VLP) but are only activated by live bovine rotavirus2007In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 65, no 6, p. 494-502Article in journal (Refereed)
    Abstract [en]

    Dendritic cells (DC) represent the link between innate and adaptive immunity. They are classified as antigen-presenting cells (APC) and can initiate and modulate the immune response. To investigate the interaction with DCs, live RF-81 bovine rotavirus strain (RFV) and rotavirus-like particles (rota-VLP), RF 2/6-GFP-VLP and rota RF 8*2/6/7-VLP, were added in vitro to murine bone marrow-derived DCs (bmDCs). Live RFV, RF 2/6-GFP-VLP and RF 8*2/6/7-VLP all bound to bmDC and were internalized but only live RFV stimulated phenotypic maturation of the bmDCs as shown by the upregulation of the co-stimulatory molecule CD86. Even though bmDCs internalized RF 2/6-GFP-VLP and RF 8*2/6/7-VLP as efficiently as live RFV, these rota-VLP were not able to activate the cells. Supernatants derived from bmDC cultures treated with live RFV, RF 2/6-GFP-VLP or RF 8*2/6/7-VLP were examined for TNF-α production. At 6, 18 and 24 h post-infection, TNF-α concentrations were significantly increased in cultures treated with live RFV and rota-VLP compared with untreated cultures. In conclusion, this study showed that live RF-81 bovine rotavirus strain was internalized and induced bmDCs activation, whereas both RF 2/6-GFP-VLP and RF 8*2/6/7-VLP were internalized by bmDCs without triggering their activation. © 2007 The Authors.

  • 26.
    Istrate, Claudia
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Charpilienne, Annie
    Poncet, Didier
    Cohen, Jean
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Johansen, Kari
    Parenteral administration of RF 8-2/6/7 rotavirus-like particles in a one-dose regimen induce protective immunity in mice2008In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 26, no 35, p. 4594-4601Article in journal (Refereed)
    Abstract [en]

    Rotavirus virus-like particles (RV-VLPs) represent a novel strategy for development of a rotavirus subunit vaccine. In this study, RF 8-2/6/7-VLPs with rotavirus VP8 protein (amino acid 1-241 of VP4) fused to the amino terminal end of a truncated VP2, were evaluated for their immunogenic and protective properties. A single intramuscular dose of, either 2 or 20 μg, RF 8-2/6/7-VLPs alone or combined with a potent adjuvant poly[di(carboxylatophenoxy)]phosphazene] (PCPP) induced rotavirus-specific serum IgG and IgA, fecal IgG titers that were enhanced 5-90-fold by adjuvant. Passive protective immunity was achieved in offspring to dams vaccinated with 2 and 20 μg RV-VLPs in presence of adjuvant and 20 μg RV-VLP without adjuvant. © 2008 Elsevier Ltd. All rights reserved.

  • 27.
    Jespers, Vicky
    et al.
    Institute for Tropical Medicine, Antwerp, Belgium .
    Harandi, Ali M
    University of Gothenburg.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Medaglini, Donata
    University of Siena.
    Le Grand, Roger
    DSV iMETI.
    Stahl-Hennig, Christiane
    German Primate Centre.
    Bogers, Willy
    Biomed Primate Research Centre.
    El Habib, Raphaelle
    Sanofi Pasteur.
    Wegmann, Frank
    University of Oxford.
    Fraser, Carol
    St Georges University London.
    Cranage, Martin
    St Georges University London.
    J Shattock, Robin
    Karolinska University Hospital.
    Assessment of mucosal immunity to HIV-12010In: EXPERT REVIEW OF VACCINES, ISSN 1476-0584, Vol. 9, no 4, p. 381-394Article in journal (Refereed)
    Abstract [en]

    A key gap in the development and evaluation of HIV-1 vaccines is insufficient knowledge with regard to sampling techniques and assessment of mucosal immune responses required for early prevention and inhibition of viral dissemination. In an attempt to start bridging this gap, the EUROPRISE network of scientists working on HIV-1 vaccine and microbicide research organized a workshop with the aim to review the types of mucosal responses/biomarkers currently measured in mucosal immunology and to define how the mucosal responses/biomarkers are measured and/or the assays and sampling methods used. The Workshop addressed two critical questions: first whether, with current knowledge, it would be possible to define a consensus set of mucosal sampling methods to facilitate cross-species comparisons and ensure standardized implementation in clinical trials; second to determine the remaining challenges (technical and logistical) and their possible solutions for assessing mucosal responses to HIV-1 vaccines.

  • 28. Johansson, Daniel X
    et al.
    Drakenberg, Katarina
    Hopmann, Kathrin H
    Schmidt, Alexej
    Yari, Fayezeh
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Persson, Mats AA
    Efficient expression of recombinant human monoclonal antibodies in Drosophila S2 cells2007In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 318, no 1-2, p. 37-46Article in journal (Refereed)
    Abstract [en]

    We have explored the Drosophila S2 cell line for expression of Ig molecules isolated as Fab or scFv cDNA from phage-displayed libraries. We present a series of vectors for inducible expression and secretion of human Ig heavy (HC) and light chains (LC), both on separate plasmids and in combination constructs. Both HC (tested as human γ1) and LC (human κ) could be expressed separately and were secreted into the medium, confirming previous reports. When the combination vector carrying both the HC and LC cDNA, as well as when the HC and LC vectors were co-transfected, complete IgG1 was found in the medium. Transient transfection resulted in production levels of 0.5-1 mg/l. Stable cell lines could be established within 2-3 weeks. After 10-12 days of expression from such cell lines, Ig molecules accumulated and the medium contained typically 5-35 mg/l of IgG1. The IgG in these preparations was purified to more than 90% purity on protein G columns. Binding characteristics for IgG of the same clone expressed in S2 cells or mammalian cells were indistinguishable. The main advantages with this system compared to mammalian expression were its robustness and the much faster establishment of stable, high level producing cell lines. © 2006 Elsevier B.V. All rights reserved.

  • 29. Johansson, E.
    et al.
    Istrate, Claudia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Charpilienne, A.
    Cohen, J.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Poncet, D.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Johansen, K.
    Amount of maternal rotavirus-specific antibodies influence the outcome of rotavirus vaccination of newborn mice with virus-like particles2008In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 26, no 6, p. 778-785Article in journal (Refereed)
    Abstract [en]

    In presence of low or high levels of rotavirus-specific maternal antibodies, the ability of newborn mice to respond to immunization with rotavirus RF 8*-2/6/7 VLPs, was evaluated. After parenteral vaccination, 100% of offspring born to low-antibody-titer dams developed rotavirus-specific IgG antibodies (n = 7). In contrast, only 25% of offsprings born to high-antibody-titer dams responded to parenteral immunization (n = 12). When comparing parenteral versus oral immunization in offspring to low-antibody-titer dams only 45% responded after oral immunization (n = 6). In conclusion, the response to parenteral immunization was not hampered by the presence of low levels of maternal antibodies induced by a natural infection while oral immunization was impaired. However, high levels of maternal antibodies impaired the response to parenteral immunization. © 2008 Elsevier Ltd. All rights reserved.

  • 30.
    Johansson, Susanne E
    et al.
    Karolinska Institutet.
    Bauner, Hanna
    Karolinska Institutet.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Wahren, Britta
    Karolinska Institutet.
    Berg, Louise
    Karolinska Institutet.
    Johansson, Maria H
    Karolinska Institutet.
    Accumulation and activation of natural killer cells in local intraperitoneal HIV-1/MuLV infection results in early control of virus infected cells2011In: Cellular Immunology, ISSN 0008-8749, E-ISSN 1090-2163, Vol. 272, no 1, p. 71-78Article in journal (Refereed)
    Abstract [en]

    Natural killer (NK) cells are important effectors in resistance to viral infections. The role of NK cells in the acute response to human immunodeficiency virus 1 (HIV-1) infected cells was investigated in a mouse model based on a HIV-1/murine leukemia virus (MuLV) pseudovirus. Splenocytes infected with HIV-1/MuLV were injected intraperitoneally and local immunologic responses and persistence of infected cells were investigated. In vivo depletion with an anti-NK1.1 antibody showed that NK cells are important in resistance to virus infected cells. Moreover, NK cell frequency in the peritoneal cavity increased in response to infected cells and these NK cells had a more mature phenotype, as determined by CD27 and Mac-1 expression. Interestingly, after injection of HIV-1/MuLV infected cells, but not MuLV infected cells, peritoneal NK cells had an increased cytotoxic activity.

  • 31.
    Johansson, Susanne E
    et al.
    Karolinska Institute.
    Hejdeman, Bo
    Soder Sjukhuset, Stockholm, Sweden .
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Johansson, Maria H
    Karolinska Institute.
    Romagne, Francois
    Innate Pharma, Marseille, France .
    Wahren, Britta
    Swedish Institute Infect Disease Control.
    Wagtmann, Nicolai R
    NovoNordisk, Bagsvaerd, Denmark .
    Karre, Klas
    Karolinska Institute.
    Berg, Louise
    Karolinska Institute.
    NK cell activation by KIR-binding antibody 1-7F9 and response to HIV-infected autologous cells in viremic and controller HIV-infected patients2010In: CLINICAL IMMUNOLOGY, ISSN 1521-6616, Vol. 134, no 2, p. 158-168Article in journal (Refereed)
    Abstract [en]

    Natural killer (NK) cells may be protective in HIV infection and are inhibited by killer cell immunoglobulin-like receptors (KIRs) interacting with MHC class I molecules, including HLA-C. Retention of HLA-C despite downregulation of other MHC class I molecules on HIV infected cells might protect infected cells from NK cell recognition in vitro. To assess the role of inhibitory HLA-C ligands in the capacity of NK cells to recognize autologous infected T cells, we measured NK cell degranulation in vitro in viremic patients, controllers with low viremia, and healthy donors. No difference in NK cell response to uninfected compared to HIV-1(IIIB) infected targets was observed. Activation of NK cells was regulated by KIRs, because NK cell degranulation was increased by 1-7F9, a human antibody that binds KIR2DL1/L2/L3 and KIR2DS1/S2, and this effect was most pronounced in KIR haplotype B individuals.

  • 32.
    Johansson, Susanne E
    et al.
    Karolinska Institute.
    Rollman, Erik
    University of Melbourne.
    Chung, Amy W
    University of Melbourne.
    Center, Rob J
    University of Melbourne.
    Hejdeman, Bo
    Söder Sjukhuset, Stockholm.
    Stratov, Ivan
    University of Melbourne.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Wahren, Britta
    Swedish Institute Infect Disease Control.
    Kaerre, Klas
    Karolinska Institute.
    Kent, Stephen J
    University of Melbourne.
    Berg, Louise
    Karolinska Institute.
    NK Cell Function and Antibodies Mediating ADCC in HIV-1-Infected Viremic and Controller Patients2011In: Viral immunology, ISSN 0882-8245, E-ISSN 1557-8976, Vol. 24, no 5, p. 359-368Article in journal (Refereed)
    Abstract [en]

    Natural killer (NK) cells have been suggested to play a protective role in HIV disease progression. One potent effector mechanism of NK cells is antibody-dependent cellular cytotoxicity (ADCC) mediated by antiviral antibodies binding to the Fc gamma RIIIa receptor (CD16) on NK cells. We investigated NK cell-mediated ADCC function and the presence of ADCC antibodies in plasma from 20 HIV-1-infected patients and 10 healthy donors. The HIV-positive patients were divided into two groups: six who controlled viremia for at least 8 y without treatment (controllers), and 14 who were persistently viremic and not currently on treatment. Plasma from both patient groups induced NK cell IFN-gamma expression and degranulation in response to HIV-1 envelope (Env) gp140-protein-coated cells. Patient antibodies mediating ADCC were largely directed towards the Env V3 loop, as identified by a gp140 protein lacking the V3 loop. Interestingly, in two controllers ADCC-mediating antibodies were more broadly directed to other parts of Env. A high viral load in patients correlated with decreased ADCC-mediated cytolysis of gp140-protein-coated target cells. NK cells from both infected patients and healthy donors degranulated efficiently in the presence of antibody-coated HIV-1-infected Jurkat cells. In conclusion, the character of ADCC-mediating antibodies differed in some controllers compared to viremic patients. NK cell ADCC activity is not compromised in HIV-infected patients.

  • 33. Johansson, Susanne
    et al.
    Goldenberg, David M
    Griffiths, Gary L
    Wahren, Britta
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Elimination of HIV-1 infection by treatment with a doxorubicin-conjugated anti-envelope antibody2006In: AIDS (London), ISSN 0269-9370, E-ISSN 1473-5571, Vol. 20, no 15, p. 1911-1915Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To test the efficacy of an immunoconjugate against HIV-1. DESIGN: A murine monoclonal antibody against the envelope antigen of HIV (P4/D10) was conjugated with the conventional anticancer drug, doxorubicin, and tested against infectious virus and infected cells, both in vitro and in vivo. METHODS: P4/D10 antibody was incubated with free virus (neutralization) or HIV-infected cells (inhibition) and the resulting infection was measured by a p24 capture enzyme-linked immunosorbent assay. In an HIV-1/MuLV murine challenge model, the ability of the conjugate to inhibit infection in vivo was measured. RESULTS: Doxorubicin-conjugated P4/D10 neutralized HIV-1IIIB and eliminated intercellular spread and HIV replication in infected Jurkat cells in vitro. The conjugate also protected mice from challenge with HIV-1IIIB/MuLV at an eightfold lower concentration than needed for free antibody, whereas no effects were observed for comparable doses of free drug or irrelevant conjugate controls. CONCLUSION: This indicates that doxorubicin is concentrated to HIV-infected cells by the P4/D10 antibody, significantly (P = 0.0001) contributing to HIV elimination. This concept could also be adapted to eradicate remaining antigen-expressing T cells in patients treated with antiretroviral therapy. © 2006 Lippincott Williams & Wilkins.

  • 34.
    Kindberg, Elin
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Hejdeman, Bo
    Bratt, Göran
    Wahren, Britta
    Lindblom, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Genetics.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    A nonsense mutation (428G→A) in the fucosyltransferase FUT2 gene affects the progression of HIV-1 infection2006In: AIDS (London), ISSN 0269-9370, E-ISSN 1473-5571, Vol. 20, no 5, p. 685-689Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The human FUT2 gene encodes the α(1,2)fucosyltransferase that determines secretor status. Homozygous for the nonsense mutation are called non-secretors and are unable to express histo-blood group antigens in secretions and on mucosal surfaces. In this study we have investigated the importance of the FUT2 fucosyltransferase activity on the progress of HIV-1 infection. METHODS: Swedish blood donors (n = 276), 15 long-term non-progressors (LTNP) and 19 progressors were genotyped with respect to the nonsense mutation 428G→A in the FUT2 gene. In addition 265/276 blood donors and 19 progressors with rapid or expected progression rate were Δ32 CCR5 genotyped. RESULTS: Of 276 blood donors 218 (79%) were found to be secretor positive (se+), either homozygous (se+/+) wild type (30%) or heterozygous (se+/-) (49%) and 58 (21%) were homozygous non-secretors (se-/-). Five LTNP (33%) were found to be secretor-positive (se+/+, se+/-) and 10 (67%) se-/-. Of the 19 individuals with normal HIV-1 progression 15 (79 %) were found to be secretor positive and four (21%) were non-secretors. No frequency differences were found in the Δ32 CCR5 allele among the groups studied. CONCLUSION: Strong association (P < 0.001) was observed between the nonsense mutation 428G→A in the FUT2 gene and a slow disease progression of HIV-1 infection. © 2006 Lippincott Williams & Wilkins.

  • 35.
    Lindh, Ingrid
    et al.
    Örebro University.
    Kalbina, Irina
    Örebro University.
    Thulin, Sara
    Örebro University.
    Scherbak, Nikolai
    Örebro University.
    Savenstrand, Helena
    Örebro University.
    Brave, Andreas
    Swedish Institute for Infectious Disease Control .
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Strid, Ake
    Örebro University.
    Andersson , Soren
    Swedish Institute for Infectious Disease Control .
    Feeding of mice with Arabidopsis thaliana expressing the HIV-1 subtype C p24 antigen gives rise to systemic immune responses2008In: APMIS: Acta pathologica, microbiologica et immunologica Scandinavica. Supplementum, ISSN 0903-465X, E-ISSN 1600-5503, Vol. 116, no 11, p. 985-994Article in journal (Refereed)
    Abstract [en]

    Development of transgenic edible plants, to be used as production, storage and delivery systems for recombinant vaccine antigens, is a promising strategy to obtain cost effective vaccines against infectious diseases, not least for use in developing countries. Therefore, we used Agrobacterium tumefaciens-mediated gene transfer to introduce the p24 gag gene encoding the nucleocapsid protein from HIV-1 subtype C into the Arabidopsis thaliana plant genome. Eighteen plant lines were confirmed positive for the p24 gene by PCR; four of these lines showed an apparent homozygous phenotype when grown on selective medium and these lines also showed transcription of the p24 gene into its corresponding mRNA. The mRNA in all four cases generated the p24 protein in plants, as verified by Western blot analysis. The plants were shown to contain between 0.2 mu g and 0.5 mu g p24 protein per g of fresh tissue. Analysis of the localisation of the p24 protein showed that stem tissue contained the largest amount of protein, more than twice as much as leaf tissue, whereas no p24 protein was detected in roots. By using Southern blotting, we found that 4, 2-3, 2 and 1 T-DNA insertion events took place in the four lines 1, 2, 7, and 10, respectively. The genetic insertions of line 1 were stable from the T-2 to the T-5 generation and gave rise to the p24 protein in all cases, as verified by Western blotting. In mice fed with fresh transgenic A. thaliana (line 10), anti-gag IgG was obtained in serum after a booster injection with recombinant p37Gag. No immune response was observed after equal booster injection of untreated mice or mice fed with A. thaliana WT plants.

  • 36. Lund, Lars H
    et al.
    Andersson, Karolina
    Zuber, Bartek
    Karlsson, Anneli
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Engström, Gunnel
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Wahren, Britta
    Winberg, Gösta
    Signal sequence deletion and fusion to tetanus toxoid epitope augment antitumor immune responses to a human carcinoembryonic antigen (CEA) plasmid DNA vaccine in a murine test system2003In: Cancer Gene Therapy, ISSN 0929-1903, E-ISSN 1476-5500, Vol. 10, p. 365-376Article in journal (Refereed)
  • 37.
    Maltais, Anna-Karin
    et al.
    Eurocine Vaccines AB, Karolinska Institutet Science Park, 171 65 Solna, Sweden.
    Stittelaar, Koert J
    Viroclinics Biosciences B.V., 3029 AK Rotterdam, The Netherlands.
    Veldhuis Kroeze, Edwin J B
    Viroclinics Biosciences B.V., 3029 AK Rotterdam, The Netherlands.
    van Amerongen, Geert
    Viroclinics Biosciences B.V., 3029 AK Rotterdam, The Netherlands.
    Dijkshoorn, Marcel L
    Department of Radiology, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands.
    Krestin, Gabriel P
    Department of Radiology, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Eurocine Vaccines AB, Karolinska Institutet Science Park, 171 65 Solna, Sweden.
    Arwidsson, Hans
    Eurocine Vaccines AB, Karolinska Institutet Science Park, 171 65 Solna, Sweden.
    Lindberg, Alf
    Eurocine Vaccines AB, Karolinska Institutet Science Park, 171 65 Solna, Sweden.
    Osterhaus, Albert D M E
    Viroclinics Biosciences B.V., 3029 AK Rotterdam, The Netherlands / Department of Viroscience, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands.
    Intranasally administered Endocine™ formulated 2009 pandemic influenza H1N1 vaccine induces broad specific antibody responses and confers protection in ferrets2014In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 32, no 26, p. 3307-15Article in journal (Refereed)
    Abstract [en]

    Influenza is a contagious respiratory disease caused by an influenza virus. Due to continuous antigenic drift of seasonal influenza viruses, influenza vaccines need to be adjusted before every influenza season. This allows annual vaccination with multivalent seasonal influenza vaccines, recommended especially for high-risk groups. There is a need for a seasonal influenza vaccine that induces broader and longer lasting protection upon easy administration. Endocine™ is a lipid-based mucosal adjuvant composed of endogenous lipids found ubiquitously in the human body. Intranasal administration of influenza antigens mixed with this adjuvant has been shown to induce local and systemic immunity as well as protective efficacy against homologous influenza virus challenge in mice. Here we used ferrets, an established animal model for human influenza virus infections, to further investigate the potential of Endocine™ as an adjuvant. Intranasal administration of inactivated pandemic H1N1/California/2009 split antigen or whole virus antigen mixed with Endocine™ induced high levels of serum hemagglutination inhibition (HI) and virus neutralization (VN) antibody titers that were also cross reactive against distant swine viruses of the same subtype. HI and VN antibody titers were already demonstrated after a single nasal immunization. Upon intratracheal challenge with a homologous challenge virus (influenza virus H1N1/The Netherlands/602/2009) immunized ferrets were fully protected from virus replication in the lungs and largely protected against body weight loss, virus replication in the upper respiratory tract and pathological changes in the respiratory tract. Endocine™ formulated vaccines containing split antigen induced higher HI and VN antibody responses and better protection from body weight loss and virus shedding in the upper respiratory tract than the Endocine™ formulated vaccine containing whole virus antigen.

  • 38.
    Nystrom, Sanna
    et al.
    Centre Infect Med, Stockholm.
    Brave, Andreas
    Karolinska Institute.
    Rissiek, Bjorn
    University of Hamburg Hospital.
    Johansson, Daniel X
    Karolinska Institute.
    Schroder, Ulf
    Eurocine Vaccines AB.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Applequist, Steven E
    Centre Infect Med, Stockholm.
    DNA-Encoded Flagellin as an Epidermal, Systemic, and Mucosal-Adjuvant in SCANDINAVIAN JOURNAL OF IMMUNOLOGY, vol 73, issue 4, pp 393-3932011In: SCANDINAVIAN JOURNAL OF IMMUNOLOGY, Blackwell Publishing Ltd , 2011, Vol. 73, no 4, p. 393-393Conference paper (Refereed)
    Abstract [en]

    n/a

  • 39.
    Nyström, Sanna
    et al.
    Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm 141 86, Sweden.
    Bråve, Andreas
    Department of Preparedness, Swedish Institute for Infectious Disease Control, Stockholm 171 82, SwedenDepartment of Preparedness, Swedish Institute for Infectious Disease Control, Stockholm 171 82, Sweden.
    Falkeborn, Tina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Devito, Claudia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Rissiek, Björn
    Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm 141 86, Sweden / Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany.
    Johansson, Daniel X
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16, Stockholm 171 77, Sweden.
    Schröder, Ulf
    Latour AB, Stockholm 171 21, Sweden.
    Uematsu, Satoshi
    Division of Innate immune regulation, International Research and Development Center for Mucosal Vaccine, Institute for Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
    Akira, Shizuo
    Department of Host of Defense, Research Institutet for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Applequist, Steven E
    Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm 141 86, Sweden.
    DNA-Encoded Flagellin Activates Toll-Like Receptor 5 (TLR5), Nod-like Receptor Family CARD Domain-Containing Protein 4 (NRLC4), and Acts as an Epidermal, Systemic, and Mucosal-Adjuvant2013In: Vaccines, ISSN 2076-393X, Vol. 1, no 4, p. 415-443Article in journal (Refereed)
    Abstract [en]

    Eliciting effective immune responses using non-living/replicating DNA vaccines is a significant challenge. We have previously shown that ballistic dermal plasmid DNA-encoded flagellin (FliC) promotes humoral as well as cellular immunity to co-delivered antigens. Here, we observe that a plasmid encoding secreted FliC (pFliC(-gly)) produces flagellin capable of activating two innate immune receptors known to detect flagellin; Toll-like Receptor 5 (TLR5) and Nod-like Receptor family CARD domain-containing protein 4 (NRLC4). To test the ability of pFliC(-gly) to act as an adjuvant we immunized mice with plasmid encoding secreted FliC (pFliC(-gly)) and plasmid encoding a model antigen (ovalbumin) by three different immunization routes representative of dermal, systemic, and mucosal tissues. By all three routes we observed increases in antigen-specific antibodies in serum as well as MHC Class I-dependent cellular immune responses when pFliC(-gly) adjuvant was added. Additionally, we were able to induce mucosal antibody responses and Class II-dependent cellular immune responses after mucosal vaccination with pFliC(-gly). Humoral immune responses elicited by heterologus prime-boost immunization with a plasmid encoding HIV-1 from gp160 followed by protein boosting could be enhanced by use of pFliC(-gly). We also observed enhancement of cross-clade reactive IgA as well as a broadening of B cell epitope reactivity. These observations indicate that plasmid-encoded secreted flagellin can activate multiple innate immune responses and function as an adjuvant to non-living/replicating DNA immunizations. Moreover, the capacity to elicit mucosal immune responses, in addition to dermal and systemic properties, demonstrates the potential of flagellin to be used with vaccines designed to be delivered by various routes.

  • 40.
    Oynebraten, Inger
    et al.
    University of Oslo, Norway Oslo University Hospital, Norway University of Oslo, Norway .
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Fredriksen, Agnete B.
    University of Oslo, Norway Oslo University Hospital, Norway University of Oslo, Norway .
    Bogen, Bjarne
    University of Oslo, Norway Oslo University Hospital, Norway University of Oslo, Norway University of Oslo, Norway .
    Increased Generation of HIV-1 gp120-Reactive CD8(+) T Cells by a DNA Vaccine Construct Encoding the Chemokine CCL32014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e104814-Article in journal (Refereed)
    Abstract [en]

    DNA vaccines based on subunits from pathogens have several advantages over other vaccine strategies. DNA vaccines can easily be modified, they show good safety profiles, are stable and inexpensive to produce, and the immune response can be focused to the antigen of interest. However, the immunogenicity of DNA vaccines which is generally quite low needs to be improved. Electroporation and co-delivery of genetically encoded immune adjuvants are two strategies aiming at increasing the efficacy of DNA vaccines. Here, we have examined whether targeting to antigen-presenting cells (APC) could increase the immune response to surface envelope glycoprotein (Env) gp120 from Human Immunodeficiency Virus type 1 (HIV- 1). To target APC, we utilized a homodimeric vaccine format denoted vaccibody, which enables covalent fusion of gp120 to molecules that can target APC. Two molecules were tested for their efficiency as targeting units: the antibody-derived single chain Fragment variable (scFv) specific for the major histocompatilibility complex (MHC) class II I-E molecules, and the CC chemokine ligand 3 (CCL3). The vaccines were delivered as DNA into muscle of mice with or without electroporation. Targeting of gp120 to MHC class II molecules induced antibodies that neutralized HIV-1 and that persisted for more than a year after one single immunization with electroporation. Targeting by CCL3 significantly increased the number of HIV-1 gp120-reactive CD8(+) T cells compared to non-targeted vaccines and gp120 delivered alone in the absence of electroporation. The data suggest that chemokines are promising molecular adjuvants because small amounts can attract immune cells and promote immune responses without advanced equipment such as electroporation.

  • 41. Rollman, Erik
    et al.
    Mathy, Nathalie
    Bråve, Andreas
    Boberg, Andreas
    Kjerrström, Anne
    van Wely, Cathy
    Engström, Gunnel
    Johansson, Susanne
    Aperia, Kajsa
    Eriksson, Lars E
    Benthin, Reinhold
    Ertl, Peter
    Heeney, Jonathan
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Voss, Gerald
    Wahren, Britta
    Evaluation of immunogenicity and efficacy of combined DNA and adjuvanted protein vaccination in a human immunodeficiency virus type 1/murine leukemia virus pseudotype challenge model2007In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 25, no 11, p. 2145-2154Article in journal (Refereed)
    Abstract [en]

    A DNA plasmid encoding human immunodeficiency virus type 1 (HIV-1) env, nef and tat genes was used in mice in a prime-boost immunization regimen with the corresponding recombinant proteins. The genetic immunogen was delivered with a gene gun and the proteins were injected intramuscularly together with the adjuvant AS02A. Immunizations were followed by experimental challenge with pseudotyped HIV-1 subtype A or B virus. In an initial experiment in which animals were challenged four weeks after the final immunization, all single modality and prime-boost vaccinations resulted in a significant level of protection as compared to control animals. There was a trend for DNA-alone immunization yielding the highest protection. In a subsequent study, a late challenge was performed 19 weeks after the final immunization. All groups having received the DNA vaccine, either alone or in combination with adjuvanted protein, exhibited strong protection against HIV replication. The subtype-specific protection against the experimental HIV challenge was significantly stronger than the cross-protection. Cellular and humoral immune responses were assessed during immunization and after challenge, but without clear correlation to protection against HIV replication. The data suggest that either DNA or protein antigens alone provide partial protection against an HIV-1/MuLV challenge and that DNA immunization is essential for achieving very high levels of efficacy in this murine HIV-1 challenge model. While prime-boost combinations were more immunogenic than DNA alone, they did not appear to provide any further enhancement over DNA vaccine mediated efficacy. The DNA immunogen might prime low levels of CD8+ T cells responsible for virus clearance or possibly a yet unidentified mechanism of protection. © 2006 Elsevier Ltd. All rights reserved.

  • 42.
    Timpka, Toomas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Gursky, Elin A
    ANSER/Analytic Services Inc, Arlington, Virginia, USA.
    Spreco, Armin
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Eriksson, Olle
    Linköping University, Department of Computer and Information Science, Statistics. Linköping University, Faculty of Arts and Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Strömgren, Magnus
    Umeå University, Sweden.
    Holm, Einar
    Umeå University, Sweden.
    Ekberg, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Nyce, Jim M
    Ball State University, Muncie, IN, USA..
    Eriksson, Henrik
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, The Institute of Technology.
    Predictive value of telenursing complaints in influenza surveillance: a prospective cohort study in Sweden2013Conference paper (Other academic)
  • 43.
    Timpka, Toomas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Center for Public Health.
    Spreco, Armin
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Dahlström, Örjan
    Linköping University, The Swedish Institute for Disability Research. Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Eriksson, Henrik
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, The Institute of Technology.
    Gursky, Elin
    ANSER/Analytic Services Inc, Arlington, Virginia, USA.
    Ekberg, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Blomqvist, Eva
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, Faculty of Arts and Sciences.
    Strömgren, Magnus
    Umeå University, Sweden.
    Karlsson, David
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, The Institute of Technology.
    Eriksson, Henrik
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, The Institute of Technology.
    Nyce, Jim
    Ball State University, Muncie, IN, USA.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Holm, Einar
    Umeå University, Sweden.
    Performance of eHealth data sources in local influenza surveillance: a 5-year open cohort study using data from Google Flu Trends, telenursing call centres, health service provider web-pages, and mass media coverage2013Conference paper (Other academic)
  • 44.
    Timpka, Toomas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Center for Public Health.
    Spreco, Armin
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Eriksson, Olle
    Linköping University, Department of Computer and Information Science, Statistics. Linköping University, Faculty of Arts and Sciences.
    Gursky, Elin
    National Strategies Support Directorate, ANSER/Analytic Services Inc., Arlington, VA, USA.
    Ekberg, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Blomqvist, Eva
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, The Institute of Technology.
    Strömgren, Magnus
    Department of Geography and Economic History, Umeå University, Sweden.
    Karlsson, David
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, The Institute of Technology.
    Eriksson, Henrik
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, The Institute of Technology.
    Nyce, James
    Department of Anthropology, Ball State University, Muncie, IN, USA.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Holm, Einar
    Department of Geography and Economic History, Umeå University, Sweden.
    Performance of eHealth data sources in local influenza surveillance: a 5-year open cohort study2014In: Journal of Medical Internet Research, ISSN 1438-8871, E-ISSN 1438-8871, Vol. 16, no 4, p. e116-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There is abundant global interest in using syndromic data from population-wide health information systems--referred to as eHealth resources--to improve infectious disease surveillance. Recently, the necessity for these systems to achieve two potentially conflicting requirements has been emphasized. First, they must be evidence-based; second, they must be adjusted for the diversity of populations, lifestyles, and environments.

    OBJECTIVE: The primary objective was to examine correlations between data from Google Flu Trends (GFT), computer-supported telenursing centers, health service websites, and influenza case rates during seasonal and pandemic influenza outbreaks. The secondary objective was to investigate associations between eHealth data, media coverage, and the interaction between circulating influenza strain(s) and the age-related population immunity.

    METHODS: An open cohort design was used for a five-year study in a Swedish county (population 427,000). Syndromic eHealth data were collected from GFT, telenursing call centers, and local health service website visits at page level. Data on mass media coverage of influenza was collected from the major regional newspaper. The performance of eHealth data in surveillance was measured by correlation effect size and time lag to clinically diagnosed influenza cases.

    RESULTS: Local media coverage data and influenza case rates showed correlations with large effect sizes only for the influenza A (A) pH1N1 outbreak in 2009 (r=.74, 95% CI .42-.90; P<.001) and the severe seasonal A H3N2 outbreak in 2011-2012 (r=.79, 95% CI .42-.93; P=.001), with media coverage preceding case rates with one week. Correlations between GFT and influenza case data showed large effect sizes for all outbreaks, the largest being the seasonal A H3N2 outbreak in 2008-2009 (r=.96, 95% CI .88-.99; P<.001). The preceding time lag decreased from two weeks during the first outbreaks to one week from the 2009 A pH1N1 pandemic. Telenursing data and influenza case data showed correlations with large effect sizes for all outbreaks after the seasonal B and A H1 outbreak in 2007-2008, with a time lag decreasing from two weeks for the seasonal A H3N2 outbreak in 2008-2009 (r=.95, 95% CI .82-.98; P<.001) to none for the A p H1N1 outbreak in 2009 (r=.84, 95% CI .62-.94; P<.001). Large effect sizes were also observed between website visits and influenza case data.

    CONCLUSIONS: Correlations between the eHealth data and influenza case rates in a Swedish county showed large effect sizes throughout a five-year period, while the time lag between signals in eHealth data and influenza rates changed. Further research is needed on analytic methods for adjusting eHealth surveillance systems to shifts in media coverage and to variations in age-group related immunity between virus strains. The results can be used to inform the development of alert-generating eHealth surveillance systems that can be subject for prospective evaluations in routine public health practice.

  • 45.
    Timpka, Toomas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Center for Public Health.
    Spreco, Armin
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Center for Public Health.
    Dahlström, Örjan
    Linköping University, The Swedish Institute for Disability Research. Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Eriksson, Olle
    Linköping University, Department of Computer and Information Science, Statistics. Linköping University, Faculty of Arts and Sciences.
    Gursky, Elin
    ANSER/Analytic Services Inc, Arlington, Virginia, USA.
    Ekberg, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Blomqvist, Eva
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, Faculty of Arts and Sciences.
    Strömgren, Magnus
    Umeå University, Sweden.
    Karlsson, David
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, The Institute of Technology.
    Eriksson, Henrik
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, The Institute of Technology.
    Nyce, Jim
    Ball State University, Muncie, IN, USA.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Holm, Einar
    Umeå University, Sweden.
    Predictive value of telenursing complaints in influenza surveillance: a prospective cohort study in Sweden2013Conference paper (Other academic)
  • 46.
    Timpka, Toomas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Center for Public Health.
    Spreco, Armin
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Dahlström, Örjan
    Linköping University, The Swedish Institute for Disability Research. Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Eriksson, Olle
    Linköping University, Department of Computer and Information Science, Statistics. Linköping University, Faculty of Arts and Sciences.
    Gursky, Elin
    ANSER/Analytic Services Inc, Arlington, Virginia, USA.
    Ekberg, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Strömgren, Magnus
    Umeå University, Sweden.
    Karlsson, David
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, The Institute of Technology.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Holm, Einar
    Umeå University, Sweden.
    Intentions to perform non-pharmaceutical protective behaviors during influenza outbreaks: a cross-sectional study of a representative sample of the Swedish adult population2013Conference paper (Other academic)
  • 47.
    Timpka, Toomas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Center for Public Health.
    Spreco, Armin
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Eriksson, Olle
    Linköping University, Department of Computer and Information Science, Statistics. Linköping University, Faculty of Arts and Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Gursky, E. A.
    Analytic Serv Inc, VA USA.
    Stromgren, M.
    Umeå University, Sweden.
    Holm, E.
    Umeå University, Sweden.
    Ekberg, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Nyce, J. M.
    Ball State University, IN 47306 USA.
    Eriksson, Henrik
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, The Institute of Technology.
    Predictive performance of telenursing complaints in influenza surveillance: a prospective cohort study in Sweden2014In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 19, no 46, p. 24-32Article in journal (Refereed)
    Abstract [en]

    Syndromic data sources have been sought to improve the timely detection of increased influenza transmission. This study set out to examine the prospective performance of telenursing chief complaints in predicting influenza activity. Data from two influenza seasons (2007/08 and 2008/09) were collected in a Swedish county (population 427,000) to retrospectively determine which grouping of telenursing chief complaints had the largest correlation with influenza case rates. This grouping was prospectively evaluated in the three subsequent seasons. The best performing telenursing complaint grouping in the retrospective algorithm calibration was fever (child, adult) and syncope (r=0.66; pless than0.001). In the prospective evaluation, the performance of 14-day predictions was acceptable for the part of the evaluation period including the 2009 influenza pandemic (area under the curve (AUC)=0.84; positive predictive value (PPV)=0.58), while it was strong (AUC=0.89; PPV=0.93) for the remaining evaluation period including only influenza winter seasons. We recommend the use of telenursing complaints for predicting winter influenza seasons. The method requires adjustments when used during pandemics.

  • 48.
    Timpka, Toomas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Center for Public Health.
    Spreco, Armin
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Center for Public Health.
    Gursky, Elin
    National Strategies Support Directorate, ANSER/Analytic Services Inc, Arlington, Virginia, USA.
    Eriksson, Olle
    Linköping University, Department of Computer and Information Science, Statistics. Linköping University, Faculty of Arts and Sciences.
    Dahlström, Örjan
    Linköping University, The Swedish Institute for Disability Research. Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Strömgren, Magnus
    Umeå University, Sweden.
    Ekberg, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Center for Public Health.
    Pilemalm, Sofie
    Linköping University, Department of Management and Engineering, Information Systems. Linköping University, Faculty of Arts and Sciences.
    Karlsson, David
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, The Institute of Technology.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Holm, Einar
    Umeå University, Sweden.
    Intentions to perform non-pharmaceutical protective behaviors during influenza outbreaks in Sweden: a cross-sectional study following a mass vaccination campaign2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 3, p. e91060-Article in journal (Refereed)
    Abstract [en]

    Failure to incorporate the beliefs and attitudes of the public into theoretical models of preparedness has been identified as a weakness in strategies to mitigate infectious disease outbreaks. We administered a cross-sectional telephone survey to a representative sample (n = 443) of the Swedish adult population to examine whether self-reported intentions to improve personal hygiene and increase social distancing during influenza outbreaks could be explained by trust in official information, self-reported health (SF-8), sociodemographic factors, and determinants postulated in protection motivation theory, namely threat appraisal and coping appraisal. The interviewees were asked to make their appraisals for two scenarios: a) an influenza with low case fatality and mild lifestyle impact; b) severe influenza with high case fatality and serious disturbances of societal functions. Every second respondent (50.0%) reported high trust in official information about influenza. The proportion that reported intentions to take deliberate actions to improve personal hygiene during outbreaks ranged between 45–85%, while less than 25% said that they intended to increase social distancing. Multiple logistic regression models with coping appraisal as the explanatory factor most frequently contributing to the explanation of the variance in intentions showed strong discriminatory performance for staying home while not ill (mild outbreaks: Area under the curve [AUC] 0.85 (95% confidence interval 0.82;0.89), severe outbreaks AUC 0.82 (95% CI 0.77;0.85)) and acceptable performance with regard to avoiding public transportation (AUC 0.78 (0.74;0.82), AUC 0.77 (0.72;0.82)), using handwash products (AUC 0.70 (0.65;0.75), AUC 0.76 (0.71;0.80)), and frequently washing hands (AUC 0.71 (0.66;0.76), AUC 0.75 (0.71;0.80)). We conclude that coping appraisal was the explanatory factor most frequently included in statistical models explaining self-reported intentions to carry out non-pharmaceutical health actions in the Swedish outlined context, and that variations in threat appraisal played a smaller role in these models despite scientific uncertainties surrounding a recent mass vaccination campaign.

  • 49.
    Tjomsland, Veronica
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Burgener, Adam
    National Laboratory for HIV Immunology, Public health Agency of Canada, 1015 Arlington Street Winnipeg, Manitoba, Canada.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Lifson, Jeffrey D
    AIDS and Cancer Virus Program, SAIC Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Complement opsonization of HIV-1 results in a different intracellular processing pattern and efficiency leading to an enhanced MHC I presentation by dendritic cells2011Manuscript (preprint) (Other academic)
    Abstract [en]

    The antigen processing and presentation processes occurring in dendritic cells (DCs) required for induction of HIV-1 specific T cell responses, which are essential for controlling the viral infection in vivo. The initial interactions of DCs with free HIV-1 (FHIV), or complement opsonized HIV-1 (C-HIV) might influence the routing and nature of pathways used for MHC class I and II restricted presentation. We have examined FHIV, C-HIV, and complement and antibody opsonized HIV-1 (C-IgG-HIV) effects on immature DCs (IDCs) and mature DCs (MDCs) antigen proteolysis, MHC class I and II antigen presentation, and the role of endocytic receptors in presentation of antigens derived from HIV-1. We found that opsonized virions promoted MHC class I presentation by both IDCs and MDCs compared to F-HIV. Indicative of that complement opsonization routes more virions towards the MHC class I presentation pathway. We found that blocking macrophage mannose receptor (MMR) rerouted the HIV-1 to a path leading to higher levels of MHC class I and II presentation. Furthermore, the blocking of β7-integrin also gave an enhanced MHC class I and II presentation by both IDCs and MDCs, whereas the block of αMβ2 integrins, i.e. complement receptor 3 (CR3), decreased the MHC class I and II presentation. In addition, we found that IDCs and MDCs proteolytic activities were modulated by the HIV-1 exposure, for example C-HIV induced an increased proteasome activity in IDCs. Taken together, these findings indicated that endocytic receptors, such as MMR, CR3, and β7 integrin, can promote or disfavor antigen presentation by routing HIV-1 into different endosomal compartments with distinct properties and efficiencies for degradation of viral antigens and MHC class I and II presentation and that HIV-1 affects the antigen processing machineries.

  • 50.
    Tjomsland, Veronica
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Burgener, Adam
    University of Manitoba, Canada.
    Mogk, Kenzie
    University of Manitoba, Canada.
    Fru Che, Karlhans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Westmacott, Garrett
    National Microbiol Lab, Canada.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Lifson, Jeffrey D.
    SAIC Frederick Inc, MD USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Complement opsonization of HIV-1 results in a different intracellular processing pattern and enhanced MHC class I presentation by dendritic cells2013In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 43, no 6, p. 1470-1483Article in journal (Refereed)
    Abstract [en]

    Induction of optimal HIV-1-specific T-cell responses, which can contribute to controlling viral infection in vivo, depends on antigen processing and presentation processes occurring in DCs. Opsonization can influence the routing of antigen processing and pathways used for presentation. We studied antigen proteolysis and the role of endocytic receptors in MHC class I (MHCI) and II (MHCII) presentation of antigens derived from HIV-1 in human monocyte-derived immature DCs (IDCs) and mature DCs, comparing free and complement opsonized HIV-1 particles. Opsonization of virions promoted MHCI presentation by DCs, indicating that complement opsonization routes more virions toward the MHCI presentation pathway. Blockade of macrophage mannose receptor (MMR) and β7-integrin enhanced MHCI and MHCII presentation by IDCs and mature DCs, whereas the block of complement receptor 3 decreased MHCI and MHCII presentation. In addition, we found that IDC and MDC proteolytic activities were modulated by HIV-1 exposure; complement-opsonized HIV-1 induced an increased proteasome activity in IDCs. Taken together, these findings indicate that endocytic receptors such as MMR, complement receptor 3, and β7-integrin can promote or disfavor antigen presentation probably by routing HIV-1 into different endosomal compartments with distinct efficiencies for degradation of viral antigens and MHCI and MHCII presentation, and that HIV-1 affects the antigen-processing machinery.

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