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  • 1.
    Abdurahman, Samir
    et al.
    Division of Clinical Microbiology, Department of Laboratory Medicine F68, Karolinska University Hospital, Stockholm, Sweden.
    Barqasho, Babilonia
    Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Nowak, Piotr
    Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Cuong, Do Duy
    Infectious Diseases Department, Bach Mai Hospital, Hanoi, Viet Nam .
    Amogné, Wondwossen
    Department of Medicine, Faculty of Medicine, University, Addis Abeba, Ethiopia .
    Larsson, Mattias
    Division of Global Health (IHCAR), Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden; Oxford University Clinical Research Unit (OUCRU), Hanoi, Viet Nam .
    Lindquist, Lars
    Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden .
    Marrone, Gaetano
    Division of Global Health (IHCAR), Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden .
    Sönnerborg, Anders
    Division of Clinical Microbiology, Department of Laboratory Medicine F68, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Pattern of microbial translocation in patients living with HIV-1 from Vietnam, Ethiopia and Sweden2014In: Journal of the International AIDS Society, ISSN 1758-2652, E-ISSN 1758-2652, Vol. 17, p. 18841-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The role of microbial translocation (MT) in HIV patients living with HIV from low- and middle-income countries (LMICs) is not fully known. The aim of this study is to investigate and compare the patterns of MT in patients from Vietnam, Ethiopia and Sweden.

    METHODS: Cross-sectional samples were obtained from treatment-naïve patients living with HIV-1 and healthy controls from Vietnam (n=83; n=46), Ethiopia (n=9492; n=50) and Sweden (n=51; n=19). Longitudinal samples were obtained from a subset of the Vietnamese (n=24) in whom antiretroviral therapy (ART) and tuberculostatics were given. Plasma lipopolysaccharide (LPS), sCD14 and anti-flagellin IgG were determined by the endpoint chromogenic Limulus Amebocyte Assay and enzyme-linked immunosorbent assay.

    RESULTS: All three biomarkers were significantly increased in patients living with HIV-1 from all countries as compared to controls. No differences were found between males and females. Vietnamese and Ethiopian patients had significantly higher levels of anti-flagellin IgG and LPS, as compared to Swedes. ART reduced these levels for the Vietnamese. Vietnamese patients given tuberculostatics at initiation of ART had significantly lower levels of anti-flagellin IgG and higher sCD14. The biomarkers were lower in Vietnamese who did not develop opportunistic infection.

    CONCLUSIONS: Higher MT is common in patients living with HIV compared to healthy individuals, and in patients from LMICs compared to patients from a high-income country. Treatment with tuberculostatics decreased MT while higher levels of MT are associated with a poorer clinical outcome.

  • 2.
    Abdurahman, Samir
    et al.
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Végvári, Akos
    Department of Electrical Measurements, Lund University, Lund, Sweden.
    Levi, Michael
    Tripep AB, Huddinge, Sweden.
    Höglund, Stefan
    Department of Biochemistry, Uppsala University, Uppsala, Sweden .
    Högberg, Marita
    Chemilia AB, Huddinge, Sweden.
    Tong, Weimin
    Chemilia AB, Huddinge, Sweden.
    Romero, Ivan
    Chemilia AB, Huddinge, Sweden.
    Balzarini, Jan
    Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
    Vahlne, Anders
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Isolation and characterization of a small antiretroviral molecule affecting HIV-1 capsid morphology2009In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 6, p. 34-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Formation of an HIV-1 particle with a conical core structure is a prerequisite for the subsequent infectivity of the virus particle. We have previously described that glycineamide (G-NH2) when added to the culture medium of infected cells induces non-infectious HIV-1 particles with aberrant core structures.

    RESULTS: Here we demonstrate that it is not G-NH2 itself but a metabolite thereof that displays antiviral activity. We show that conversion of G-NH2 to its antiviral metabolite is catalyzed by an enzyme present in bovine and porcine but surprisingly not in human serum. Structure determination by NMR suggested that the active G-NH2 metabolite was alpha-hydroxy-glycineamide (alpha-HGA). Chemically synthesized alpha-HGA inhibited HIV-1 replication to the same degree as G-NH2, unlike a number of other synthesized analogues of G-NH2 which had no effect on HIV-1 replication. Comparisons by capillary electrophoresis and HPLC of the metabolite with the chemically synthesized alpha-HGA further confirmed that the antiviral G-NH2-metabolite indeed was alpha-HGA.

    CONCLUSION: alpha-HGA has an unusually simple structure and a novel mechanism of antiviral action. Thus, alpha-HGA could be a lead for new antiviral substances belonging to a new class of anti-HIV drugs, i.e. capsid assembly inhibitors.

  • 3.
    Abdurahman, Samir
    et al.
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Végvári, Akos
    Clinical Protein Science, Department of Electrical Measurements, Lund University, Lund, Sweden.
    Youssefi, Masoud
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Levi, Michael
    Tripep AB, Huddinge, Sweden .
    Höglund, Stefan
    Department of Biochemistry, Uppsala University, Uppsala, Sweden .
    Andersson, Elin
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Horal, Peter
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Svennerholm, Bo
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Balzarini, Jan
    Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
    Vahlne, Anders
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity2008In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 10, p. 3737-3744Article in journal (Refereed)
    Abstract [en]

    Upon maturation of the human immunodeficiency virus type 1 (HIV-1) virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24, which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the optimal semistability of the capsid cone structure. We have reported earlier that glycineamide (G-NH(2)), when added to the culture medium of infected cells, inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH(2) itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of 10 different RNA and DNA viruses. alpha-HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by matrix-assisted laser desorption ionization-mass spectrometry results. As an antiviral compound, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity, and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.

  • 4.
    Barqasho, Babilonia
    et al.
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden .
    Nowak, Piotr
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden; Division of Infectious Diseases, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Abdurahman, Samir
    Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden .
    Walther-Jallow, Lillian
    Center for Infectious Medicine, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden .
    Sönnerborg, Anders
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden; Division of Infectious Diseases, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Implications of the release of high-mobility group box 1 protein from dying cells during human immunodeficiency virus type 1 infection in vitro2010In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 91, no Pt 7, p. 1800-1809Article in journal (Refereed)
    Abstract [en]

    Plasma levels of high-mobility group box 1 protein (HMGB1) are elevated during the course of human immunodeficiency virus type 1 (HIV-1) infection and the molecule has an impact on virus replication. This study investigated the mode of cell death and release of HMGB1 during HIV-1 infection in vitro. MT4 cells and primary CD4(+) T cells were infected with HIV-1 isolates, and HMGB1 release was monitored in relation to cytopathic effects (CPE) and apoptosis. HMGB1 release from cells was analysed by Western blotting. For MT4 cells, an enzyme-linked immunosorbent spot (ELISPOT) assay was adapted to measure the release during necrosis. Lactate dehydrogenase (LDH) activity was quantified using a commercial assay. Flow cytometry was used to determine the level of infection and apoptosis. MT4 cells were > or =90 % infected at 48 h post-infection (p.i.). CPE was first observed at 60 h and correlated with release of HMGB1, LDH activity and caspase-3 (C3) activation. HMGB1 spots were clearly detected by ELISPOT assay at 72 h p.i. Annexin V and C3 staining showed that apoptosis was substantially involved in HIV-1-related cell death. Addition of Z-VAD (a caspase inhibitor) in a single dose at 24 or 40 h p.i. decreased both the number of caspase-positive cells and the release of HMGB1. Infection of primary CD4(+) T cells showed a 22 % (median) infection rate at 96 h. Related CPE corresponded to LDH and HMGB1 release. Both necrosis and apoptosis contributed to HMGB1 liberation during HIV-1-induced cell death and the protein could induce tumour necrosis factor-alpha release from peripheral mononuclear blood cells. These data imply that passive HMGB1 release contributes to the excessive immune activation characteristic of HIV-1 pathogenesis.

  • 5.
    Bäckström Winquist, Ellenor
    et al.
    Department of Laboratory Medicine, Section of Medical Microbiology, Lund University, Lund, Sweden; Department of Medical Biochemistry and Microbiology, Biomedical Centre, Uppsala University, Uppsala, Sweden .
    Abdurahman, Samir
    Department of Medical Biochemistry and Microbiology, Department of Laboratory Medicine, Section of Medical Microbiology, Lund University, Lund, Sweden; Department of Medical Biochemistry and Microbiology, Biomedical Centre, Uppsala University, Uppsala, Sweden .
    Tranell, Anna
    Department of Medical Biochemistry and Microbiology, Department of Laboratory Medicine, Section of Medical Microbiology, Lund University, Lund, Sweden; Department of Medical Biochemistry and Microbiology, Biomedical Centre, Uppsala University, Uppsala, Sweden .
    Lindström, Sofia
    Department of Medical Biochemistry and Microbiology, Department of Laboratory Medicine, Section of Medical Microbiology, Lund University, Lund, Sweden; Department of Medical Biochemistry and Microbiology, Biomedical Centre, Uppsala University, Uppsala, Sweden .
    Tingsborg, Susanne
    Department of Medical Biochemistry and Microbiology, Department of Laboratory Medicine, Section of Medical Microbiology, Lund University, Lund, Sweden; Department of Medical Biochemistry and Microbiology, Biomedical Centre, Uppsala University, Uppsala, Sweden .
    Schwartz, Stefan
    Department of Medical Biochemistry and Microbiology,Department of Laboratory Medicine, Section of Medical Microbiology, Lund University, Lund, Sweden; Department of Laboratory Medicine, Section of Medical Microbiology, Lund University, Lund, Sweden; Department of Medical Biochemistry and Microbiology, Biomedical Centre, Uppsala University, Uppsala, Sweden .
    Inefficient splicing of segment 7 and 8 mRNAs is an inherent property of influenza virus A/Brevig Mission/1918/1 (H1N1) that causes elevated expression of NS1 protein.2012In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 422, no 1, p. 46-58Article in journal (Refereed)
    Abstract [en]

    Influenza A virus encodes two segments (7 and 8) that produce mRNAs that can be spliced. We have investigated if naturally occurring sequence polymorphisms in the influenza A virus family affects splicing of these viral mRNAs, as that could potentially alter the NS1/NS2- and/or M1/M2-protein ratios. We compared splicing efficiency of segment 7 and 8 mRNAs of A/Brevig Mission/1918/1 (H1N1) and A/Netherlands/178/95 (H3N2), as well as various H5N1 avian strains. Results revealed that both segment 7 and 8 mRNAs of A/Brevig Mission/1918/1 (H1N1) were inefficiently spliced compared to other influenza virus segment 7 and 8 mRNAs. This resulted in production of higher levels of functional NS1 protein, which could potentially contribute to the pathogenic properties of the A/Brevig Mission/1918/1 (H1N1). We also show that A/Brevig Mission/1918/1 (H1N1) segment 8 mRNAs responded differently to overexpression of SR proteins than A/Netherlands/178/95 (H3N2).

  • 6.
    Dlugosz, A.
    et al.
    Department of Medicine and Center for Digestive Diseases, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Nowak, P.
    Department of Medicine, Unit of Infectious Diseases, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
    D'Amato, M.
    Department of Biosciences and Nutrition, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Mohammadian Kermani, G.
    Department of Medicine and Center for Digestive Diseases, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Nyström, J.
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Abdurahman, Samir
    Örebro University, School of Science and Technology.
    Lindberg, G.
    Department of Medicine and Center for Digestive Diseases, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Increased serum levels of lipopolysaccharide and antiflagellin antibodies in patients with diarrhea-predominant irritable bowel syndrome2015In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 27, no 12, p. 1747-1754Article in journal (Refereed)
    Abstract [en]

    Background: Innate immune responses to conserved microbial products such as lipopolysaccharide (LPS) and flagellin are likely important in microbial-host interactions and intestinal homeostasis. We hypothesized that bacterial translocation and activation of mucosal immunity against common microbial antigens might be involved in the development of irritable bowel syndrome (IBS). We therefore compared serum levels of LPS, soluble CD14 (sCD14), and flagellin antibodies between patients with different subtypes of IBS and healthy controls.

    Methods: We analyzed serum obtained from 88 patients (74 females) aged 19(43)-73 years and 106 healthy volunteers (77 females) aged 19(38)-62 years. Diarrhea-predominant IBS (D-IBS) was present in 32 patients (36%), 23 patients (26%) had constipation-predominant IBS (C-IBS), and 33 patients (38%) had A-IBS. We used ELISA for sCD14 and antiflagellin immunoglobulin G and limulus amebocyte assay for LPS. Abdominal symptoms and psychiatric comorbidities were assessed using validated questionnaires.

    Key Results: We found a significantly higher serum level of LPS in patients with D-IBS compared to controls (p = 0.0155). The level of antibodies to flagellin was higher in patients with IBS than in controls (mainly driven by higher levels in D-IBS, p = 0.0018). The levels of sCD14 were lower in D-IBS patients compared to controls (p = 0.0498). We found a weak, but significant correlation between the levels of antiflagellin antibodies and anxiety among IBS patients ( = 0.38; p = 0.0045).

    Conclusions & Inferences: Our results support the concept that immune reactivity to luminal antigens may have a role in the development of D-IBS. The serum level of antiflagellin antibodies was found to correlate with patients' self-reported anxiety score.

  • 7.
    Ekici, Halime
    et al.
    Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden.
    Amogne, Wondwossen
    Department of Medicine, Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
    Aderaye, Getachew
    Department of Medicine, Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
    Lindquist, Lars
    Department of Medicine, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Sonnerborg, Anders
    Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden; Department of Medicine, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Abdurahman, Samir
    Örebro University, School of Science and Technology. Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden.
    Minority drug-resistant HIV-1 variants in treatment Naive East-African and Caucasian patients detected by allele-specific real-time PCR2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e111042-Article in journal (Refereed)
    Abstract [en]

    Objective: To assess the presence of two major non-nucleoside reverse transcriptase inhibitors (NNRTI) drug resistance mutations (DRMs), Y181C and K103N, in minor viral quasispecies of treatment naive HIV-1 infected East-African and Swedish patients by allele-specific polymerase chain reaction (AS-PCR).

    Methods: Treatment naive adults (n = 191) with three epidemiological backgrounds were included: 92 Ethiopians living in Ethiopia; 55 East-Africans who had migrated to Sweden; and 44 Caucasians living in Sweden. The pol gene was analysed by standard population sequencing and by AS-PCR for the detection of Y181C and K103N.

    Results: The Y181C was detected in the minority quasispecies of six Ethiopians (6.5%), in two Caucasians (4.5%), and in one East-African (1.8%). The K103N was detected in one East-African (1.8%), by both methods. The proportion of mutants ranged from 0.25% to 17.5%. Additional DRMs were found in all three treatment naive patient groups by population sequencing.

    Conclusions: Major NNRTI mutations can be found by AS-PCR in minor quasispecies of treatment naive HIV-1 infected Ethiopians living in Ethiopia, in East-African and Caucasian patients living in Sweden in whom population sequencing reveal wild-type virus only. Surveys with standard sequencing are likely to underestimate transmitted drug resistance and the presence of resistant minor quasispecies in treatment naive patients should be topic for future large scale studies.

  • 8.
    Kalu, Amare Worku
    et al.
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute Huddinge, Stockholm, Sweden; Department of Microbiology, Immunology and Parasitology, Addis Ababa University, Addis Ababa, Ethiopia.
    Telele, Nigus Fikrie
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute Huddinge, Stockholm, Sweden; Department of Microbiology, Immunology and Parasitology, Addis Ababa University, Addis Ababa, Ethiopia.
    Gebreselasie, Solomon
    Department of Microbiology, Immunology and Parasitology, Addis Ababa University, Addis Ababa, Ethiopia.
    Fekade, Daniel
    Department of internal Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
    Abdurahman, Samir
    Örebro University, School of Science and Technology. Public Health Agency of Sweden, Solna, Sweden.
    Marrone, Gaetano
    Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Sönnerborg, Anders
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute Huddinge, Stockholm, Sweden; Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Monophylogenetic HIV-1C epidemic in Ethiopia is dominated by CCR5-tropic viruses-an analysis of a prospective country-wide cohort2017In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 17, no 1, article id 37Article in journal (Refereed)
    Abstract [en]

    Background: CCR5 coreceptor using HIV-1 subtype C (HIV-1C) has been reported to dominate the Ethiopian epidemic. However, almost all data have been obtained from two large cities in the central and north-west regions and recent data is lacking.

    Methods: Plasma were obtained from 420 treatment-naïve patients recruited 2009-2011 to a large country-wide Ethiopian cohort. The V3 region was sequenced and the co-receptor tropism was predicted by the clinical and clonal models of the geno2pheno tool at different false positive rates (fpr) and for subtype. In an intention to treat analysis the impact of baseline tropism on outcome of antiretroviral therapy was evaluated.

    Results: V3 loop sequencing was successful in 352 (84%) patients. HIV-1C was found in 350 (99.4%) and HIV-1A in two (0.6%) patients. When comparing the geno2pheno fpr10% clonal and clinical models, 24.4% predictions were discordant. X4-virus was predicted in 17.0 and 19.0%, respectively, but the predictions were concordant in only 6%. At fpr5%, concordant X4-virus predictions were obtained in 3.1%. The proportion of X4-tropic virus (clonal fpr10%) increased from 5.6 to 17.3% (p < 0.001) when 387 Ethiopian V3 loop sequences dated from 1984 to 2003 were compared with ours. In an intention to treat analysis, 67.9% reached treatment success at month 6 and only 50% at month 12. Only age and not tropism predicted therapy outcome and no difference was found in CD4+ cell gain between R5-tropic and X4-tropic infected patients. At viral failure, R5 to X4 switch was rare while X4 to R5 switch occurred more frequently (month 6: p = 0.006; month 12: p = 0.078).

    Conclusion: The HIV-1C epidemic is monophylogenetic in all regions of Ethiopia and R5-tropic virus dominates, even in patients with advanced immunodeficiency, although the proportion of X4-tropic virus seems to have increased over the last two decades. Geno2pheno clinical and clonal prediction models show a large discrepancy at fpr10%, but not at fpr5%. Hence further studies are needed to assess the utility of genotypic tropism testing in HIV-1C. In ITT analysis only age and not tropism influenced the outcome.

  • 9.
    Nowak, Piotr
    et al.
    Department of Infectious Diseases, Institution of Medicine, Karolinska University Hospital, Stockholm, Sweden .
    Abdurahman, Samir
    Department of Infectious Diseases, Institution of Medicine, Karolinska University Hospital, Stockholm, Sweden .
    Lindkvist, Annica
    Department of Clinical Microbiology, Institution of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden .
    Troseid, Marius
    Department of Infectious Diseases, Oslo University Hospital Ullevål, Oslo, Norway .
    Sönnerborg, Anders
    Department of Infectious Diseases, Institution of Medicine, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Microbiology, Institution of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden .
    Impact of HMGB1/TLR ligand complexes on HIV-1 replication: possible role for flagellin during HIV-1 infection2012In: International Journal of Microbiology, ISSN 1687-918X, E-ISSN 1687-9198, p. 263836-Article in journal (Refereed)
    Abstract [en]

    Objective: We hypothesized that HMGB1 in complex with bacterial components, such as flagellin, CpG-ODN, and LPS, promotes HIV-1 replication. Furthermore, we studied the levels of antiflagellin antibodies during HIV-1-infection.

    Methods: Chronically HIV-1-infected U1 cells were stimulated with necrotic extract/recombinant HMGB1 in complex with TLR ligands or alone. HIV-1 replication was estimated by p24 antigen in culture supernatants 48-72 hours after stimulation. The presence of systemic anti-flagellin IgG was determined in 51 HIV-1-infected patients and 19 controls by immunoblotting or in-house ELISA.

    Results: Flagellin, LPS, and CpG-ODN induced stronger HIV-1 replication when incubated together with necrotic extract or recombinant HMGB1 than activation by any of the compounds alone. Moreover, the stimulatory effect of necrotic extract was inhibited by depletion of HMGB1. Elevated levels of anti-flagellin antibodies were present in plasma from HIV-1-infected patients and significantly decreased during 2 years of antiretroviral therapy.

    Conclusions: Our findings implicate a possible role of HGMB1-bacterial complexes, as a consequence of microbial translocation and cell necrosis, for immune activation in HIV-1 pathogenesis. We propose that flagellin is an important microbial product, that modulates viral replication and induces adaptive immune responses in vivo.

  • 10.
    Trøseid, Marius
    et al.
    Department of Clinical Virology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden; Department of Infectious Diseases, Oslo University Hospital Ullevål, Oslo, Norway .
    Nowak, Piotr
    Department of Clinical Virology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden; Department of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden .
    Nyström, Jessica
    Department of Clinical Virology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
    Lindkvist, Annica
    Department of Clinical Virology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
    Abdurahman, Samir
    Department of Clinical Virology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden; Department of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden .
    Sönnerborg, Anders
    Department of Clinical Virology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden; Department of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden .
    Elevated plasma levels of lipopolysaccharide and high mobility group box-1 protein are associated with high viral load in HIV-1 infection: reduction by 2-year antiretroviral therapy2010In: AIDS (London), ISSN 0269-9370, E-ISSN 1473-5571, Vol. 24, no 11, p. 1733-1737Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate plasma levels of high mobility group box-1 protein (HMGB1), a marker of tissue necrosis and immune activation, as well as lipopolysaccharide (LPS), a marker of bacterial translocation, in HIV-1-infected patients.

    DESIGN: We studied 32 HIV-1-positive patients who had responded to antiretroviral therapy with undetectable viremia after 2 years, 10 nonresponders and 19 healthy controls.

    METHODS: HMGB1 was analyzed by ELISA, and LPS by Lamilus colometric assay. Nonparametric statistics were applied.

    RESULTS: In naive HIV-1 patients, HMGB1 and LPS were elevated as compared with controls (P < 0.001). LPS levels were higher in African and Oriental patients compared with whites (P = 0.007). Notably, viral load was two-fold higher in patients with LPS, and HMGB1 was above median as compared with other patients (P = 0.005). This association was largely driven by African patients, who had a five-fold increased viral load in the presence of elevated LPS and HMGB1. After 2 years of effective antiretroviral therapy, LPS was reduced to the same median level as in the control group (P < 0.001), and HMGB1 was also reduced (P = 0.001), whereas no reductions were seen in nonresponders.

    CONCLUSION: The new findings are the association of elevated plasma levels of LPS and HMGB1 with high viral load, as well as the normalized levels of LPS, and the reduction of HMGB1 after 2 years of effective antiretroviral therapy. As LPS and HMGB1 tend to form immunologically active complexes in vitro, we propose that such complexes may be involved in the immune activation and pathogenesis of HIV-1 infection.

  • 11.
    Vesterbacka, Jan
    et al.
    Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden .
    Nowak, Piotr
    Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Barqasho, Babilonia
    Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Abdurahman, Samir
    Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden .
    Nyström, Jessica
    Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden .
    Nilsson, Staffan
    Department of Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden.
    Funaoka, Hiroyuki
    DS Pharma Biomedical Company Limited, Osaka, Japan .
    Kanda, Tatsuo
    Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan .
    Andersson, Lars-Magnus
    Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden .
    Gisslèn, Magnus
    Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden .
    Sönnerborg, Anders
    Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Kinetics of microbial translocation markers in patients on efavirenz or lopinavir/r based antiretroviral therapy2013In: PloS one, ISSN 1932-6203, Vol. 8, no 1, p. e55038-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: We investigated whether there are differences in the effects on microbial translocation (MT) and enterocyte damage by different antiretroviral therapy (ART) regimens after 1.5 years and whether antibiotic use has impact on MT. In a randomized clinical trial (NCT01445223) on first line ART, patients started either lopinavir/r (LPV/r) (n = 34) or efavirenz (EFV) containing ART (n = 37). Lipopolysaccharide (LPS), sCD14, anti-flagellin antibodies and intestinal fatty acid binding protein (I-FABP) levels were determined in plasma at baseline (BL) and week 72 (w72).

    RESULTS: The levels of LPS and sCD14 were reduced from BL to w72 (157.5 pg/ml vs. 140.0 pg/ml, p = 0.0003; 3.13 ug/ml vs. 2.85 ug/ml, p = 0.005, respectively). The levels of anti-flagellin antibodies had decreased at w72 (0.35 vs 0.31 [OD]; p<0.0004), although significantly only in the LPV/r arm. I-FABP levels increased at w72 (2.26 ng/ml vs 3.13 ng/ml; p<0.0001), although significantly in EFV treated patients only. Patients given antibiotics at BL had lower sCD14 levels at w72 as revealed by ANCOVA compared to those who did not receive (Δ = -0.47 µg/ml; p = 0.015).

    CONCLUSIONS: Markers of MT and enterocyte damage are elevated in untreated HIV-1 infected patients. Long-term ART reduces the levels, except for I-FABP which role as a marker of MT is questionable in ART-experienced patients. Why the enterocyte damage seems to persist remains to be established. Also antibiotic usage may influence the kinetics of the markers of MT.

    TRIAL REGISTRATION: ClinicalTrials.gov NCT01445223.

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