oru.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Publications (10 of 10) Show all publications
Dlugosz, A., Nowak, P., D'Amato, M., Mohammadian Kermani, G., Nyström, J., Abdurahman, S. & Lindberg, G. (2015). Increased serum levels of lipopolysaccharide and antiflagellin antibodies in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterology and Motility, 27(12), 1747-1754
Open this publication in new window or tab >>Increased serum levels of lipopolysaccharide and antiflagellin antibodies in patients with diarrhea-predominant irritable bowel syndrome
Show others...
2015 (English)In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 27, no 12, p. 1747-1754Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2015
Keywords
Flagellin, irritable bowel syndrome, lipopolysaccharide, soluble CD14, toll-like receptors
National Category
Gastroenterology and Hepatology Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:oru:diva-47297 (URN)10.1111/nmo.12670 (DOI)000365679000006 ()26387872 (PubMedID)2-s2.0-84947868732 (Scopus ID)
Note

Funding Agencies:

Stockholm County Council (ALF) 20120246

Bengt Ihres fond

Karolinska Institutet

Stockholm County Council

Available from: 2016-01-05 Created: 2016-01-04 Last updated: 2018-07-02Bibliographically approved
Ekici, H., Amogne, W., Aderaye, G., Lindquist, L., Sonnerborg, A. & Abdurahman, S. (2014). Minority drug-resistant HIV-1 variants in treatment Naive East-African and Caucasian patients detected by allele-specific real-time PCR. PLoS ONE, 9(10), e111042
Open this publication in new window or tab >>Minority drug-resistant HIV-1 variants in treatment Naive East-African and Caucasian patients detected by allele-specific real-time PCR
Show others...
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e111042-Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-39034 (URN)10.1371/journal.pone.0111042 (DOI)000343731200098 ()25333961 (PubMedID)2-s2.0-84908338845 (Scopus ID)
Funder
Swedish Research CouncilSida - Swedish International Development Cooperation Agency
Note

Funding Agencies:

European and Developing Countries Clinical Trial Partnership

Swedish Civil Contingencies Agency

7th Framework Programme of European Union, Collaborative HIV and Anti-HIV Drug Resistance Network

Available from: 2014-11-27 Created: 2014-11-27 Last updated: 2018-09-11Bibliographically approved
Abdurahman, S., Barqasho, B., Nowak, P., Cuong, D. D., Amogné, W., Larsson, M., . . . Sönnerborg, A. (2014). Pattern of microbial translocation in patients living with HIV-1 from Vietnam, Ethiopia and Sweden. Journal of the International AIDS Society, 17, 18841
Open this publication in new window or tab >>Pattern of microbial translocation in patients living with HIV-1 from Vietnam, Ethiopia and Sweden
Show others...
2014 (English)In: Journal of the International AIDS Society, ISSN 1758-2652, E-ISSN 1758-2652, Vol. 17, p. 18841-Article in journal (Refereed) Published
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.

Keywords
HIV in Ethiopia; HIV in Sweden; HIV in Vietnam; Immune activation; LPS; Microbial translocation; sCD14; Treatment-naïve patients living with HIV
National Category
Infectious Medicine Immunology in the medical area
Research subject
Infectious Diseases; Immunology
Identifiers
urn:nbn:se:oru:diva-41998 (URN)10.7448/IAS.17.1.18841 (DOI)000330631300001 ()24461466 (PubMedID)2-s2.0-84896819433 (Scopus ID)
Funder
Sida - Swedish International Development Cooperation AgencySwedish Research Council, 521-2012-3476
Note

Funding Agencies:

European and Developing Countries Clinical Trial Partnership

Swedish Civil Contingencies Agency SWE-2009-151

Available from: 2015-03-05 Created: 2015-01-16 Last updated: 2018-06-18Bibliographically approved
Vesterbacka, J., Nowak, P., Barqasho, B., Abdurahman, S., Nyström, J., Nilsson, S., . . . Sönnerborg, A. (2013). Kinetics of microbial translocation markers in patients on efavirenz or lopinavir/r based antiretroviral therapy. PloS one, 8(1), e55038
Open this publication in new window or tab >>Kinetics of microbial translocation markers in patients on efavirenz or lopinavir/r based antiretroviral therapy
Show others...
2013 (English)In: PloS one, ISSN 1932-6203, Vol. 8, no 1, p. e55038-Article in journal (Refereed) Published
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.

National Category
Clinical Medicine
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-41997 (URN)10.1371/journal.pone.0055038 (DOI)000315211500050 ()23383047 (PubMedID)2-s2.0-84873813972 (Scopus ID)
Funder
Swedish Research Council
Note

Funding Agencies:

Stockholm County Council

Swedish Physicians against AIDS

Swedish Medical Society (SLS)

Swedish Society for Medical Research (SSMF for Piotr Nowak)

Sahlgrenska Academy at University of Gothenburg

Health & Medical Care Committee of the Region Vastra Gotaland

Available from: 2015-03-05 Created: 2015-01-16 Last updated: 2018-08-28Bibliographically approved
Nowak, P., Abdurahman, S., Lindkvist, A., Troseid, M. & Sönnerborg, A. (2012). Impact of HMGB1/TLR ligand complexes on HIV-1 replication: possible role for flagellin during HIV-1 infection. International Journal of Microbiology, 263836
Open this publication in new window or tab >>Impact of HMGB1/TLR ligand complexes on HIV-1 replication: possible role for flagellin during HIV-1 infection
Show others...
2012 (English)In: International Journal of Microbiology, ISSN 1687-918X, E-ISSN 1687-9198, p. 263836-Article in journal (Refereed) Published
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.

National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:oru:diva-41996 (URN)10.1155/2012/263836 (DOI)22719767 (PubMedID)2-s2.0-84863676731 (Scopus ID)
Available from: 2015-03-05 Created: 2015-01-16 Last updated: 2017-12-04Bibliographically approved
Bäckström Winquist, E., Abdurahman, S., Tranell, A., Lindström, S., Tingsborg, S. & Schwartz, S. (2012). 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.. Virology, 422(1), 46-58
Open this publication in new window or tab >>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.
Show others...
2012 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 422, no 1, p. 46-58Article in journal (Refereed) Published
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).

Keywords
ASF/SF2; Influenza; NS1; Polyadenylation; Spanish flu; Splicing; SR proteins; SRp30c; SRp40
National Category
Basic Medicine
Identifiers
urn:nbn:se:oru:diva-41995 (URN)10.1016/j.virol.2011.10.004 (DOI)000297902300006 ()22036312 (PubMedID)2-s2.0-82355190150 (Scopus ID)
Funder
Swedish Research CouncilAFA Insurance
Note

Funding Agency:

European Commission 201607 (RNAFLU)

Available from: 2015-03-05 Created: 2015-01-16 Last updated: 2018-05-14Bibliographically approved
Trøseid, M., Nowak, P., Nyström, J., Lindkvist, A., Abdurahman, S. & Sönnerborg, A. (2010). 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 therapy. AIDS (London), 24(11), 1733-1737
Open this publication in new window or tab >>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 therapy
Show others...
2010 (English)In: AIDS (London), ISSN 0269-9370, E-ISSN 1473-5571, Vol. 24, no 11, p. 1733-1737Article in journal (Refereed) Published
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.

Keywords
antiretroviral therapy; high mobility group box-1 protein; HIV-1; immune activation; lipopolysaccharide; microbial translocation
National Category
Infectious Medicine Immunology in the medical area
Research subject
Infectious Diseases; Immunology
Identifiers
urn:nbn:se:oru:diva-41994 (URN)10.1097/QAD.0b013e32833b254d (DOI)000279396600014 ()20502315 (PubMedID)2-s2.0-77954349457 (Scopus ID)
Note

Funding Agencies:

Swedish Medical Research Council

Karolinska Institutet

Swedish International Developing Agency

Available from: 2015-03-05 Created: 2015-01-16 Last updated: 2018-08-27Bibliographically approved
Barqasho, B., Nowak, P., Abdurahman, S., Walther-Jallow, L. & Sönnerborg, A. (2010). Implications of the release of high-mobility group box 1 protein from dying cells during human immunodeficiency virus type 1 infection in vitro. Journal of General Virology, 91(Pt 7), 1800-1809
Open this publication in new window or tab >>Implications of the release of high-mobility group box 1 protein from dying cells during human immunodeficiency virus type 1 infection in vitro
Show others...
2010 (English)In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 91, no Pt 7, p. 1800-1809Article in journal (Refereed) Published
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.

National Category
Medical Biotechnology Basic Medicine
Identifiers
urn:nbn:se:oru:diva-41993 (URN)10.1099/vir.0.016915-0 (DOI)000279747600018 ()20200191 (PubMedID)2-s2.0-77954168421 (Scopus ID)
Note

Funding Agencies:

Swedish Medical Research Council

Swedish Foundation for Strategic Research

Swedish Physicians Against AIDS Research Fund 

Available from: 2015-03-05 Created: 2015-01-16 Last updated: 2018-04-25Bibliographically approved
Abdurahman, S., Végvári, A., Levi, M., Höglund, S., Högberg, M., Tong, W., . . . Vahlne, A. (2009). Isolation and characterization of a small antiretroviral molecule affecting HIV-1 capsid morphology. Retrovirology, 6, 34
Open this publication in new window or tab >>Isolation and characterization of a small antiretroviral molecule affecting HIV-1 capsid morphology
Show others...
2009 (English)In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 6, p. 34-Article in journal (Refereed) Published
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.

National Category
Basic Medicine
Identifiers
urn:nbn:se:oru:diva-41992 (URN)10.1186/1742-4690-6-34 (DOI)000265396300002 ()19356241 (PubMedID)2-s2.0-65449131619 (Scopus ID)
Funder
Swedish Research Council, K2000-06X-09501-10BSida - Swedish International Development Cooperation Agency, HIV-2006-050
Note

Funding Agencies:

K. U. Leuven GOA-05/19

Tripep AB

Available from: 2015-03-05 Created: 2015-01-16 Last updated: 2018-01-11Bibliographically approved
Abdurahman, S., Végvári, A., Youssefi, M., Levi, M., Höglund, S., Andersson, E., . . . Vahlne, A. (2008). Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity. Antimicrobial Agents and Chemotherapy, 52(10), 3737-3744
Open this publication in new window or tab >>Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity
Show others...
2008 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 10, p. 3737-3744Article in journal (Refereed) Published
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.

National Category
Microbiology in the medical area Pharmacology and Toxicology
Research subject
Microbiology
Identifiers
urn:nbn:se:oru:diva-41991 (URN)10.1128/AAC.00265-08 (DOI)000259480800036 ()18644965 (PubMedID)2-s2.0-54049099240 (Scopus ID)
Funder
Swedish Research Council, K2000-06X09501-10B
Note

Funding Agencies:

European Commission HPAW-2002-90005

Swedish International development Cooperation Agency HIV-2006-050

Available from: 2015-03-05 Created: 2015-01-16 Last updated: 2018-01-11Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0902-508X

Search in DiVA

Show all publications