| 1. |
- Abdurahman, Samir, 1965-, et al.
(författare)
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Pattern of microbial translocation in patients living with HIV-1 from Vietnam, Ethiopia and Sweden
- 2014
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Ingår i: Journal of the International AIDS Society. - 1758-2652. ; 17, s. 18841-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Barqasho, Babilonia
(författare)
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HMBG1 and other soluble factors in HIV-1 pathogenesis
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The innate immune system is the first defense mechanism invading pathogens encounter. Macrophages, dendritic cells and cytokines/chemokines are important factors for the functionality of the innate immunity, and provide the adaptive immune system with sufficient signals for the proper action. Immune activation occurring during HIV-1 infection is essential to understand and investigate. The aims of this thesis were to evaluate the role of immune activation factors of the innate immune system, such as cytokines and chemokines, in different sets of patient categories, cellular systems and phases during the HIV-1 infection. We were most interested in a particular cytokine, the high mobility group box protein 1 (HMGB1). In addition to our in vitro experiments, we had access to an unique cohort, the Quest study, which is the first placebo controlled treatment trial in acute HIV-1 infection. For our substudy, we selected 22 patients, categorized into responders and non-responders regarding the outcome of their viral load after analytical treatment interruption (ATI). We found that high levels of immune activation as determined by the pattern of cytokines/chemokines during PHI, did not favor a better virological outcome after ATI. The early initiation of ART did not seem to affect the preservation of the immune system. HMGB1 is a proinflammatory cytokine, ubiquitously expressed in all nucleated cells, with a functional importance as a regulator of transcription and stabilization of the nucleosomal structure. HMGB1 is actively secreted from LPS- or TNF-activated macrophages/monocytes, pituicytes and other cells. HMGB1 can also be passively released by damaged necrotic or apoptotic cells. We studied the role of HGMB1 in different systems and modes during HIV-1 infection. Extracellular HMGB1 upregulated HIV-1 infection in latently infected U1 monocytic cells, but did not have impact on viral replication in ACH-2 Tlymphocytic cells. In acute HIV-1 infected monocyte-derived macrophages (MDMs), HIV-1 production was downregulated, most likely due to the increased production of the chemokines MIP-1alpha, MIP-1beta and Rantes. Furthermore, higher levels of HMGB1 were found in HIV-1 infected patients with deteriorated immune status and opportunistic conditions, compared to uninfected individuals and HIV-1 infected patients with less preserved immune status. Additionally, HMGB1 was released by HIV-1 infected MT4 cells and CD4+ T-cells, in connection with virus induced cell death. This release could be interfered by addition of a pan-caspase inhibitor Z-vad to MT4 cells cultures. We suggest that HMGB1 was released passively from MT4 cells not only during necrosis but also during apoptosis. In conclusion, the presented data cast a light on the importance of the immune activation process during HIV-1 pathogenesis. HMGB1 is released during the viral cell infection and may be a molecule connecting the cell death processes and the immune activation during HIV-1 infection.
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| 3. |
- Barqasho, Babilonia, et al.
(författare)
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Implications of the release of high-mobility group box 1 protein from dying cells during human immunodeficiency virus type 1 infection in vitro
- 2010
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Ingår i: Journal of General Virology. - : Microbiology Society. - 0022-1317 .- 1465-2099. ; 91:Pt 7, s. 1800-1809
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Vesterbacka, Jan, et al.
(författare)
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Kinetics of microbial translocation markers in patients on efavirenz or lopinavir/r based antiretroviral therapy
- 2013
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1, s. e55038-
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Tidskriftsartikel (refereegranskat)abstract
- 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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