| 1. |
- Ellegård, Rada, 1985-
(författare)
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Effects of Complement Opsonization of HIV on Dendritic Cells : and Implications for the Immune Response
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dendritic cells are key players during HIV pathogenesis, and shape both the immediate immune response at the site of infection as well as directing the adaptive immune response against the virus. HIV has developed a plethora of immune evasion mechanisms that hijack dendritic cell functions, suppressing their ability to mount an accurate immune response and exploiting them for efficient viral transfer to target T cells.To achieve successful replication within dendritic cells without triggering danger signaling, HIV accomplishes a delicate balance where only a low level of transcription can be sustained without triggering antiviral responses that would harm the virus. Here, we describe how the presence of HSV2 coinfection, which is very common in geographic areas with a high HIV prevalence and almost triples the risk of HIV acquisition, alters dendritic cell state to support much higher levels of HIV infection. We found this effect to be mediated by the STING pathway, which is involved in the sensing of DNA in the cell cytosol. STING activation led to an upregulation of factors such as IRF3 and NFkB that can be used for HIV transcription and a degradation of factors that restrict HIV replication.In addition, we describe how HIV exploits the human complement system, a group of proteins that usually help the human body to identify dangerous pathogens while avoiding reaction towards self. HIV can coat itself, i.e. become opsonized, in complement fragments that are typically only present on the body’s own cells, allowing it to activate signaling pathways that are associated with tolerance. Dendritic cells that come into contact with complement opsonized HIV do not mount danger responses, despite the fact that HIV-derived single stranded RNA triggers the pathogen recognition receptor TLR8. The suppression of danger responses is mediated by activation of complement receptor 3, and leads to an increased infection of the dendritic cell and affects its interactions with other immune cells. There is a lack of recruitment of NK cells to the site of infection, and an inhibition of NK cell killing, which plays an important role in the destruction of HIV-infected cells in vivo. T cells primed by dendritic cells exposed to complement opsonized HIV have a lower ability to develop towards effector phenotype, and have an increased expression of the markers PD1, TIM3 and LAG3 which are associated with T cell dysfunction and exhaustion. In addition, T cells primed by these dendritic cells in the presence of NK cells upregulate markers CD38, CXCR3 and CCR4, which have been linked to an increased susceptibility to HIV infection.In summary, we add to the current knowledge on HIV immune evasion mechanisms that allow the virus to establish infection, as well as describing mechanisms that govern whether dendritic cells mount danger signaling and an immune response or not.
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| 2. |
- Azharuddin, Mohammad, 1986-, et al.
(författare)
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Nano toolbox in immune modulation and nanovaccines
- 2022
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Ingår i: Trends in Biotechnology. - Oxford, United Kingdom : Elsevier. - 0167-7799 .- 1879-3096. ; 40:10, s. 1195-1212
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Forskningsöversikt (refereegranskat)abstract
- Despite the great success of vaccines over two centuries, the conventional strategy is based on attenuated/altered microorganisms. However, this is not effective for all microbes and often fails to elicit a protective immune response, and sometimes poses unexpected safety risks. The expanding nano toolbox may overcome some of the roadblocks in vaccine development given the plethora of unique nanoparticle (NP)-based platforms that can successfully induce specific immune responses leading to exciting and novel solutions. Nanovaccines necessitate a thorough understanding of the immunostimulatory effect of these nanotools. We present a comprehensive description of strategies in which nanotools have been used to elicit an immune response and provide a perspective on how nanotechnology can lead to future personalized nanovaccines.
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| 3. |
- Boberg, Andreas, et al.
(författare)
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Immunization with HIV protease peptides linked to syngeneic erythrocytes
- 2007
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Ingår i: Infectious Agents and Cancer. - : Springer Science and Business Media LLC. - 1750-9378. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Boberg, Andreas, et al.
(författare)
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Murine models for HIV vaccination and challenge
- 2008
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Ingår i: Expert Review of Vaccines. - : Informa UK Limited. - 1476-0584 .- 1744-8395. ; 7:1, s. 117-130
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Bråve, Andreas, et al.
(författare)
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Intranasal immunization of young mice with a multigene HIV-1 vaccine in combination with the N3 adjuvant induces mucosal and systemic immune responses
- 2008
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 26:40, s. 5075-5078
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Buonaguro, L, et al.
(författare)
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DNA-VLP prime-boost intra-nasal immunization induces cellular and humoral anti-HIV-1 systemic and mucosal immunity with cross-clade neutralizing activity
- 2007
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 25:32, s. 5968-5977
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Cardona Gomez, Maria Eugenia, et al.
(författare)
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Specific properties of shRNA-mediated CCR5 downregulation that enhance the inhibition of HIV-1 infection in combination with shRNA targeting HIV-1 rev
- 2022
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Ingår i: Molecular Biology Reports. - : Springer. - 0301-4851 .- 1573-4978. ; 49, s. 11187-11192
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Tidskriftsartikel (refereegranskat)abstract
- Treatment with RNAi against HIV-1 transcripts efficiently inhibits viral replication but induces selection of escape mutants; therefore, the CCR5 coreceptor was suggested as an additional target. Blocking viral and host transcripts improved the antiviral effect. We have used short hairpin RNA (shRNA) targeting the human CCR5 (shCCR5) or the HIV-1 rev (shRev) transcripts to demonstrate distinctive properties of anti-CCR5 shRNA: shCCR5 induced more sustained protection than shRev; partial reduction in CCR5 expression substantially decreased HIV-1 infection, and shCCR5 performed better than shRev in the mixed shRNA-treated and untreated cultures. These observations indicate that CCR5 inhibitors should be conveniently included in HIV-1 gene silencing treatment schedules when only a certain cell fraction is protected to further reduce endogenous virus in a properly ART-treated HIV-1 infected individual.
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| 8. |
- Carlsson, Hanna, 1978-
(författare)
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Laboratory methods for investigation of the immunological orchestra in response to pathogens
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Laboratory methods used for investigation of immune response often involve collection of whole blood and analysis of different biomarkers in blood components or generated from pathogen stimulation of whole blood or peripheral blood mononuclear cells (PBMC). Methods used to measure biomarkers are for example enzyme-linked immunosorbent assay (ELISA) which measures one biomarker at a time or multiplex assays for example x-unknown, multi-analyte profiling (xMAP) by Luminex or proximity extension assay (PEA), which can measure up to just over 3000 biomarkers at a time. Analysis of one biomarker at a time are time consuming, costly, and dependent of a large sample size to enable repeated measurements of different analytes. Therefore, multiplex assays that are time saving, more cost effective and measures multiple bi-omarkers at once in a small sample can be applied. The aim of this thesis was to evaluate multiplex laboratory methods for investigation of the immunological orchestra in response to Borrelia infection and influenza immunisation and if possible, further characterize individuals with different clinical outcomes or serological response, respectively. In our studies (paper I-III) we included 1113 blood donors of which 66 were found to previously have had a subclinical borreliosis (defined as presence of Borrelia-specific antibodies without recall of previous Lyme borreliosis), of the 66 individuals 60 were available for participation. We also included 22 patients previously diagnosed with Lyme neuroborreliosis (LNB). In paper IV we included in total 73 individuals consisting of healthcare workers and patients attending seasonal influenza vaccination. We applied whole blood, PBMC and plasma stimulations and measured a range of cytokines, chemokines and complement factors with ELISA, nephelometry, xMAP and PEA. Our results show that subclinical Lyme borreliosis (SB) individuals display the following pattern, low age, male sex, low amount of secreted interleukin (IL)-17, CCL20 and higher secretion of IL-10 by PBMCs stimulated three days with Borrelia garinii compared to patients with previous Lyme neuroborreliosis (LNB). The subclinical individuals also show higher activation of the complement system in response to Borrelia afzelii. We performed multiplex analysis of complement factors in attempt to further characterize our SB individuals and LNB patient but found the results to deviate largely from reference values retrieved with other standardized methods. This highlights the importance of critical review of generated results from all form of assays. To investigate immune responses after influenza immunisation and further characterize serological responders and nonresponders we included measurement of influenza-specific antibodies and total immunoglobulins (Ig) in blood serum, influenza-specific mucosal IgA (nasal-swabs) and cell-mediated immune response in supernatants from PBMCs stimulated with influenza vaccine using PEA. We found the serological responders to be characterised by lower levels of total IgM, Granzyme B (GZMB) and IL-12 together with higher levels of CXCL13 compared with nonresponders. To conclude, xMAP and PEA are two valuable methods that can be applied together with multivariate statistical methods in the investigation of both innate and adaptive immunity characteristics and association to clinical outcome or serological response after Borrelia infection and influenza immunisation, respectively.
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| 9. |
- Harila, Kirsi, et al.
(författare)
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Vpu and Tsg101 regulate intracellular targeting of the human immunodeficiency virus type 1 core protein precursor Pr55gag
- 2006
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Ingår i: Journal of Virology. - 0022-538X .- 1098-5514. ; 80:8, s. 3765-3772
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 10. |
- Hinkula, Jorma, 1958-
(författare)
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Clarification of how HIV-1 DNA and protein immunizations may be better used to obtain HIV-1-specific mucosal and systemic immunity
- 2007
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Ingår i: Expert Review of Vaccines. - : Informa UK Limited. - 1476-0584 .- 1744-8395. ; 6:2, s. 203-212
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 11. |
- Hinkula, Jorma, 1958-, et al.
(författare)
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Safety and immunogenicity, after nasal application of HIV-1 DNA gagp37 plasmid vaccine in young mice
- 2008
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 26:40, s. 5101-5106
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 12. |
- Istrate, C, et al.
(författare)
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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 rotavirus
- 2007
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 65:6, s. 494-502
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 13. |
- Istrate, Claudia, 2000-, et al.
(författare)
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Parenteral administration of RF 8-2/6/7 rotavirus-like particles in a one-dose regimen induce protective immunity in mice
- 2008
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 26:35, s. 4594-4601
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 14. |
- Johansson, Daniel X, et al.
(författare)
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Efficient expression of recombinant human monoclonal antibodies in Drosophila S2 cells
- 2007
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Ingår i: JIM - Journal of Immunological Methods. - : Elsevier BV. - 0022-1759 .- 1872-7905. ; 318:1-2, s. 37-46
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 15. |
- Johansson, E., et al.
(författare)
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Amount of maternal rotavirus-specific antibodies influence the outcome of rotavirus vaccination of newborn mice with virus-like particles
- 2008
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 26:6, s. 778-785
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 16. |
- Johansson, Susanne, et al.
(författare)
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Elimination of HIV-1 infection by treatment with a doxorubicin-conjugated anti-envelope antibody
- 2006
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Ingår i: AIDS. - : Ovid Technologies (Wolters Kluwer Health). - 0269-9370 .- 1473-5571. ; 20:15, s. 1911-1915
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 17. |
- Kindberg, Elin, 1981-, et al.
(författare)
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A nonsense mutation (428G→A) in the fucosyltransferase FUT2 gene affects the progression of HIV-1 infection
- 2006
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Ingår i: AIDS. - : Ovid Technologies (Wolters Kluwer Health). - 0269-9370 .- 1473-5571. ; 20:5, s. 685-689
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 18. |
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| 19. |
- Omer, Abubakr A. M., 1982-, et al.
(författare)
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Plantaricin NC8 αβ rapidly and efficiently inhibits flaviviruses and SARS-CoV-2 by disrupting their envelopes
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 17:11
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Tidskriftsartikel (refereegranskat)abstract
- Potent broad-spectrum antiviral agents are urgently needed to combat existing and emerging viral infections. This is particularly important considering that vaccine development is a costly and time consuming process and that viruses constantly mutate and render the vaccine ineffective. Antimicrobial peptides (AMP), such as bacteriocins, are attractive candidates as antiviral agents against enveloped viruses. One of these bacteriocins is PLNC8 αβ, which consists of amphipathic peptides with positive net charges that display high affinity for negatively charged pathogen membrane structures, including phosphatidylserine rich lipid membranes of viral envelopes. Due to the morphological and physiological differences between viral envelopes and host cell plasma membranes, PLNC8 αβ is thought to have high safety profile by specifically targeting viral envelopes without effecting host cell membranes. In this study, we have tested the antiviral effects of PLNC8 αβ against the flaviviruses Langat and Kunjin, coronavirus SARS-CoV-2, influenza A virus (IAV), and human immunodeficiency virus-1 (HIV-1). The concentration of PLNC8 αβ that is required to eliminate all the infective virus particles is in the range of nanomolar (nM) to micromolar (μM), which is surprisingly efficient considering the high content of cholesterol (8–35%) in their lipid envelopes. We found that viruses replicating in the endoplasmic reticulum (ER)/Golgi complex, e.g. SARS-CoV-2 and flaviviruses, are considerably more susceptible to PLNC8 αβ, compared to viruses that acquire their lipid envelope from the plasma membrane, such as IAV and HIV-1. Development of novel broad-spectrum antiviral agents can significantly benefit human health by rapidly and efficiently eliminating infectious virions and thereby limit virus dissemination and spreading between individuals. PLNC8 αβ can potentially be developed into an effective and safe antiviral agent that targets the lipid compartments of viral envelopes of extracellular virions, more or less independent of virus antigenic mutations, which faces many antiviral drugs and vaccines.
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| 20. |
- Patra, Hirak Kumar, 1981-, et al.
(författare)
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Rational Nanotoolbox with Theranostic Potential for Medicated Pro-Regenerative Corneal Implants
- 2019
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Ingår i: Advanced Functional Materials. - : John Wiley & Sons. - 1616-301X .- 1616-3028. ; 29:38
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Tidskriftsartikel (refereegranskat)abstract
- Cornea diseases are a leading cause of blindness and the disease burden is exacerbated by the increasing shortage around the world for cadaveric donor corneas. Despite the advances in the field of regenerative medicine, successful transplantation of laboratory‐made artificial corneas is not fully realized in clinical practice. The causes of failure of such artificial corneal implants are multifactorial and include latent infections from viruses and other microbes, enzyme overexpression, implant degradation, extrusion or delayed epithelial regeneration. Therefore, there is an urgent unmet need for developing customized corneal implants to suit the host environment and counter the effects of inflammation or infection, which are able to track early signs of implant failure in situ. This work reports a nanotoolbox comprising tools for protection from infection, promotion of regeneration, and noninvasive monitoring of the in situ corneal environment. These nanosystems can be incorporated within pro‐regenerative biosynthetic implants, transforming them into theranostic devices, which are able to respond to biological changes following implantation.
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| 21. |
- Rollman, Erik, et al.
(författare)
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Evaluation of immunogenicity and efficacy of combined DNA and adjuvanted protein vaccination in a human immunodeficiency virus type 1/murine leukemia virus pseudotype challenge model
- 2007
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 25:11, s. 2145-2154
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 22. |
- Svanberg, Cecilia, 1991-
(författare)
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HIV-1 Exploitation of Dendritic Cell Functionality and Initial Responses in Mucosal Tissues : Elucidation of Influence of HIV-1 Complement Opsonization, and HIV-1-HSV-2 Co-infection
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human immunodeficiency virus (HIV)-1 is transmitted between individuals via sexual intercourse or via blood products. To date there are 38 million people living with chronic HIV infection and around 1.5 million yearly acquire a new infection. HIV is known to have detrimental effects on the immune system and its cell function and leads to the development of acquired immune deficiency syndrome (AIDS). AIDS is characterized by opportunistic infections often fatal to the individual. Mucosal tissues, which are the main site of HIV-1 infection, consist of a complex network of different cell types building up a barrier against the outside world. In the mucosa there are multiple immune cells and one of them is the dendritic cells (DCs), a professional antigen presenting cell needed for priming of adaptive T cell responses. DCs are rarely productively infected with HIV-1 but the virus can modulate the DC phenotype and function by mere exposure to the virus. There are many factors that influence viral transmission including prevalent inflammatory conditions or infections in the genital tract. For instance, a newly acquired herpes simplex virus-2 (HSV-2) infection increases the risk of transmission at HIV-1 exposure by four times. A vital part of the innate immune defense is the complement system, which consists of proteins found in all body fluids. Normally during complement activation, it leads to lysis of pathogens, but HIV-1 can evade this process. This is achieved by the incorporated complement regulatory proteins in the viral plasma membrane leading to accumulation of opsonizing complement fragments on the HIV-1 particles. Our aim with these studies was to deepen the understanding of the HIV-1 exploitation of DC function and elucidate the initial effects exposure and establishment of HIV-1 infection has on the mucosal tissues and immune cells. In addition, we aimed to elucidate the effects HSV-2 exerts on the HIV-1-infection of DCs and how viral complement opsonization affects the viral infection and activation of immune responses. In Paper I we found that coinfection of monocyte derived DCs (MDDCs) with HIV-1 and HSV-2 decreases the amount of the HIV-1 restriction factors SAMHD1 and TREX1 in MDDCs, leading to increased productive HIV-1 infection. In Paper II and III we found that HIV-1 utilizes the complement system to induce higher productive infection of the colorectal and cervical mucosal DCs. The different forms of HIV, free or complement opsonized, had distinct effects on the immune responses and T cell phenotypes in the tissues, all in favor of HIV-1 establishment and productive infection. In Paper IV, HIV-1 exposed DCs triggered after crosstalk with suppressive T cells a prolonged type I interferon response and an upregulation of coinhibitory molecules on the DCs. The findings in this thesis add to the knowledge of HIV-1 early transmission events, how co-infection modulates DC function, and how the presence of HIV-1 affects the priming of adaptive immune responses.
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| 23. |
- Vandesande, Helena, 1991-
(författare)
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Infection, early entry events and replication processes of picornaviruses
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Picornaviridae is a large and diverse family of small RNA viruses, several of which have exhibited a distinct clinical and socioeconomic impact on human society. While many infections are asymptomatic, some members of this virus family have the potential to cause severe disease, including, but not limited to, poliomyelitis, myocarditis, meningitis, and foot-and-mouth disease. Picornaviruses have been the knowledge foundation of modern virology, and as such, they have been studied extensively over the past century. This thesis aimed to further that understanding by examining the early entry and replication kinetics of echovirus 30 (E30), coxsackievirus B5 (CVB5), and rhinovirus C34 (RV-C34), as well as the presence and transmission of Saffold virus (SAFV) in Sweden. E30 appears to exploit one previously known enterovirus entry pathway to facilitate its infection, using DAF as an attachment receptor and leading to early endosomal uncoating. In CVB5, it is the structural proteins that dictate the increase in empty particles and reduction in infective particles, resulting in a slowed infection between passages in cultured cells. As it stands, the key factor to establish a persistent infection seems to be the small number of infective particles as opposed to the high number of empty particles. Furthermore, we present in this thesis the prototype genome of RV-C34, a member of the rhinovirus C species which shows limited replication potential in cell culture. Finally, analysis of Swedish patient samples confirmed the circulation of SAFV-3 in Sweden and, for the first time, demonstrated the presence of this virus in elderly people. Furthermore, we showed that the circulating strain is phylogenetically closely related to several Asian strains, as well as the Dutch strain described in 2009. Taken together, this thesis contributes to a better understanding of enteroviral entry and infection, as well as SAFV epidemiology in Sweden.
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| 24. |
- Veldhuis Kroeze, Edwin J. B., et al.
(författare)
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Consecutive CT in vivo lung imaging as quantitative parameter of influenza vaccine efficacy in the ferret model
- 2012
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Ingår i: Vaccine. - : Elsevier. - 0264-410X .- 1873-2518. ; 30:51, s. 7391-7394
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical vaccine efficacy studies are generally limited to certain read out parameters such as assessment of virus titers in swabs and organs, clinical signs, serum antibody titers, and pathological changes. These parameters are not always routinely applied and not always scheduled in a logical standardized way. We used computed tomography (CT) imaging as additional and novel read out parameter in a vaccine efficacy study by quantifying alterations in aerated lung volumes in ferrets challenged with the 2009 pandemic A/H1N1 influenza virus.Vaccination protected from marked variations in aerated lung volumes compared to naive controls. The vaccinated group showed a daily gradual mean reduction with a maximum of 7.8%, whereas the controls showed a maximum of 14.3% reduction. The pulmonary opacities evident on CT images were most pronounced in the placebo-treated controls, and corresponded to significantly increased relative lung weights at necropsy.This study shows that consecutive in vivo CT imaging allows for a day to day read out of vaccine efficacy by quantification of altered aerated lung volumes.
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