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Winni De Haes,
Joanna Rejman,
Charlotte Pollard,
Céline Merlin, Marc Vekemans,
Eric Florence,
Stefaan C De Smedt,
Johan Grooten,
Guido Vanham,
Stefaan De Koker,
Ellen Van Gulck
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ABSTRACT: Aim: Cationic lipids (Lipofectamine™ [Invitrogen, Merelbeke, Belgium] and 1,2-dioleoyl-3-trimethylammonium-propane/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and polymers (jetPEI™ and in vivo-jetPEI™ [Polyplus-transfection, Illkirch, France]) were evaluated for their potential to deliver mRNA to monocyte-derived dendritic cells. Materials & methods: Lipoplexes and polyplexes, containing mRNA-encoding GFP or Gag protein, were incubated with human monocyte-derived dendritic cells and transfection efficiencies were assessed by flow cytometry. Results: Lipofectamine was by far the most efficient in mRNA delivery, therefore it was used in further experiments. Incubation of monocyte-derived dendritic cells isolated from HIV-1-positive donors with mRNA-encoding Gag protein complexed to Lipofectamine resulted in 50% transfection. Importantly, coculture of these Gag-transfected dendritic cells with autologous T cells induced an over tenfold expansion of IFN-γ- and IL-2-secreting CD4(+) and CD8(+) T cells. Conclusion: Cationic lipid-mediated mRNA delivery may be a useful tool for therapeutic vaccination against HIV-1. This approach can be applied to develop vaccination strategies for other infectious diseases and cancer. Original submitted 26 January 2012; Revised submitted 17 April 2012.
Nanomedicine 08/2012; · 5.05 Impact Factor
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ABSTRACT: A variety of immune-based therapies has been developed in order to boost or induce protective CD8(+) T cell responses in order to control HIV replication. Since dendritic cells (DCs) are professional antigen-presenting cells (APCs) with the unique capability to stimulate naïve T cells into effector T cells, their use for the induction of HIV-specific immune responses has been studied intensively. In the present study we investigated whether modulation of the activation state of DCs electroporated with consensus codon-optimized HxB2 gag mRNA enhances their capacity to induce HIV gag-specific T cell responses. To this end, mature DCs were (i) co-electroporated with mRNA encoding interleukin (IL)-12p70 mRNA, or (ii) activated with a cytokine cocktail consisting of R848 and interferon (IFN)-γ. Our results confirm the ability of HxB2 gag-expressing DCs to expand functional HIV-specific CD8(+) T cells. However, although most of the patients had detectable gag-specific CD8(+) T cell responses, no significant differences in the level of expansion of functional CD8(+) T cells could be demonstrated when comparing conventional or immune-modulated DCs expressing IL-12p70. This result which goes against expectation may lead to a re-evaluation of the need for IL-12 expression by DCs in order to improve T-cell responses in HIV-1-infected individuals.
Clinical and Developmental Immunology 01/2012; 2012:184979. · 1.84 Impact Factor
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Rafael Van den Bergh,
Sébastien Morin,
Hans Jürgen Sass,
Stephan Grzesiek, Marc Vekemans,
Eric Florence,
Huyen Thanh Thi Tran,
Rosina Gabriel Imiru,
Leo Heyndrickx,
Guido Vanham,
Patrick De Baetselier,
Geert Raes
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ABSTRACT: The immune system exerts a diversifying selection pressure on HIV through cellular, humoral and innate mechanisms. This pressure drives viral evolution throughout infection. A better understanding of the natural immune pressure on the virus during infection is warranted, given the clinical interest in eliciting and sustaining an immune response to HIV which can help to control the infection. We undertook to evaluate the potential of the novel HIV-induced, monocyte-derived factor visfatin to modulate viral infection, as part of the innate immune pressure on viral populations.
We show that visfatin is capable of selectively inhibiting infection by R5 HIV strains in macrophages and resting PBMC in vitro, while at the same time remaining indifferent to or even favouring infection by X4 strains. Furthermore, visfatin exerts a direct effect on the relative fitness of R5 versus X4 infections in a viral competition setup. Direct interaction of visfatin with the CCR5 receptor is proposed as a putative mechanism for this differential effect. Possible in vivo relevance of visfatin induction is illustrated by its association with the dominance of CXCR4-using HIV in the plasma.
As an innate factor produced by monocytes, visfatin is capable of inhibiting infections by R5 but not X4 strains, reflecting a potential selective pressure against R5 viruses.
PLoS ONE 01/2012; 7(4):e35074. · 4.09 Impact Factor
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Ellen Van Gulck,
Erika Vlieghe, Marc Vekemans,
Viggo F I Van Tendeloo,
Ann Van De Velde,
Evelien Smits,
Sébastien Anguille,
Nathalie Cools,
Herman Goossens,
Liesbet Mertens,
Winni De Haes,
Johnsson Wong,
Eric Florence,
Guido Vanham,
Zwi N Berneman
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ABSTRACT: In an effort to raise protective antiviral immunity, dendritic cell immunotherapy was evaluated in six adults infected with human immunodeficiency virus (HIV)-1 and stable under highly active antiretroviral therapy (HAART).
Autologous monocyte-derived dendritic cells electroporated with mRNA encoding Gag and a chimeric Tat-Rev-Nef protein were administered, whereas patients remained on HAART. Feasibility, safety, immunogenicity and antiviral responses were investigated.
Dendritic cell vaccine preparation and administration were successful in all patients and only mild adverse events were seen. There was a significant increase post-dendritic cell as compared to pre-dendritic cell vaccination in magnitude and breadth of HIV-1-specific interferon (IFN)-γ response, in particular to Gag, and in T-cell proliferation. Breadth of IFN-γ response and T-cell proliferation were both correlated with CD4(+) and CD8(+) polyfunctional T-cell responses. Importantly, dendritic cell vaccination induced or increased the capacity of autologous CD8(+) T cells to inhibit superinfection of CD4(+) T cells with the vaccine-related IIIB virus and some but not all other HIV-1 strains tested. This HIV-1-inhibitory activity, indicative of improved antiviral response, was correlated with magnitude and breadth of Gag-specific IFN-γ response.
Therapeutic immunization with dendritic cells was safe and successful in raising antiviral cellular immune responses, including effector CD8(+) T cells with virus inhibitory activity. The stimulation of those potent immunological and antiviral effects, which have been associated with control of HIV-1, underscores the potential of dendritic cell vaccination in the treatment of HIV-1. The incomplete nature of the response in some patients helped to identify potential targets for future improvement, that is increasing antigenic spectrum and enhancing T-cell response.
AIDS (London, England) 12/2011; 26(4):F1-12. · 4.91 Impact Factor
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ABSTRACT: HIV subtype-specific data on mutation type, rate, and accumulation following HAART treatment failure are limited. We studied patterns and accrual of drug resistance mutations in a Cambodian CRF01_AE-infected cohort continuing a virologically failing first-line, nonnucleoside reverse transcriptase inhibitor- (NNRTI-) based, HAART. Between 2005 and 2007, 837 adult HIV-infected patients had regular plasma HIV-1 RNA viral load measurements at Sihanouk Hospital Centre of Hope (SHCH), Cambodia. Drug resistance testing was performed in all patients with HIV-1 RNA >1000 copies/ml after at least 6 months of HAART. Seventy-one patients with a mean age of 34 years, of whom 68% were male, were retrospectively assessed at virological failure. The median duration of antiretroviral therapy was 12.3 (IQR 7.1-18.23) months, the median CD4 cell count was 173 (IQR 118-256) cells/mm(3), and the mean plasma HIV-1 RNA viral load was 3.9 log (SD 0.72) at failure. NNRTI mutations, M184I/V mutation, thymidine analogue mutations, and K65R were observed in 78.9%, 69%, 20%, and 12.7% of patients, respectively. For 33 patients, genotypic testing was carried out on at least two occasions before the switch to second-line HAART after a median duration of 5.8 (IQR 4.3-6.1) months of virological failure: 54.5% of patients accumulated new mutations with a rate of 1.6 mutations per person-year. Accumulation was seen both for nucleoside and nonnucleoside reverse transcriptase inhibitors, and also in patients with low-level viremia. Subtype-specific data on mutation type, rate, and accumulation after HAART failure are urgently needed to optimize treatment strategies in resource-limited settings.
AIDS research and human retroviruses 07/2011; 27(7):727-35. · 2.18 Impact Factor
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ABSTRACT: Vector-borne protozoan infections are responsible for a wide variety of illnesses (mainly malaria, trypanosomiasis and leishmaniasis) affecting tropical and subtropical areas, but increasingly diagnosed in nonendemic settings. This article summarizes the therapeutic developments for these conditions during the past decade and focuses specifically on treatment recommendations for returning travelers and migrants. The treatment of malaria has known the most spectacular improvements. Progress in the management of leishmaniasis and trypanosomiasis has also been substantial and includes introduction of new drugs into clinical practice, combinations of existing drugs, or new laboratory tools for treatment monitoring as well as extension of treatment indications to new groups of patients. Serious gaps still exist in terms of effectiveness and tolerance. Since the research pipeline is very limited for the coming 5-10 years, optimized combinations of existing drugs need to be urgently explored.
Expert Review of Anticancer Therapy 05/2011; 9(5):583-608. · 3.28 Impact Factor
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ABSTRACT: Tuberculosis (TB) infection is relatively frequent among travellers to high incidence-countries, especially in long-term travellers and those involved in health work. It is important to diagnose recent infection, both for the affected individual and to prevent further transmission. Based on published literature, we assess the value of interferon-γ release assays (IGRAs) as a complement to or replacement of the tuberculin skin test (TST) for the diagnosis of latent TB infection in the setting of a travel clinic. A comparison of available IGRAs with the TST in terms of operating characteristics and practical considerations is presented. We conclude that IGRAs offer some practical advantages that may benefit certain well-defined patient groups of a travel clinic, but that current evidence is incomplete. We identify research questions to better define the role of IGRAs in these populations.
Current Infectious Disease Reports 02/2011; 13(3):229-35.
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Retrovirology. 01/2009;
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Jurgen Vercauteren,
Inge Derdelinckx,
André Sasse,
Marleen Bogaert,
Helga Ceunen,
Ann De Roo,
Stephane De Wit,
Koen Deforche,
Fedoua Echahidi,
Katrien Fransen, [......],
Annelies van den Heuvel,
Bea van der Gucht,
Marc van Ranst,
Eric van Wijngaerden,
Bernard Vandercam, Marc Vekemans,
Chris Verhofstede,
Nathan Clumeck,
Anne-Mieke Vandamme,
Kristel van Laethem
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ABSTRACT: This study is the first prospective study to assess the prevalence, epidemiology, and risk factors of HIV-1 drug resistance in newly diagnosed HIV-infected patients in Belgium. In January 2003 it was initiated as part of the pan-European SPREAD program, and continued thereafter for four inclusion rounds until December 2006. Epidemiological, clinical, and behavioral data were collected using a standardized questionnaire and genotypic resistance testing was done on a sample taken within 6 months of diagnosis. Two hundred and eighty-five patients were included. The overall prevalence of transmitted HIV-1 drug resistance in Belgium was 9.5% (27/285, 95% CI: 6.6-13.4). Being infected in Belgium, which largely coincided with harboring a subtype B virus, was found to be significantly associated with transmission of drug resistance. The relatively high rate of baseline resistance might jeopardize the success of first line treatment as more than 1 out of 10 (30/285, 10.5%) viruses did not score as fully susceptible to one of the recommended first-line regimens, i.e., zidovudine, lamivudine, and efavirenz. Our results support the implementation of genotypic resistance testing as a standard of care in all treatment-naive patients in Belgium.
AIDS Research and Human Retroviruses 04/2008; 24(3):355-62. · 2.25 Impact Factor
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AIDS 06/2007; 21(9):1205-6. · 6.24 Impact Factor
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ABSTRACT: Zygomycosis is a highly aggressive infection observed in immunocompromised patients, such as those with haematological malignancies. The sites most frequently involved are the sinuses and the lungs. New diagnostic tools and new antifungal treatments are essential in order to diagnose early and treat efficiently infections due to moulds. We report a case of sinusitis due to Absidia corymbifera occurring during chemotherapy-induced bone marrow aplasia in a patient with acute leukaemia. The sinusitis was successfully treated with AmBisome, and surgical debridement.
Acta bio-medica: Atenei Parmensis 02/2006; 77 Suppl 2:5-9.
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Panagiotis Fanourgiakis,
Aspasia Georgala, Marc Vekemans,
Agnes Triffet,
Jean-Marc De Bruyn,
Valerie Duchateau,
Philippe Martiat,
Erik De Clercq,
Robert Snoeck,
Elke Wollants,
Annabel Rector,
Marc Van Ranst,
Michael Aoun
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ABSTRACT: Hemorrhagic cystitis that occurs late after bone marrow transplantation (BMT) in BMT recipients is often associated with adenovirus or polyomavirus BK infections. Intravesical instillation of cidofovir in a BMT recipient with intractable hemorrhagic cystitis resulted in clinical improvement. Local cidofovir therapy for viral hemorrhagic cystitis could be an alternative to intravenous administration of cidofovir.
Clinical Infectious Diseases 02/2005; 40(1):199-201. · 9.15 Impact Factor
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