المؤلفون: Thessa Laeremans, Sabine den Roover, Cynthia Lungu, Sigrid D’haese, Rob A. Gruters, Sabine D. Allard, Joeri L. Aerts

المصدر: npj Vaccines, Vol 8, Iss 1, Pp 1-13 (2023)

مصطلحات موضوعية: Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Although natural killer (NK) cells have been studied in connection with dendritic cell (DC)-based vaccination in the field of cancer immunology, their role has barely been addressed in the context of therapeutic vaccination against HIV-1. In this study, we evaluated whether a therapeutic DC-based vaccine consisting of monocyte-derived DCs electroporated with Tat, Rev and Nef encoding mRNA affects NK cell frequency, phenotype and functionality in HIV-1-infected individuals. Although the frequency of total NK cells did not change, we observed a significant increase in cytotoxic NK cells following immunisation. In addition, significant changes in the NK cell phenotype associated with migration and exhaustion were observed together with increased NK cell-mediated killing and (poly)functionality. Our results show that DC-based vaccination has profound effects on NK cells, which highlights the importance of evaluating NK cells in future clinical trials looking at DC-based immunotherapy in the context of HIV-1 infection.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2059-0105Test

الوصول الحر: https://doaj.org/article/8d718e76751947ccbcc26ed725f9a812Test

المؤلفون: Jeroen J.A. van Kampen, Hanh Thi Pham, Sunbin Yoo, Ronald J. Overmars, Cynthia Lungu, Rizwan Mahmud, Carolina A.M. Schurink, Sander van Boheemen, Rob A. Gruters, Pieter L.A. Fraaij, David M. Burger, Jolanda J.C. Voermans, Casper Rokx, David A.M.C. van de Vijver, Thibault Mesplède

المصدر: Journal of Global Antimicrobial Resistance, Vol 31, Iss , Pp 323-327 (2022)

مصطلحات موضوعية: Dolutegravir, HIV, Drug resistance, Treatment adherence, Next-generation sequencing, Mutations, Microbiology, QR1-502

الوصف: ABSTRACT: Objectives: We report a case of incomplete HIV-1 suppression on a dolutegravir, lamivudine, and abacavir single-tablet regimen with the emergence of the H51Y and G118R integrase resistance mutations. Methods: Integrase sequencing was performed retrospectively by Sanger and next-generation sequencing. Rates of emergence and decline of resistance mutations were calculated using next-generation sequencing data. Dolutegravir plasma concentrations were measured by ultra-performance liquid chromatography-tandem mass spectrometry. The effects of H51Y and G118R on infectivity, fitness, and susceptibility to dolutegravir were quantified using cell-based assays. Results: During periods of non-adherence to treatment, mutations were retrospectively documented only by next-generation sequencing. Misdiagnosis by Sanger sequencing was caused by the rapid decline of mutant strains within the retroviral population. This observation was also true for a M184V lamivudine-resistant reverse transcriptase mutation found in association with integrase mutations on single HIV genomes. Resistance rebound upon treatment re-initiation was swift (>8000 copies per day). Next-generation sequencing indicated cumulative adherence to treatment. Compared to WT HIV-1, relative infectivity was 73%, 38%, and 43%; relative fitness was 100%, 35%, and 10% for H51Y, G118R, and H51Y+G118R viruses, respectively. H51Y did not change the susceptibility to dolutegravir, but G188R and H51Y+G118R conferred 7- and 28-fold resistance, respectively. Conclusion: This case illustrates how poorly-fit drug-resistant viruses wax and wane alongside erratic treatment adherence and are easily misdiagnosed by Sanger sequencing. We recommend next-generation sequencing to improve the clinical management of incomplete virological suppression with dolutegravir.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2213716522002478Test; https://doaj.org/toc/2213-7165Test

الوصول الحر: https://doaj.org/article/0a938eb9f0cb4d779bb3ebd4b1d4ed7eTest

المؤلفون: Cynthia Lungu, Ronald J. Overmars, Esmée Grundeken, Patrick H. M. Boers, Marchina E. van der Ende, Thibault Mesplède, Rob A. Gruters

المصدر: Viruses, Vol 15, Iss 11, p 2236 (2023)

مصطلحات موضوعية: HIV-2, long-term non-progressors, transactivation, Tat, Microbiology, QR1-502

الوصف: Although some individuals with HIV-2 develop severe immunodeficiency and AIDS-related complications, most may never progress to AIDS. Replication-competent HIV-2 isolated from asymptomatic long-term non-progressors (controllers) have lower replication rates than viruses from individuals who progress to AIDS (progressors). To investigate potential retroviral factors that correlate with disease progression in HIV-2, we sequenced the near full-length genomes of replication-competent viruses previously outgrown from controllers and progressors and used phylogeny to seek genotypic correlates of disease progression. We validated the integrity of all open reading frames and used cell-based assays to study the retroviral transcriptional activity of the long terminal repeats (LTRs) and Tat proteins of HIV-2 from controllers and progressors. Overall, we did not identify genotypic defects that may contribute to HIV-2 non-progression. Tat-induced, LTR-mediated transcription was comparable between viruses from controllers and progressors. Our results were obtained from a small number of participants and should be interpreted accordingly. Overall, they suggest that progression may be determined before or during integration of HIV-2.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1999-4915/15/11/2236Test; https://doaj.org/toc/1999-4915Test

الوصول الحر: https://doaj.org/article/77e38f7aaf384a6b80059352043cad5bTest

المؤلفون: Shringar Rao, Cynthia Lungu, Raquel Crespo, Thijs H. Steijaert, Alicja Gorska, Robert-Jan Palstra, Henrieke A. B. Prins, Wilfred van Ijcken, Yvonne M. Mueller, Jeroen J. A. van Kampen, Annelies Verbon, Peter D. Katsikis, Charles A. B. Boucher, Casper Rokx, Rob A. Gruters, Tokameh Mahmoudi

المصدر: Nature Communications, Vol 12, Iss 1, Pp 1-20 (2021)

مصطلحات موضوعية: Science

الوصف: DEAD-box polypeptide 3 (DDX3) is a host protein belonging to the family of ATP-dependent RNA helicases. Here, the authors demonstrate that DDX3 inhibitors reverse HIV-1 latency and selectively induce cell death in HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/983a234271bf4954b9536cec417f77dfTest

المؤلفون: Cynthia Lungu, Riddhima Banga, Rob A. Gruters, Francesco A. Procopio

المصدر: Frontiers in Microbiology, Vol 12 (2021)

مصطلحات موضوعية: HIV-1 latency, HIV-1 cure, reservoir quantification, inducible reservoir, TILDA, Microbiology, QR1-502

الوصف: The presence of a stable HIV-1 reservoir persisting over time despite effective antiretroviral suppression therapy precludes a cure for HIV-1. Characterizing and quantifying this residual reservoir is considered an essential prerequisite to develop and validate curative strategies. However, a sensitive, reproducible, cost-effective, and easily executable test is still needed. The quantitative viral outgrowth assay is considered the gold standard approach to quantify the reservoir in HIV-1-infected patients on suppressive ART, but it has several limitations. An alternative method to quantify the viral reservoir following the reactivation of latent HIV-1 provirus detects multiply-spliced tat/rev RNA (msRNA) molecules by real-time PCR [tat/rev induced limiting dilution assay (TILDA)]. This article provides a perspective overview of the clinical relevance, various applications, recent advancements of TILDA, and how the assay has contributed to our understanding of the HIV-1 reservoir.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fmicb.2021.686690/fullTest; https://doaj.org/toc/1664-302XTest

الوصول الحر: https://doaj.org/article/42383371a44d4c09ab5af6a05357b34fTest

المؤلفون: Csaba Fehér, Roque Pastor-lbáñez, Lorna Leal, Montserrat Plana, Mireia Arnedo, Henk-Jan van den Ham, Arno C. Andeweg, Rob A. Gruters, Francisco Díez-Fuertes, José Alcamí, Patrick Aloy, Felipe García

المصدر: Vaccines, Vol 9, Iss 7, p 799 (2021)

مصطلحات موضوعية: dendritic cell-based therapeutic HIV-1 vaccine, differential gene expression, mRNA, miRNA, gene set enrichment analysis, Medicine

الوصف: Systems vaccinology has seldomly been used in therapeutic HIV-1 vaccine research. Our aim was to identify early gene ‘signatures’ that predicted virus load control after analytical therapy interruption (ATI) in participants of a dendritic cell-based HIV-1 vaccine trial (DCV2). mRNA and miRNA were extracted from frozen post-vaccination PBMC samples; gene expression was determined by microarray method. In gene set enrichment analysis, responders showed an up-regulation of 14 gene sets (TNF-alpha/NFkB pathway, inflammatory response, the complement system, Il6 and Il2 JAK-STAT signaling, among others) and a down-regulation of 7 gene sets (such as E2F targets or interferon alpha response). The expression of genes regulated by three (miR-223-3p, miR-1183 and miR-8063) of the 9 differentially expressed miRNAs was significantly down-regulated in responders. The deregulation of certain gene sets related to inflammatory processes seems fundamental for viral control, and certain miRNAs may be important in fine-tuning these processes.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2076-393X/9/7/799Test; https://doaj.org/toc/2076-393XTest

الوصول الحر: https://doaj.org/article/b66f9bb6df33467aa8678305d18bebfbTest

المؤلفون: Cynthia Lungu, Francesco A. Procopio, Ronald J. Overmars, Rob J. J. Beerkens, Jolanda J. C. Voermans, Shringar Rao, Henrieke A. B. Prins, Casper Rokx, Giuseppe Pantaleo, David A. M. C. van de Vijver, Tokameh Mahmoudi, Charles A. B. Boucher, Rob A. Gruters, Jeroen J. A. van Kampen

المصدر: Viruses, Vol 12, Iss 9, p 973 (2020)

مصطلحات موضوعية: HIV-1 latency, reservoir quantification, inducible reservoirs, TILDA, assay performance, Microbiology, QR1-502

الوصف: Substantial efforts to eliminate or reduce latent HIV-1 reservoirs are underway in clinical trials and have created a critical demand for sensitive, accurate, and reproducible tools to evaluate the efficacy of these strategies. Alternative reservoir quantification assays have been developed to circumvent limitations of the quantitative viral outgrowth assay. One such assay is tat/rev induced limiting dilution assay (TILDA), which measures the frequency of CD4+ T cells harboring inducible latent HIV-1 provirus. We modified pre-amplification reagents and conditions (TILDA v2.0) to improve assay execution and first internally validated assay performance using CD4+ T cells obtained from cART-suppressed HIV-1-infected individuals. Detection of tat/rev multiply spliced RNA was not altered by modifying pre-amplification conditions, confirming the robustness of the assay, and supporting the technique’s amenability to limited modifications to ensure better implementation for routine use in clinical studies of latent HIV-1 reservoirs. Furthermore, we cross-validated results of TILDA v2.0 and the original assay performed in two separate laboratories using samples from 15 HIV-1-infected individuals. TILDA and TILDA v2.0 showed a strong correlation (Lin’s Concordance Correlation Coefficient = 0.86). The low inter-laboratory variability between TILDAs performed at different institutes further supports use of TILDA for reservoir quantitation in multi-center interventional HIV-1 Cure trials.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1999-4915/12/9/973Test; https://doaj.org/toc/1999-4915Test

الوصول الحر: https://doaj.org/article/c343245b74494b32b05a015c30171e4eTest

المؤلفون: Lennert W.J. van den Dries, Rob A. Gruters, Sascha B.C. Hövels – van der Borden, Marieke J.H.A. Kruip, Moniek ede Maat, Eric C.M. van Gorp, Marchina E. van der Ende

المصدر: Frontiers in Microbiology, Vol 6 (2015)

مصطلحات موضوعية: HIV, Thrombosis, LPS, coagulation, immune activation, von Wilebrand factor, Microbiology, QR1-502

الوصف: BackgroundArterial and venous thrombotic events are more prevalent in HIV infected individuals compared to the general population, even in the era of combination antiretroviral therapy. Although the mechanism is not fully understood, recent evidence suggests a role for chronic immune activation.MethodsWe reviewed the Dutch National HIV registry database for HIV infected patients in Rotterdam with a history of arterial or venous thrombosis and calculated the incidence. We collected samples from patients with and without thrombosis to compare plasma levels of lipopolysaccharide (LPS), LPS binding protein (LBP), soluble CD14 (sCD14), and von Willebrand Factor antigen level (vWF). ResultsDuring a 10-year period, a total of 60 documented events in 14,026 person years of observation (PYO) occurred, resulting in an incidence rate of 2.50, 2.21 and 4.28 for arterial, venous and combined thrombotic events per 1000 PYO, respectively. The vWF was elevated in the majority of study subjects (mean 2,36 SD±0.88 IU/ml); we found a significant difference when comparing venous cases to controls (mean 2.68 SD±0.82 IU/ml vs 2.20 SD±0.77 IU/ml; p=0.024). This difference remained significant for recurrent events (mean 2.78 SD±0.75p=0,043).). sCD14 was positively correlated with LPS (r=0.255; p=0.01).ConclusionThe incidence of venous thrombosis was twofold higher in HIV infected patients compared to age-adjusted data from general population cohort studies. We couldn't find a clear association between immune activation markers to either arterial or venous thrombotic events. We observed a marked increase in vWF levels and observed a correlation of vWF to first and recurrent venous thrombo-embolic events.These findings suggest that HIV infection is an independent risk factor for coagulation abnormalities and could contribute to the observed high incidence in venous thrombosis. This could be a reason to prolong anti-thrombotic treatment in HIV patients with a history of thrombosis.

وصف الملف: electronic resource

العلاقة: http://journal.frontiersin.org/Journal/10.3389/fmicb.2015.00180/fullTest; https://doaj.org/toc/1664-302XTest

الوصول الحر: https://doaj.org/article/fca6f61fb949430b8834099c42bb9dd1Test

المؤلفون: Jeroen J. A. van Kampen, Mariska L. Reedijk, Peter C. Burgers, Lennard J. M. Dekker, Nico G. Hartwig, Ineke E. van der Ende, Ronald de Groot, Albert D. M. E. Osterhaus, David M. Burger, Theo M. Luider, Rob A. Gruters

المصدر: PLoS ONE, Vol 5, Iss 7 (2010)

مصطلحات موضوعية: Medicine, Science

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC2910089Test; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/b9c8d0f659a84a83aa1f70d4e0a400bcTest

المؤلفون: Henrieke A. B. Prins, Raquel Crespo, Cynthia Lungu, Shringar Rao, Letao Li, Ronald J. Overmars, Grigorius Papageorgiou, Yvonne M. Mueller, Mateusz Stoszko, Tanvir Hossain, Tsung Wai Kan, Bart J. A. Rijnders, Hannelore I. Bax, Eric C. M. van Gorp, Jan L. Nouwen, Theodora E. M. S. de Vries-Sluijs, Carolina A. M. Schurink, Mariana de Mendonça Melo, Els van Nood, Angela Colbers, David Burger, Robert-Jan Palstra, Jeroen J. A. van Kampen, David A. M. C. van de Vijver, Thibault Mesplède, Peter D. Katsikis, Rob A. Gruters, Birgit C. P. Koch, Annelies Verbon, Tokameh Mahmoudi, Casper Rokx

المساهمون: Internal Medicine, Medical Microbiology & Infectious Diseases, Biochemistry, Pharmacy, Virology, Immunology, Pathology, Urology

المصدر: Science Advances, 9
Science Advances, 9, 11
Science advances, 9(11):eade6675. American Association for the Advancement of Science

مصطلحات موضوعية: All institutes and research themes of the Radboud University Medical Center, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Multidisciplinary, SDG 3 - Good Health and Well-being

الوصف: Contains fulltext : 291084.pdf (Publisher’s version ) (Open Access) Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4c3887f3da1a82107e3f551dccee2edbTest
https://doi.org/10.1126/sciadv.ade6675Test