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  1. AU="Angélique B van 't Wout"
  2. AU="Roberts, Nicholas J"
  3. AU="Chauhan, Gaurav B"
  4. AU=Hanjaya-Putra Donny
  5. AU=Powell James
  6. AU="Russell, Todd"
  7. AU=Forth Scott
  8. AU="Kreutzer, Susanne" AU="Kreutzer, Susanne"
  9. AU="St John, Maie"
  10. AU=Gerhardy A
  11. AU="Qi, Huixin"
  12. AU="Dobosiewicz, May"
  13. AU="Srivastava, Rakesh"
  14. AU="Grevtsov K.I."

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  1. Artikel ; Online: Transient opening of trimeric prefusion RSV F proteins

    Morgan S. A. Gilman / Polina Furmanova-Hollenstein / Gabriel Pascual / Angélique B. van ‘t Wout / Johannes P. M. Langedijk / Jason S. McLellan

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Band 13

    Abstract: The respiratory syncytial virus (RSV) F glycoprotein forms a trimeric complex and mediates viral entry. Using structures of RSV F in complex with antibodies, Gilman et al. here show a breathing motion of the prefusion conformation of F, resulting in ... ...

    Abstract The respiratory syncytial virus (RSV) F glycoprotein forms a trimeric complex and mediates viral entry. Using structures of RSV F in complex with antibodies, Gilman et al. here show a breathing motion of the prefusion conformation of F, resulting in transient opening of the trimeric complex in solution and on the cell surface.
    Schlagwörter Science ; Q
    Sprache Englisch
    Erscheinungsdatum 2019-05-01T00:00:00Z
    Verlag Nature Publishing Group
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  2. Artikel ; Online: Transient opening of trimeric prefusion RSV F proteins

    Morgan S. A. Gilman / Polina Furmanova-Hollenstein / Gabriel Pascual / Angélique B. van ‘t Wout / Johannes P. M. Langedijk / Jason S. McLellan

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Band 13

    Abstract: The respiratory syncytial virus (RSV) F glycoprotein forms a trimeric complex and mediates viral entry. Using structures of RSV F in complex with antibodies, Gilman et al. here show a breathing motion of the prefusion conformation of F, resulting in ... ...

    Abstract The respiratory syncytial virus (RSV) F glycoprotein forms a trimeric complex and mediates viral entry. Using structures of RSV F in complex with antibodies, Gilman et al. here show a breathing motion of the prefusion conformation of F, resulting in transient opening of the trimeric complex in solution and on the cell surface.
    Schlagwörter Science ; Q
    Sprache Englisch
    Erscheinungsdatum 2019-05-01T00:00:00Z
    Verlag Nature Portfolio
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  3. Artikel ; Online: DYRK1A Controls HIV-1 Replication at a Transcriptional Level in an NFAT Dependent Manner.

    Thijs Booiman / Vladimir V Loukachov / Karel A van Dort / Angélique B van 't Wout / Neeltje A Kootstra

    PLoS ONE, Vol 10, Iss 12, p e

    2015  Band 0144229

    Abstract: Transcription of the HIV-1 provirus is regulated by both viral and host proteins and is very important in the context of viral latency. In latently infected cells, viral gene expression is inhibited as a result of the sequestration of host transcription ... ...

    Abstract Transcription of the HIV-1 provirus is regulated by both viral and host proteins and is very important in the context of viral latency. In latently infected cells, viral gene expression is inhibited as a result of the sequestration of host transcription factors and epigenetic modifications.In our present study we analyzed the effect of host factor dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) on HIV-1 replication. We show that DYRK1A controls HIV-1 replication by regulating provirus transcription. Downregulation or inhibition of DYRK1A increased LTR-driven transcription and viral replication in cell lines and primary PBMC. Furthermore, inhibition of DYRK1A resulted in reactivation of latent HIV-1 provirus to a similar extent as two commonly used broad-spectrum HDAC inhibitors. We observed that DYRK1A regulates HIV-1 transcription via the Nuclear Factor of Activated T-cells (NFAT) by promoting its translocation from the nucleus to the cytoplasm. Therefore, inhibition of DYRK1A results in increased nuclear levels of NFAT and increased NFAT binding to the viral LTR and thus increasing viral transcription.Our data indicate that host factor DYRK1A plays a role in the regulation of viral transcription and latency. Therefore, DYRK1A might be an attractive candidate for therapeutic strategies targeting the viral reservoir.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2015-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  4. Artikel ; Online: Phosphodiesterase 8a supports HIV-1 replication in macrophages at the level of reverse transcription.

    Thijs Booiman / Viviana Cobos Jiménez / Karel A van Dort / Angélique B van 't Wout / Neeltje A Kootstra

    PLoS ONE, Vol 9, Iss 10, p e

    2014  Band 109673

    Abstract: BACKGROUND:HIV-1 infected macrophages play a key role in HIV-1 infection. Even during anti-retroviral treatment, macrophages keep producing virus due to suboptimal tissue penetration and reduced efficacy of antiretrovirals. It is therefore of major ... ...

    Abstract BACKGROUND:HIV-1 infected macrophages play a key role in HIV-1 infection. Even during anti-retroviral treatment, macrophages keep producing virus due to suboptimal tissue penetration and reduced efficacy of antiretrovirals. It is therefore of major importance to understand which host factors are involved in HIV-1 replication in macrophages. Previously, we have shown that genetic polymorphisms in phosphodiesterase 8a (PDE8A) are strongly associated with HIV-1 replication in these cells. Here we analyzed the mechanism and regulation of PDE8A in HIV-1 replication in macrophages. RESULTS:PDE8A mRNA expression strongly increases upon differentiation of monocytes into macrophages, which corresponds to the increased susceptibility of mature macrophages to HIV-1. In parallel, expression of microRNA miR-145-5p, predicted to target PDE8A mRNA, strongly decreased. The interaction of miR-145-5p with the 3' UTR of PDE8A mRNA could be experimentally validated, suggesting that indeed miR-145-5p can regulate PDE8A expression levels. Knockdown of PDE8A in macrophages resulted in a decrease in total HIV-1 replication and proviral DNA levels. These observations confirm that PDE8A regulates HIV-1 replication in macrophages and that this effect is mediated through early steps in the viral replication cycle. CONCLUSIONS:PDE8A is highly expressed in macrophages, and its expression is regulated by miR-145-5p. Our findings strongly suggest that PDE8A supports HIV-1 replication in macrophages and that this effect is mediated at the level of reverse transcription.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2014-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
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  5. Artikel ; Online: Structural basis for recognition of the central conserved region of RSV G by neutralizing human antibodies.

    Harrison G Jones / Tina Ritschel / Gabriel Pascual / Just P J Brakenhoff / Elissa Keogh / Polina Furmanova-Hollenstein / Ellen Lanckacker / Jehangir S Wadia / Morgan S A Gilman / R Anthony Williamson / Dirk Roymans / Angélique B van 't Wout / Johannes P Langedijk / Jason S McLellan

    PLoS Pathogens, Vol 14, Iss 3, p e

    2018  Band 1006935

    Abstract: Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants and the elderly, and yet there remains no effective treatment or vaccine. The surface of the virion is decorated with the fusion glycoprotein (RSV ... ...

    Abstract Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants and the elderly, and yet there remains no effective treatment or vaccine. The surface of the virion is decorated with the fusion glycoprotein (RSV F) and the attachment glycoprotein (RSV G), which binds to CX3CR1 on human airway epithelial cells to mediate viral attachment and subsequent infection. RSV G is a major target of the humoral immune response, and antibodies that target the central conserved region of G have been shown to neutralize both subtypes of RSV and to protect against severe RSV disease in animal models. However, the molecular underpinnings for antibody recognition of this region have remained unknown. Therefore, we isolated two human antibodies directed against the central conserved region of RSV G and demonstrated that they neutralize RSV infection of human bronchial epithelial cell cultures in the absence of complement. Moreover, the antibodies protected cotton rats from severe RSV disease. Both antibodies bound with high affinity to a secreted form of RSV G as well as to a peptide corresponding to the unglycosylated central conserved region. High-resolution crystal structures of each antibody in complex with the G peptide revealed two distinct conformational epitopes that require proper folding of the cystine noose located in the C-terminal part of the central conserved region. Comparison of these structures with the structure of fractalkine (CX3CL1) alone or in complex with a viral homolog of CX3CR1 (US28) suggests that RSV G would bind to CX3CR1 in a mode that is distinct from that of fractalkine. Collectively, these results build on recent studies demonstrating the importance of RSV G in antibody-mediated protection from severe RSV disease, and the structural information presented here should guide the development of new vaccines and antibody-based therapies for RSV.
    Schlagwörter Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2018-03-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
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  6. Artikel ; Online: The presence of CXCR4-using HIV-1 prior to start of antiretroviral therapy is an independent predictor of delayed viral suppression.

    Esther F Gijsbers / Ard van Sighem / Agnes M Harskamp / Matthijs R A Welkers / Frank de Wolf / Kees Brinkman / Jan M Prins / Hanneke Schuitemaker / Angélique B van 't Wout / Neeltje A Kootstra

    PLoS ONE, Vol 8, Iss 10, p e

    2013  Band 76255

    Abstract: The emergence of CXCR4-using HIV variants (X4-HIV) is associated with accelerated disease progression in the absence of antiretroviral therapy. However, the effect of X4-HIV variants on the treatment response remains unclear. Here we determined whether ... ...

    Abstract The emergence of CXCR4-using HIV variants (X4-HIV) is associated with accelerated disease progression in the absence of antiretroviral therapy. However, the effect of X4-HIV variants on the treatment response remains unclear. Here we determined whether the presence of X4-HIV variants influenced the time to undetectable viral load and CD4+ T cell reconstitution after initiation of cART in 732 patients. The presence of X4-HIV variants was determined by MT-2 assay prior to cART initiation and viral load and CD4+ T cell counts were analyzed every 3 to 6 months during a three year follow-up period. Kaplan-Meier and Cox proportional hazard analyses were performed to compare time to viral suppression and the absolute CD4+ T cell counts and increases in CD4+ T cell counts during follow-up were compared for patients with and without X4-HIV at start of cART. Patients harboring X4-HIV variants at baseline showed a delay in time to achieve viral suppression below the viral load detection limit. This delay in viral suppression was independently associated with high viral load and the presence of X4-HIV variants. Furthermore, the absolute CD4+ T cell counts were significantly lower in patients harboring X4-HIV variants at all time points during follow-up. However, no differences were observed in the increase in absolute CD4+ T cell numbers after treatment initiation, indicating that the reconstitution of CD4+ T cells is independent of the presence of X4-HIV variants. The emergence of X4-HIV has been associated with an accelerated CD4+ T cell decline during the natural course of infection and therefore, patients who develop X4-HIV variants may benefit from earlier treatment initiation in order to obtain faster reconstitution of the CD4+ T cell population to normal levels.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2013-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
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  7. Artikel ; Online: HIV-1 disease progression is associated with bile-salt stimulated lipase (BSSL) gene polymorphism.

    Martijn J Stax / Neeltje A Kootstra / Angélique B van 't Wout / Michael W T Tanck / Margreet Bakker / Georgios Pollakis / William A Paxton

    PLoS ONE, Vol 7, Iss 3, p e

    2012  Band 32534

    Abstract: Background DC-SIGN expressed by dendritic cells captures HIV-1 resulting in trans-infection of CD4(+) T-lymphocytes. However, BSSL (bile-salt stimulated lipase) binding to DC-SIGN interferes with HIV-1 capture. DC-SIGN binding properties of BSSL ... ...

    Abstract Background DC-SIGN expressed by dendritic cells captures HIV-1 resulting in trans-infection of CD4(+) T-lymphocytes. However, BSSL (bile-salt stimulated lipase) binding to DC-SIGN interferes with HIV-1 capture. DC-SIGN binding properties of BSSL associate with the polymorphic repeated motif of BSSL exon 11. Furthermore, BSSL binds to HIV-1 co-receptor CXCR4. We hypothesized that BSSL modulates HIV-1 disease progression and emergence of CXCR4 using HIV-1 (X4) variants. Results The relation between BSSL genotype and HIV-1 disease progression and emergence of X4 variants was studied using Kaplan Meier and multivariate Cox proportional hazard analysis in a cohort of HIV-1 infected men having sex with men (n = 334, with n = 130 seroconverters). We analyzed the association of BSSL genotype with set-point viral load and CD4 cell count, both pre-infection and post-infection at viral set-point. The number of repeats in BSSL exon 11 were highly variable ranging from 10 to 18 in seropositive individuals and from 5-17 in HRSN with 16 repeats being dominant (>80% carry at least one allele with 16 repeats). We defined 16 to 18 repeats as high (H) and less than 16 repeats as low (L) repeat numbers. Homozygosity for the high (H) repeat number BSSL genotype (HH) correlated with high CD4 cell numbers prior to infection (p = 0.007). In HIV-1 patients, delayed disease progression was linked to the HH BSSL genotype (RH = 0.462 CI = 0.282-0.757, p = 0.002) as was delayed emergence of X4 variants (RH = 0.525, 95% CI = 0.290-0.953, p = 0.034). The LH BSSL genotype, previously found to be associated with enhanced DC-SIGN binding of human milk, was identified to correlate with accelerated disease progression in our cohort of HIV-1 infected MSM (RH = 0.517, 95% CI = 0.328-0.818, p = 0.005). Conclusion We identify BSSL as a marker for HIV-1 disease progression and emergence of X4 variants. Additionally, we identified a relation between BSSL genotype and CD4 cell counts prior to infection.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2012-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
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  8. Artikel ; Online: Reconstructing the dynamics of HIV evolution within hosts from serial deep sequence data.

    Art F Y Poon / Luke C Swenson / Evelien M Bunnik / Diana Edo-Matas / Hanneke Schuitemaker / Angélique B van 't Wout / P Richard Harrigan

    PLoS Computational Biology, Vol 8, Iss 11, p e

    2012  Band 1002753

    Abstract: At the early stage of infection, human immunodeficiency virus (HIV)-1 predominantly uses the CCR5 coreceptor for host cell entry. The subsequent emergence of HIV variants that use the CXCR4 coreceptor in roughly half of all infections is associated with ... ...

    Abstract At the early stage of infection, human immunodeficiency virus (HIV)-1 predominantly uses the CCR5 coreceptor for host cell entry. The subsequent emergence of HIV variants that use the CXCR4 coreceptor in roughly half of all infections is associated with an accelerated decline of CD4+ T-cells and rate of progression to AIDS. The presence of a 'fitness valley' separating CCR5- and CXCR4-using genotypes is postulated to be a biological determinant of whether the HIV coreceptor switch occurs. Using phylogenetic methods to reconstruct the evolutionary dynamics of HIV within hosts enables us to discriminate between competing models of this process. We have developed a phylogenetic pipeline for the molecular clock analysis, ancestral reconstruction, and visualization of deep sequence data. These data were generated by next-generation sequencing of HIV RNA extracted from longitudinal serum samples (median 7 time points) from 8 untreated subjects with chronic HIV infections (Amsterdam Cohort Studies on HIV-1 infection and AIDS). We used the known dates of sampling to directly estimate rates of evolution and to map ancestral mutations to a reconstructed timeline in units of days. HIV coreceptor usage was predicted from reconstructed ancestral sequences using the geno2pheno algorithm. We determined that the first mutations contributing to CXCR4 use emerged about 16 (per subject range 4 to 30) months before the earliest predicted CXCR4-using ancestor, which preceded the first positive cell-based assay of CXCR4 usage by 10 (range 5 to 25) months. CXCR4 usage arose in multiple lineages within 5 of 8 subjects, and ancestral lineages following alternate mutational pathways before going extinct were common. We observed highly patient-specific distributions and time-scales of mutation accumulation, implying that the role of a fitness valley is contingent on the genotype of the transmitted variant.
    Schlagwörter Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 310
    Sprache Englisch
    Erscheinungsdatum 2012-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
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  9. Artikel ; Online: Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity

    Xue-Song Zhang / Jackie Li / Kimberly A Krautkramer / Michelle Badri / Thomas Battaglia / Timothy C Borbet / Hyunwook Koh / Sandy Ng / Rachel A Sibley / Yuanyuan Li / Wimal Pathmasiri / Shawn Jindal / Robin R Shields-Cutler / Ben Hillmann / Gabriel A Al-Ghalith / Victoria E Ruiz / Alexandra Livanos / Angélique B van ‘t Wout / Nabeetha Nagalingam /
    Arlin B Rogers / Susan Jenkins Sumner / Dan Knights / John M Denu / Huilin Li / Kelly V Ruggles / Richard Bonneau / R Anthony Williamson / Marcus Rauch / Martin J Blaser

    eLife, Vol

    2018  Band 7

    Abstract: The early-life intestinal microbiota plays a key role in shaping host immune system development. We found that a single early-life antibiotic course (1PAT) accelerated type 1 diabetes (T1D) development in male NOD mice. The single course had deep and ... ...

    Abstract The early-life intestinal microbiota plays a key role in shaping host immune system development. We found that a single early-life antibiotic course (1PAT) accelerated type 1 diabetes (T1D) development in male NOD mice. The single course had deep and persistent effects on the intestinal microbiome, leading to altered cecal, hepatic, and serum metabolites. The exposure elicited sex-specific effects on chromatin states in the ileum and liver and perturbed ileal gene expression, altering normal maturational patterns. The global signature changes included specific genes controlling both innate and adaptive immunity. Microbiome analysis revealed four taxa each that potentially protect against or accelerate T1D onset, that were linked in a network model to specific differences in ileal gene expression. This simplified animal model reveals multiple potential pathways to understand pathogenesis by which early-life gut microbiome perturbations alter a global suite of intestinal responses, contributing to the accelerated and enhanced T1D development.
    Schlagwörter microbiome ; autoimmune ; NOD mice ; animal models ; immune maturation ; gene expression ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Sprache Englisch
    Erscheinungsdatum 2018-07-01T00:00:00Z
    Verlag eLife Sciences Publications Ltd
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  10. Artikel ; Online: Detection of inferred CCR5- and CXCR4-using HIV-1 variants and evolutionary intermediates using ultra-deep pyrosequencing.

    Evelien M Bunnik / Luke C Swenson / Diana Edo-Matas / Wei Huang / Winnie Dong / Arne Frantzell / Christos J Petropoulos / Eoin Coakley / Hanneke Schuitemaker / P Richard Harrigan / Angélique B van 't Wout

    PLoS Pathogens, Vol 7, Iss 6, p e

    2011  Band 1002106

    Abstract: The emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants is associated with accelerated disease progression. CXCR4-using variants are believed to evolve from CCR5-using variants, but due to the extremely low frequency at which ... ...

    Abstract The emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants is associated with accelerated disease progression. CXCR4-using variants are believed to evolve from CCR5-using variants, but due to the extremely low frequency at which transitional intermediate variants are often present, the kinetics and mutational pathways involved in this process have been difficult to study and are therefore poorly understood. Here, we used ultra-deep sequencing of the V3 loop of the viral envelope in combination with the V3-based coreceptor prediction tools PSSM(NSI/SI) and geno2pheno([coreceptor]) to detect HIV-1 variants during the transition from CCR5- to CXCR4-usage. We analyzed PBMC and serum samples obtained from eight HIV-1-infected individuals at three-month intervals up to one year prior to the first phenotypic detection of CXCR4-using variants in the MT-2 assay. Between 3,482 and 10,521 reads were generated from each sample. In all individuals, V3 sequences of predicted CXCR4-using HIV-1 were detected at least three months prior to phenotypic detection of CXCR4-using variants in the MT-2 assay. Subsequent analysis of the genetic relationships of these V3 sequences using minimum spanning trees revealed that the transition in coreceptor usage followed a stepwise mutational pathway involving sequential intermediate variants, which were generally present at relatively low frequencies compared to the major predicted CCR5- and CXCR4-using variants. In addition, we observed differences between individuals with respect to the number of predicted CXCR4-using variants, the diversity among major predicted CCR5-using variants, and the presence or absence of intermediate variants with discordant phenotype predictions. These results provide the first detailed description of the mutational pathways in V3 during the transition from CCR5- to CXCR4-usage in natural HIV-1 infection.
    Schlagwörter Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2011-06-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
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