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Determinants of virus-specific CD8+ T-cell failure in chronic HBV infection
No full textThe hallmark of successful viral elimination in hepatitis B virus (HBV) infection is a strong and sustained cytotoxic CD8+ T-cell response. Two major mechanisms may result in CD8+ T-cell failure and thus viral persistence: CD8+ T-cell exhaustion and mutational viral escape. CD8+ T-cell exhaustion is considered to be mainly induced by continuous antigen stimulation. In this thesis, phenotypic and functional properties of exhausted HBV-specific CD8+ T cells targeting different antigens, particularly focusing on the HLA-A*02-restricted epitopes HBV core18-27 and HBV pol455-463 and the HLA-A*11-restricted epitope HBV core141-151 and the HLA-B*35-restricted epitope HBV pol173-181. By ex vivo pMHC I tetramer-associated enrichment, HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase protein were detected in the majority of patients with chronic HBV infection allowing the in-depth analyses of their molecular profiles. It was shown that exhausted HBV-specific CD8+ T cells do not represent a homogeneous population, but differ in frequency, phenotype, and functionality depending on the target antigen. In particular, HBV pol173-181/455-463-specific CD8+ T cells showed a more exhausted phenotype compared to HBV core18-27/141-151-specific CD8+ T cells by exhibiting higher expression of KLRG1 and Eomes, accompanied by lower expression of Tbet. HBV pol173-181/455-463-specific CD8+ T cells expressed more CD38 than core18-27/141-151-specific CD8+ T cells, thus were more activated. Based on the co-expression of CD127/PD1, differences in CD127/PD1-based subset distribution between core18-27/141-151-specific and pol173-181/455-463-specific CD8+ T cells were observed in chronically HBV-infected patients. Thus, pol173-181/455-463-specific CD8+ T cells displayed a lower proportion of the less differentiated memory-like CD127+PD1+subset compared to core18-27/141-151-specific CD8+ T cells. Further, HBV core18-27/141-151-specific CD8+ T cells displayed a better expansion capacity compared to HBV pol173-181/455-463-specific CD8+ T cells that was mainly due to their better survival capacity, which was reflected in the higher expression of BCL2 compared to HBV pol173-181/455-463-specific CD8+ T cells.In contrast to CD8+ T-cell exhaustion, the role of viral escape in HBV infection is less well defined. For a long time, studies of viral escape in HBV focused mainly on HLA-A*02-restricted epitopes. However, in HIV and HCV infection, HLA-B alleles, particularly HLA-B*27, play a critical role in viral clearance and disease outcome. Therefore, in this thesis HLA-B*27 was used as a model to elucidate the role of viral escape in CD8+T-cell failure in chronic HBV infection. Seven HLA-B27+-restricted epitopes were identified based on HLA-B*27-associated sequence polymorphisms (HLA-B*27 footprints). Indeed, these HLA-B*27 footprints were functionally confirmed as viral escape mutations in patients chronically infected with HBV. Five additional HLA-B*27-limited epitopes were identified by unbiased in silico prediction of strong HLA B*27 binders without evidence of viral escape. Importantly, epitopes with evidence for viral escape and without evidence for viral escape were targeted at similar frequencies by epitope-specific CD8+ T cells in chronic HBV infection. Of note, CD8+ T cells targeting escaped epitopes in chronic HBV infection expressed a less exhausted phenotype compared to CD8+ T cells targeting conserved epitopes. In sum, this thesis demonstrates that exhausted HBV-specific CD8+ T cells exhibit different functional and phenotypic characteristics depending on the target antigen. Furthermore, it was shown that viral escape plays an important role in HBV infection, is associated with HLA class I-restriction, and may specifically affect CD8+ T-cell epitopes that are targeted only during persistent infection. The results of this work suggest that tailored of future immunotherapeutic approaches to the different HBV-specific CD8+ T-cell populations is needed and that viral escape as well as T-cell exhaustion must be considered to achieve the goal of HBV cure.Das wesentliche Merkmal einer erfolgreichen Viruseliminierung bei Infektionen mit dem Hepatitis-B-Virus (HBV) ist eine starke und anhaltende zytotoxische CD8+ T-Zell-Reaktion. Dabei kann das Versagen der CD8+T-Zellantwort auf zwei Hauptmechanismen begründet sein und damit zur viralen Persistenz führen: CD8+ T-Zellerschöpfung und viraler Escape. Die Erschöpfung der CD8+ T-Zellen wird wesentlich durch kontinuierliche Antigenstimulation verursacht. In dieser Arbeit wurden die phänotypischen und funktionellen Eigenschaften von erschöpften HBV-spezifischen CD8+ T-Zellen untersucht, die verschiedene Antigene erkennen, insbesondere die HLA-A*02-restringierten Epitope HBV core18-27 und HBV pol455-463 sowie das HLA-A*11-restringierte Epitop HBV core141-151 und das HLA-B*35-restringierte Epitop HBV pol173-181. Mit Hilfe der ex vivo Tetramer-assoziierten magnetischen Anreicherung, konnten HBV-spezifische CD8+ T-Zellen, die Epitope im HBV-Kernprotein und im Polymeraseprotein erkennen, bei der Mehrzahl der Patienten mit chronischer HBV-Infektion nachgewiesen werden, wodurch eine nachfolgende Analyse ihrer molekularen Profile ermöglicht wurde. Es konnte gezeigt werden, dass erschöpfte HBV-spezifischen CD8+ T-Zellen keine homogene Population darstellen, sondern, je nach Zielantigen, sich in Frequenz, Phänotyp und Funktionalität unterscheiden. Im Einzelnen zeigten HBV pol173-181/455-463-spezifische CD8+ T-Zellen im Vergleich zu HBV core18-27/141-151 -spezifischen CD8+ T-Zellen einen erschöpfteren Phänotyp, indem sie eine höhere Expression von KLRG1 und Eomes, einhergehend mit einer niedrigeren Expression von Tbet aufwiesen. HBV pol173-181/455-463-spezifische CD8+ T-Zellen exprimierten mehr CD38 als core18-27/141-151-spezifische CD8+ T-Zellen und zeigten damit eine verstärkte Aktivierung. Auf der Grundlage der Koexpression von CD127/PD1, konnten bei chronisch HBV-infizierten Patienten Unterschiede in der CD127/PD1-basierten Subgruppenverteilung zwischen core18-27/141-151-spezifischen und pol173-181/455-463-spezifischen CD8+ T-Zellen beobachtet werden. So wiesen pol173-181/455-463-spezifische CD8+ T-Zellen im Vergleich zu core18-27/141-151-spezifischen CD8+ T-Zellen einen geringeren Anteil an der weniger differenzierten gedächtnisähnlichen CD127+PD1+-Untergruppe auf. Darüber hinaus zeigten HBV core18-27/141-151-spezifische CD8+ T-Zellen eine bessere Expansionskapazität im Vergleich zu HBV pol173-181/455-463-spezifischen CD8+ T-Zellen, was hauptsächlich auf ihre bessere Überlebensfähigkeit zurückzuführen ist, die sich in der höheren Expression von BCL2 im Vergleich zu HBV pol173-181/455-463-spezifischen CD8+ T-Zellen widerspiegelte.Im Gegensatz zur CD8+ T-Zellerschöpfung ist die Rolle des viralen Escape bei der HBV-Infektion weniger gut definiert. Lange Zeit konzentrierten sich die Studien zum viralen Escape bei HBV hauptsächlich auf HL-A*02-restringierte Epitope. In der HIV- und HCV-Infektion spielen jedoch HLA-B-Allele, insbesondere HLA-B*27, eine entscheidende Rolle für die Viruseliminierung und den Krankheitsverlauf. Daher wurde in dieser Arbeit HLA-B*27 als Modell verwendet, um die Rolle des viralen Escapes beim Versagen der CD8+ T-Zellantwort in der chronischen HBV-Infektion zu beleuchten. Auf der Grundlage von HLA-B*27-assoziierten Sequenzpolymorphismen (sog. HLA-B*27 Footprint) wurden sieben HLA-B27+-restringierte Epitope identifiziert. Diese HLA-B*27-Footprints wurden in Patienten mit chronischer HBV Infektion funktionell als virale Escapemutationen bestätigt. Fünf weitere HLA-B*27-restringierte Epitope wurden durch unvoreingenommene in-silico-Vorhersage von starken HLA-B*27-Bindern ohne Hinweise auf virale Escapemutationen identifiziert. Hervorzuheben ist, dass sowohl Epitope mit Anzeichen für viralen Escapen als auch solche ohne Anzeichen für viralen Escape von HBV Epitop-spezifischen CD8+ T-Zellen in der chronischen HBV-Infektion in ähnlicher Häufigkeit erkannt wurden. CD8+ T-Zellen, die in einer chronischen HBV-Infektion auf Epitope mit Escapemutationen abzielen, wiesen im Vergleich zu CD8+ T-Zellen, die auf konservierte Epitope abzielen einen weniger erschöpften Phänotyp auf. Zusammenfassend zeigte diese Arbeit, dass erschöpfte HBV-spezifische CD8+ T-Zellen je nach Zielantigen unterschiedliche funktionelle und phänotypische Merkmale aufweisen. Des Weiteren wurde gezeigt, dass viraler Escape eine wichtige Rolle bei der HBV-Infektion spielt und spezifisch CD8+ T-Zellepitope betreffen kann, die nur während der persistierenden Infektion angegriffen werden. Die Ergebnisse dieser Arbeit deuten darauf hin, dass eine sehr genaue Anpassung künftiger immuntherapeutischer Ansätze auf die verschiedenen HBV-spezifischen CD8+ T-Zellpopulationen erforderlich ist und dass sowohl viraler Escape als auch T-Zellerschöpfung berücksichtigt werden müssen um das Ziel einer HBV-Heilung zu erreichen
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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