Lack of variant specific CD8+T-cell response against mutant and pre-existing variants leads to outgrowth of particular clones in acute hepatitis C

Background: CTL escape mutations have been described during acute hepatitis C in patients who developed chronic disease later on. Our aim was to investigate the mutual relationship between HCV specific CD8+ T cells and evolution of the viral sequence during early acute HCV infection. Results: We sequenced multiple clones of NS3 1406 epitope in 4 HLA-A{*}02 patients with acute hepatitis C genotype 1b infection. Pentamers specific for the variants were used to monitor the corresponding CD8+ T cell response. We observed outgrowth of mutations, which induced only a weak and thus potentially insufficient CD8+ T cell response. In one patient we observed outgrowth of variant epitopes with similarities to a different genotype rather than de novo mutations most probably due to a lack of responsiveness to these likely pre-existing variants. We could show that in acute hepatitis C CTL escape mutations occur much earlier than demonstrated in previous studies. Conclusions: The adaption of the virus to a new host is characterized by a high and rapid variability in epitopes under CD8+ T cell immune pressure. This adaption takes place during the very early phase of acute infection and strikingly some sequences were reduced below the limit of detection at some time points but were detected at high frequency again at later time points. Independent of the observed variability, HCV-specific CD8+ T cell responses decline and no adaption to different or new antigens during the course of infection could be detected

Association of Hepatitis C Virus—Specific CD8+ T Cells with Viral Clearance in Acute Hepatitis C

CD8+ T lymphocytes play a major role in antiviral immune defense. Their significance for acute hepatitis C is unclear. Our aim was to correlate the CD8+ T cell response with the outcome of infection. Eighteen patients with acute hepatitis C and 19 normal donors were studied. Hepatitis C virus (HCV)—specific CD8+ T cells were identified in the enzyme-linked immunospot assay by their interferon-γ (IFN-γ) production after specific stimulation. The highest numbers of IFN-γ—producing HCV-specific CD8+ T cells were found in patients with acute hepatitis C and a self-limited course of disease during the first 6 months after onset of disease, but these numbers dropped thereafter to undetectable levels. The differences in responsiveness between patients with self-limited disease versus patients with a chronic course were statistically significant (P < .001). Our data show that the number of IFN—γ-producing HCV-specific CD8+ T cells during the first 6 months after onset of disease is associated with eradication of the HCV infectio

Association of Hepatitis C Virus—Specific CD8+ T Cells with Viral Clearance in Acute Hepatitis C

CD8+ T lymphocytes play a major role in antiviral immune defense. Their significance for acute hepatitis C is unclear. Our aim was to correlate the CD8+ T cell response with the outcome of infection. Eighteen patients with acute hepatitis C and 19 normal donors were studied. Hepatitis C virus (HCV)—specific CD8+ T cells were identified in the enzyme-linked immunospot assay by their interferon-γ (IFN-γ) production after specific stimulation. The highest numbers of IFN-γ—producing HCV-specific CD8+ T cells were found in patients with acute hepatitis C and a self-limited course of disease during the first 6 months after onset of disease, but these numbers dropped thereafter to undetectable levels. The differences in responsiveness between patients with self-limited disease versus patients with a chronic course were statistically significant (P < .001). Our data show that the number of IFN—γ-producing HCV-specific CD8+ T cells during the first 6 months after onset of disease is associated with eradication of the HCV infection

Inhibitory Phenotype of HBV-Specific CD4⁺ T-Cells Is Characterized by High PD-1 Expression but Absent Coregulation of Multiple Inhibitory Molecules

Background: T-cell exhaustion seems to play a critical role in CD8(+) T-cell dysfunction during chronic viral infections. However, up to now little is known about the mechanisms underlying CD4(+) T-cell dysfunction during chronic hepatitis B virus (CHB) infection and the role of inhibitory molecules such as programmed death 1 (PD-1) for CD4(+) T-cell failure. Methods: The expression of multiple inhibitory molecules such as PD-1, CTLA-4, TIM-3, CD244, KLRG1 and markers defining the grade of T-cell differentiation as CCR7, CD45RA, CD57 and CD127 were analyzed on virus-specific CD4(+) T-cells from peripheral blood using a newly established DRB1*01-restricted MHC class II Tetramer. Effects of in vitro PD-L1/2 blockade were defined by investigating changes in CD4(+) T-cell proliferation and cytokine production. Results: CD4(+) T-cell responses during chronic HBV infection was characterized by reduced Tetramer(+)CD4(+) T-cell frequencies, effector memory phenotype, sustained PD-1 but low levels of CTLA-4, TIM-3, KLRG1 and CD244 expression. PD-1 blockade revealed individualized patterns of in vitro responsiveness with partly increased IFN-gamma, IL-2 and TNF-alpha secretion as well as enhanced CD4(+) T-cell expansion almost in treated patients with viral control. Conclusion: HBV-specific CD4(+) T-cells are reliably detectable during different courses of HBV infection by MHC class II Tetramer technology. CD4(+) T-cell dysfunction during chronic HBV is basically linked to strong PD-1 upregulation but absent coregulation of multiple inhibitory receptors. PD-L1/2 neutralization partly leads to enhanced CD4(+) T-cell functionality with heterogeneous patterns of CD4(+) T-cell rejunivation

Conserving approximations in direct perturbation theory: new semianalytical impurity solvers and their application to general lattice problems

For the treatment of interacting electrons in crystal lattices approximations based on the picture of effective sites, coupled in a self-consistent fashion, have proven very useful. Particularly in the presence of strong local correlations, a local approach to the problem, combining a powerful method for the short ranged interactions with the lattice propagation part of the dynamics, determines the quality of results to a large extent. For a considerable time the non crossing approximation (NCA) in direct perturbation theory, an approach originally developed by Keiter for the Anderson impurity model, built a standard for the description of the local dynamics of interacting electrons. In the last couple of years exact methods like the numerical renormalization group (NRG) as pioneered by Wilson, have surpassed this approximation as regarding the description of the low energy regime. We present an improved approximation level of direct perturbation theory for finite Coulomb repulsion U, the crossing approximation one (CA1) and discuss its connections with other generalizations of NCA. CA1 incorporates all processes up to fourth order in the hybridization strength V in a self-consistent skeleton expansion, retaining the full energy dependence of the vertex functions. We reconstruct the local approach to the lattice problem from the point of view of cumulant perturbation theory in a very general way and discuss the proper use of impurity solvers for this purpose. Their reliability can be tested in applications to e.g. the Hubbard model and the Anderson-lattice model. We point out shortcomings of existing impurity solvers and improvements gained with CA1 in this context. This paper is dedicated to the memory of Hellmut Keiter.Comment: 45 pages, 22 figure

Tracking Virus-Specific CD4+ T Cells during and after Acute Hepatitis C Virus Infection

CD4+ T cell help is critical in maintaining antiviral immune responses and such help has been shown to be sustained in acute resolving hepatitis C. In contrast, in evolving chronic hepatitis C CD4+ T cell helper responses appear to be absent or short-lived, using functional assays. Here we used a novel HLA-DR1 tetramer containing a highly targeted CD4+ T cell epitope from the hepatitis C virus non-structural protein 4 to track number and phenotype of hepatitis C virus specific CD4+ T cells in a cohort of seven HLA-DR1 positive patients with acute hepatitis C in comparison to patients with chronic or resolved hepatitis C. We observed peptide-specific T cells in all seven patients with acute hepatitis C regardless of outcome at frequencies up to 0.65% of CD4+ T cells. Among patients who transiently controlled virus replication we observed loss of function, and/or physical deletion of tetramer+ CD4+ T cells before viral recrudescence. In some patients with chronic hepatitis C very low numbers of tetramer+ cells were detectable in peripheral blood, compared to robust responses detected in spontaneous resolvers. Importantly we did not observe escape mutations in this key CD4+ T cell epitope in patients with evolving chronic hepatitis C. During acute hepatitis C a CD4+ T cell response against this epitope is readily induced in most, if not all, HLA-DR1+ patients. This antiviral T cell population becomes functionally impaired or is deleted early in the course of disease in those where viremia persists

Wie wirkt sich die Variation von Politikmaßnahmen und Kontext auf agrarökonomische Entscheidungen in Unternehmensplanspielen aus?

In vielen ökonomischen Experimenten konnte beobachtet werden, dass menschliches Verhalten nicht nur von der ökonomischen Vorteilhaftigkeit individueller Wahlhandlungen, sondern auch vom Entscheidungskontext abhängt. Der kontrollierte artifizielle Entscheidungskontext in herkömmlichen ökonomischen Experimenten wie z.B. dem Ultimatum- oder Vertrauens-spiel wird zwar teilweise systematisch variiert, der Abstraktionsgrad im Vergleich zu realweltlichen Entscheidungsumgebungen ist jedoch groß. Deshalb sind sie für die Politikfolgenabschätzung nicht ausreichend. Dies gilt insbesondere für die Umweltpolitik, in der man versucht, durch eine Veränderung des Entscheidungsumfelds (institutionelle Innovation) das einzelwirtschaftliche Verhalten so zu verändern, dass negative Externalitäten abgebaut und positive Externalitäten bereitgestellt werden. Die vorliegende experimentelle Studie greift deshalb auf zwei kontrollierte, aber realistische und sozial relevante Entscheidungsfelder zu-rück und untersucht mit Hilfe von zwei vergleichbar designten Unternehmensplanspielen das Verhalten bei der Technologiewahl „Nicht-Anwendung vs. Anwendung der grünen Gentechnik“ und „niedriger vs. hoher Stickstoffeinsatz“. Zur Untersuchung der Beeinflussbarkeit des Verhaltens werden die Teilnehmer im Laufe der beiden Unternehmensplanspiele jeweils mit drei Politikmaßnahmen konfrontiert, die die ökonomische Vorzüglichkeit des als sozial unerwünscht deklarierten Verhaltens in identischem Umfang reduzieren: (1) Auszeichnung mit Preisgeld für das als sozial erwünscht deklarierte Verhalten sowie (2) Schadensersatzforderung und (3) Abgabe für das als sozial unerwünscht deklarierte Verhalten. Die zentralen experimentellen Ergebnisse sind: Erstens, die „sozial erwünschten“ Technologien wurden trotz ökonomischer Nachteile in erheblichem Umfang eingesetzt. Der Einsatzumfang ist in beiden Entscheidungsfeldern ähnlich. Zweitens, die Rangordnung der Verhaltenswirkung der Politikmaßnahmen ist zwischen den beiden Kontexten unterschiedlich, allerdings nicht statistisch signifikant. Eine erste Schlussfolgerung hieraus ist, dass weitere Forschung erforderlich ist, um zu überprüfen, wie politische Maßnahmen, sich in Kombination mit verschiedenen Entscheidungskontexten auswirken

A Primer on p-Value Thresholds and α-Levels – Two Different Kettles of Fish

It has often been noted that the “null-hypothesis-significance-testing” (NHST) framework is an incon-sistent hybrid of Neyman-Pearson’s “hypothesis test-ing” and Fisher’s “significance testing” that almost inevitably causes misinterpretations. To facilitate a realistic assessment of the potential and the limits of statistical inference, we briefly recall widespread inferential errors and outline the two original ap-proaches of these famous statisticians. Based on the understanding of their irreconcilable perspectives, we propose “going back to the roots” and using the ini-tial evidence in the data in terms of the size and the uncertainty of the estimate for the purpose of statisti-cal inference. Finally, we make six propositions that hopefully contribute to improving the quality of infer-ences in future research