Stable Cytotoxic T Cell Escape Mutation in Hepatitis C Virus Is Linked to Maintenance of Viral Fitness

Mechanisms by which hepatitis C virus (HCV) evades cellular immunity to establish persistence in chronically infected individuals are not clear. Mutations in human leukocyte antigen (HLA) class I-restricted epitopes targeted by CD8+ T cells are associated with persistence, but the extent to which these mutations affect viral fitness is not fully understood. Previous work showed that the HCV quasispecies in a persistently infected chimpanzee accumulated multiple mutations in numerous class I epitopes over a period of 7 years. During the acute phase of infection, one representative epitope in the C-terminal region of the NS3/4A helicase, NS31629-1637, displayed multiple serial amino acid substitutions in major histocompatibility complex (MHC) anchor and T cell receptor (TCR) contact residues. Only one of these amino acid substitutions at position 9 (P9) of the epitope was stable in the quasispecies. We therefore assessed the effect of each mutation observed during in vivo infection on viral fitness and T cell responses using an HCV subgenomic replicon system and a recently developed in vitro infectious virus cell culture model. Mutation of a position 7 (P7) TCR-contact residue, I1635T, expectedly ablated the T cell response without affecting viral RNA replication or virion production. In contrast, two mutations at the P9 MHC-anchor residue abrogated antigen-specific T cell responses, but additionally decreased viral RNA replication and virion production. The first escape mutation, L1637P, detected in vivo only transiently at 3 mo after infection, decreased viral production, and reverted to the parental sequence in vitro. The second P9 variant, L1637S, which was stable in vivo through 7 years of follow-up, evaded the antigen-specific T cell response and did not revert in vitro despite being less optimal in virion production compared to the parental virus. These studies suggest that HCV escape mutants emerging early in infection are not necessarily stable, but are eventually replaced with variants that achieve a balance between immune evasion and fitness for replication

Errichtung und Betrieb einer Messstelle fuer das ECE-Projekt Integrated Monitoring im Rahmen der ECE-Luftreinhaltekonvention

Since 1990 research stations and permanent plots were installed at Forellenbach area in the National Park Bayerischer Wald and the state of the ecosystem was described in order to provide the basis for long-term integrated monitoring. Immisions are dominated by ozone, sulphur and nitrogen oxides are of low concentrations. Thalli of sensitive lichens show distinct damages. The poor nutrient status of spruce and beech trees regarding calcium and magnesium on acid brown soils corresponds to the above-average portion of distinctively damaged tree individuals. Acid, nitrate and sulfate inputs as well as aluminium released in mineral soils are stored in the subsoil and buffered by silicate weathering respectively. Runoff water is of low ion strength and alkalinity. During snow melt acid and aluminium concentrations in this water increase to harmful levels regarding aquatic biota. Stabilization of this labile ecosystem requires reduced emissions of air pollutants. (orig.)Seit 1990 wurden im Forellenbachgebiet des Nationalparks Bayerischer Wald Messstationen und Dauerbeobachtungsflaechen eingerichtet, die naturraeumliche Ausstattung des Gebietes charakterisiert, und die Basis fuer ein langfristiges integriertes Monitoring gelegt. Das Immissionsklima ist O_3-betont mit geringen SO_2- und NO_x-Konzentrationen. Sensitive Flechtenarten weisen deutliche Thallusschaeden auf. Die schwache Naehrstoffversorgung von Fichten und Buchen v.a. mit Kalzium und Magnesium auf sauren Braunerden aus Fliesserden und Granitersatz korrespondiert mit dem ueberdurchschnittlich hohen Anteil deutlich geschaedigter Baeume. Die Saeure-, Nitrat- und Sulfateintraege und die im Mineralboden freigesetzten Aluminiumionen werden insb. unter Fichte erst im Untergrund gebunden bzw. ueber Silikatverwitterung abgepuffert. Das schwach mineralisierte Vorfluterwasser erreicht bei der Schneeschmelze unphysiologisch niedrige pH-Werte und hohe Aluminiumkonzentrationen. Die Stabilisierung dieses sensiblen Oekosystems erfordert eine weitere Reduzierung der atmosphaerischen Belastung. (orig.)SIGLEAvailable from TIB Hannover: RN 8908(95-057) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Bonn (Germany)DEGerman

Impact of soluble CD26 on treatment outcome and hepatitis C virus-specific T cells in chronic hepatitis C virus genotype 1 infection

Background: Interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection yields sustained virological response (SVR) rates of 50–80%. Several factors such as non-1 genotype, beneficial IL28B genetic variants, low baseline IP-10, and the functionality of HCV-specific T cells predict SVR. With the pending introduction of new therapies for HCV entailing very rapid clearance of plasma HCV RNA, the importance of baseline biomarkers likely will increase in order to tailor therapy. CD26 (DPPIV) truncates the chemokine IP-10 into a shorter antagonistic form, and this truncation of IP-10 has been suggested to influence treatment outcome in patients with chronic HCV infection patients. In addition, previous reports have shown CD26 to be a co-stimulator for T cells. The aim of the present study was to assess the utility of CD26 as a biomarker for treatment outcome in chronic hepatitis C and to define its association with HCV-specific T cells. Methods: Baseline plasma from 153 genotype 1 and 58 genotype 2/3 infected patients enrolled in an international multicenter phase III trial (DITTO-HCV) and 36 genotype 1 infected patients participating in a Swedish trial (TTG1) were evaluated regarding baseline soluble CD26 (sCD26) and the functionality of HCV-specific CD8+ T cells. Results: Genotype 1 infected patients achieving SVR in the DITTO (P = 0.002) and the TTG1 (P = 0.02) studies had lower pretreatment sCD26 concentrations compared with non-SVR patients. Sixty-five percent of patients with sCD26 concentrations below 600 ng/mL achieved SVR compared with 39% of the patients with sCD26 exceeding 600 ng/mL (P = 0.01). Patients with sCD26 concentrations below 600 ng/mL had significantly higher frequencies of HCV-specific CD8+ T cells (P = 0.02). Conclusions: Low baseline systemic concentrations of sCD26 predict favorable treatment outcome in chronic HCV infection and may be associated with higher blood counts of HCV-specific CD8+ T cells