Adaptation of antiviral CD8+ t-cells and the evolution of hepatitis c virus

In dieser Arbeit wurde die Interaktion zwischen der zellulären Immunantwort und der Evolution des Hepatitis C Virus untersucht. Zum einen wurde die Abhängigkeit der Virusevolution von der HLA-Klasse I-Ausstattung untersucht und die immunologischen Auswirkungen von Mutationen in CD8+ T-Zell-Epitopen charakterisiert. Zum anderen wurde die Bedeutung von Mutationen in Zielepitopen von CD8+ T-Zellen für die virale Fitness untersucht. Schließlich wurde ein experimentelles System etabliert, mit dem man die Auswirkungen von Sequenzunterschieden auf die Präsentation von endogen prozessierten Antigenen bestimmen kann. Grundlage für diese Untersuchungen ist eine Kohorte von 2867 Patientinnen, die 1977/78 durch kontaminierte Anti-D Immunglobuline in einem großen Ausbruch infiziert worden ist. Da der Infektionszeitpunkt und die Virussequenz der Infektionsquelle bekannt sind, konnte die Virusevolution nach 30 Jahren detailliert untersucht werden.In the present study the interaction between the adaptive cellular immune response and the evolution of the hepatitis C virus was analyzed in great detail. In the first part the impact of HLA-class-I associated selection pressure on viral evolution and influence of mutations in epitopes on recognition by CD8+ T-cell was characterized. Next the consequences of escape mutations on viral fitness were determined. Finally, an experimental system was established that allows analysis of the impact of viral sequence polymorphisms on presentation of the endogenously processed antigen. This project was based on a common HCV genotype (GT) 1b outbreak that occurred after inoculation of contaminated anti-D immunoglobulin to women in 1977/78. This East-German anti-D cohort represents a unique HCV cohort, because sequence heterogeneity of the inoculum and most transmission factors are known and well controlled

Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation.

Exhausted CD8+ T cell responses during chronic viral infections are defined by a complex expression pattern of inhibitory receptors. However, very little information is currently available about the coexpression patterns of these receptors on human virus-specific CD8+ T cells and their correlation with antiviral functions, T cell differentiation and antigen recognition. We addressed these important aspects in a cohort of 38 chronically HCV infected patients and found a coexpression of inhibitory receptors such as 2B4, CD160 and KLRG1 in association with PD-1 in about half of the HCV-specific CD8+ T cell responses. Importantly, this exhaustive phenotype was associated with low and intermediate levels of CD127 expression, an impaired proliferative capacity, an intermediate T cell differentiation stage and absence of sequence variations within the corresponding epitopes, indicating ongoing antigen triggering. In contrast, a low expression of inhibitory receptors by the remaining HCV-specific CD8+ T cells occurred in concert with a CD127hi phenotype, an early T cell differentiation stage and presence of viral sequence variations within the corresponding epitopes. In sum, these results suggest that T cell exhaustion contributes to the failure of about half of HCV-specific CD8+ T cell responses and that it is determined by a complex interplay of immunological (e.g. T cell differentiation) and virological (e.g. ongoing antigen triggering) factors

Natural variability or anthropogenically-induced variation? Insights from 15 years of multidisciplinary observations at the arctic marine LTER site HAUSGARTEN

Time-series studies of arctic marine ecosystems are rare. This is not surprising since polar regions arelargely only accessible by means of expensive modern infrastructure and instrumentation. In 1999, theAlfred Wegener Institute, Helmholtz-Centre for Polar and Marine Research (AWI) established the LTER(Long-Term Ecological Research) observatory HAUSGARTEN crossing the Fram Strait at about 79◦N.Multidisciplinary investigations covering all parts of the open-ocean ecosystem are carried out at a totalof 21 permanent sampling sites in water depths ranging between 250 and 5500 m. From the outset,repeated sampling in the water column and at the deep seafloor during regular expeditions in summermonths was complemented by continuous year-round sampling and sensing using autonomous instru-ments in anchored devices (i.e., moorings and free-falling systems). The central HAUSGARTEN stationat 2500 m water depth in the eastern Fram Strait serves as an experimental area for unique biologicalin situ experiments at the seafloor, simulating various scenarios in changing environmental settings.Long-term ecological research at the HAUSGARTEN observatory revealed a number of interesting tem-poral trends in numerous biological variables from the pelagic system to the deep seafloor. Contrary tocommon intuition, the entire ecosystem responded exceptionally fast to environmental changes in theupper water column. Major variations were associated with a Warm-Water-Anomaly evident in sur-face waters in eastern parts of the Fram Strait between 2005 and 2008. However, even after 15 years ofintense time-series work at HAUSGARTEN, we cannot yet predict with complete certainty whether thesetrends indicate lasting alterations due to anthropologically-induced global environmental changes of thesystem, or whether they reflect natural variability on multiyear time-scales, for example, in relation todecadal oscillatory atmospheric processes.peerReviewe