Feilke revisited : 60 Stellenbesuche

Weitere Hrsg.: Thorsten Pohl, Sara Rezat, Torsten Steinhoff, Martin SteinseiferAnlässlich des 60. Geburtstags des Linguisten und Sprachdidaktikers Helmuth Feilke wurden Wegbegleiterinnen und Wegbegleiter gebeten, einzelne Stellen in seinen wissenschaftlichen Schriften erneut zu besuchen. Entstanden sind pointierte Kommentare, kurze wissenschaftliche Abhandlungen und Analysen, Varianten auch des kritischen und kontroversen Nach- und Weiterdenkens und Ansätze zur Neu- oder Re-Kontextualisierung. Je nach wissenschaftlicher Vita der Autorinnen und Autoren kann es sich um Stellen handeln, deren Rezeption zeitlich weit zurückliegt, oder um Passagen, die ganz aktuelle Fragen der eigenen Forschungsarbeit tangieren. Abgesehen davon, dass ein kurzes Format für die Beiträge gewählt und die Autorinnen und Autoren gebeten wurden, die ausgewählte Stelle knapp zu verorten und zu erläutern, war die Bearbeitungsform gänzlich freigestellt. So sind Texte in einer Bandbreite von pointierten Kommentaren, kurzen wissenschaftlichen Abhandlungen und Analysen, Varianten des Nach- und Weiterdenkens, Ansätze zur Neu- oder Re-Kontextualisierung bis hin zu Formen des kritischen Hinterfragens und der kontroversen Auseinandersetzung entstanden

Adaptation of CD8 T Cell Responses to Changing HIV-1 Sequences in a Cohort of HIV-1 Infected Individuals Not Selected for a Certain HLA Allele

<div><p>HIV evades CD8 T cell mediated pressure by viral escape mutations in targeted CD8 T cell epitopes. A viral escape mutation can lead to a decline of the respective CD8 T cell response. Our question was what happened after the decline of a CD8 T cell response and - in the case of viral escape – if a new CD8 T cell response towards the mutated antigen could be generated in a population not selected for certain HLA alleles. We studied 19 antiretroviral-naïve HIV-1 infected individuals with different disease courses longitudinally. A median number of 12 (range 2-24) CD8 T cell responses towards Gag and Nef were detected per study subject. A total of 30 declining CD8 T cell responses were studied in detail and viral sequence analyses showed amino acid changes in 25 (83%) of these. Peptide titration assays and definition of optimal CD8 T cell epitopes revealed 12 viral escape mutations with one de-novo response (8%). The de-novo response, however, showed less effector functions than the original CD8 T cell response. In addition we identified 4 shifts in immunodominance. For one further shift in immunodominance, the mutations occurred outside the optimal epitope and might represent processing changes. Interestingly, four adaptations to the virus (the de-novo response and 3 shifts in immunodominance) occurred in the group of chronically infected progressors. None of the subjects with adaptation to the changing virus carried the HLA alleles B57, B*58:01 or B27. Our results show that CD8 T cell responses adapt to the mutations of HIV. However it was limited to only 20% (5 out of 25) of the epitopes with viral sequence changes in a cohort not expressing protective HLA alleles.</p> </div

HIV-specific CD8 T cell responses.

<p>Overview of longitudinal changes in magnitude of HIV-specific CD8 T cell responses towards overlapping screening peptides spanning Gag (white bars), Pol (black bars) and Nef (grey bars) in 7 early infected individuals (A), 4 chronically infected controllers (B) and 8 chronically infected progressors (C) as measured by Elispot assay. Exact peptide denomination follows in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080045#pone-0080045-g002" target="_blank">Figure 2</a>. Only responses are depicted where sequencing of autologous virus was done subsequentially. X-axis: first and second time point of each individual. Y-axis: magnitude of CD8 T cell responses expressed in spot forming cells per million PBMC. </p

Shifts in immunodominance.

<p>In blue wildtype peptide recognition, in red mutated peptide recognition at first and second time point as measured by titration Elispot assays. X-axis: peptide concentration in increasing dilution. Y-axis: magnitude of CD8 T cell response expressed in spot forming cells per million PBMC. Below the graphs are shown amino acid sequences of consensus sequence and autologous virus‘sequences of first and second time point. The optimal epitopes are highlighted in grey (P08: HLA-A*01:01 restricted Gag 21-29 (LRPGGKKRY); P02: HLA-B*39:01 restricted Nef 187-195 (SRLAFNHMA); A09: HLA-A*02:01 restricted Gag 77-85 (SLYNTVATL); C02: HLA-B*08:01 restricted Gag 93-101 (EVKDTMEAL); P05: HLA-B*35:01 restricted Nef 74-81 (VPLRPMTY). Values are presented as mean values.</p

de-novo response of subject P08.

<p>(A) In blue wildtype peptide recognition, in red mutated peptide recognition at first and second time point as measured by titration Elispot assays. X-axis: peptide concentration in increasing dilution. Y-axis: magnitude of CD8 T cell response expressed in spot forming cells per million PBMC. Below the graphs are shown amino acid sequences of consensus sequence and autologous virus‘sequences of first and second time point. The optimal HLA-C*06:02 restricted epitope Pol 706-715 (LVSAGIRKVL) is highlighted in grey. Values are presented as mean values. (B) Evaluation of different effector functions towards the two different peptides. Bars represent the total CD8 T cell frequency to Pol 706-715 in subject P08 expressing the particular combination of functions shown. WT: recognition of wildtype peptide (Pol 706-715); M: recognition of mutated peptide (Pol 706-715; V714I). Left side: blood samples from early time point (2006), right side: blood samples from late time point (2008).</p

Prenatal vs postnatal diagnosis of 22q11.2 deletion syndrome: cardiac and noncardiac outcomes through 1 year of age

Background The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis. Objective This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome. Study Design This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site. Results A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56–11.18; P&lt;.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69–0.89; P&lt;.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06–0.23; P&lt;.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03–0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36–0.91; P=.019). Conclusion Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection