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Background & Aims: Immune responses by CD8 T cells are essential for control of HBV replication. Although selection of escape mutations in CD8 T-cell epitopes has been previously described in HBV infection, its overall influence on HBV sequence diversity and correlation with markers of HBV replication remain unclear., Methods: Whole-genome sequencing was applied to HBV isolates from 532 patients with chronic HBV infection and high-resolution HLA class I genotyping. Using a Bayesian model (HAMdetector) for identification of HLA-associated mutational states (HAMs), the frequency and location of residues under CD8 T-cell selection pressure were determined and the levels of adaptation of individual isolates were quantified., Results: Using previously published thresholds for the identification of HAMs, a total of 295 residues showed evidence of CD8 T-cell escape, the majority of which were located in previously unidentified epitopes. Interestingly, HAMs were highly enriched in the HBV core protein compared to all other proteins. When individual HBV isolates were compared, different levels of adaptation to HLA class I immune pressure were noted. The level of adaptation increased with patient age and correlated with markers of replication, with low levels of adaptation in HBeAg-positive infection. Furthermore, the levels of adaptation negatively correlated with HBV viral load and HBsAg levels, consistent with high levels of HLA class I-associated selection pressure in patients with low replication levels., Conclusions: HBV sequence diversity is shaped by HLA class I-associated selection pressure with the HBV core protein being a predominant target of selection. Importantly, different levels of adaptation to immune pressure were observed between HBV infection stages, which need to be considered in the context of T-cell-based therapies., Impact and Implications: The immune response mediated by CD8 T cells plays a critical role in controlling HBV infection and shows promise for therapeutic strategies aimed at achieving a functional cure. This study demonstrates that mutational escape within CD8 T-cell epitopes is common in HBV and represents a key factor in the failure of immune control. Notably, the HBV core protein emerges as the primary target of CD8 T-cell selection pressure. Additionally, the observed correlation between HBV adaptation levels and viral replication markers indicates that CD8 T-cell immunity may influence transitions between phases of chronic HBV infection., Competing Interests: Conflict of interest TS, JP, MD, SG, DH, FMH, JLM, TL, CM, AK, ESA, CNH, DH, MM, RT, PH declare no conflict of interest. JT reports honoraria for lectures from AbbVie and GSK. AW has received grants for HCV genomic surveillance from Gilead Sciences. HB reports honoraria for lectures or presentations from AbbVie and Gilead Sciences, travel support from AbbVie and Gilead Sciences, and participates on advisory boards for AbbVie, Gilead Sciences, and Ipsen. MKM reports funding from Gilead Sciences for HBV immunology research and received consulting fees from Astrivax and Moderna. MC reports consulting fees from Gilead Sciences, AbbVie, MSD Sharp & Dohme, Falk Foundation, and is the medical CEO of the German Liver Foundation. JN reports grants from the German Research Council, the German Center for Infection Research, the Hector Foundation, and the German Cancer Aid. JSzW reports grants from EU Horizon 20/20, DZIF, DFG CRC1328. HW reports grants from Abbott, Biotest, consulting fees from Abbott, Bristol-Myers-Squibb, F. Hoffmann-La Roche Ltd., Gilead Science, GlaxoSmithKline, Janssen, Roche Diagnostics International Ltd., Vir Biotechnology Inc. and honoraria from Biotest Ag and Gilead Science. HK reports grants from the German Center for Infection Research, EU Horizon Health, German Research Foundation, and internal Funds from Hannover Medical School and support for attending the International DeltaCure Meeting and EASL/AASLD Masterclass. GL reports funding from NIH. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The effect of iodine present in 1.0% table salt in combination with the use of starter cultures in sauerkraut fermentations were investigated in order to determine whether iodine interferes with lactic acid bacteria responsible for the fermentation. The effect of iodine was tested in fermentations performed using selected starter cultures or without starters (spontaneous fermentation). Lactobacillus plantarum and Leuconostoc mesenteroides used as starters at levels of ca. 1 × 10 7  cfu ml -1 led to a quick establishment of lactic acid bacteria (LAB) as predominant microorganisms, reaching 1 × 10 9  cfu ml -1 after 24 h decreasing the pH to below 4.0. In contrast, LAB counts in control fermentations without starters increased slower from 1 × 10 5  cfu ml -1 to 1 × 10 9  cfu ml -1 and a pH reduction below 4.0 was achieved only after 3 days fermentation. A metagenomic investigation showed a more diverse bacterial community in fermentations without starters, consisting of enterobacteria and pseudomonads in the first days of fermentation, and of LAB such as lactococci in the later stages. In fermentations with starters, lactobacilli predominated. Leuconostocs also occurred, but at much lower sequence abundance than lactobacilli, and thus were not able to predominate. Determination of iodine in the fermentation with starter bacteria and with iodized salt showed that the fermentation did not affect iodine concentration. The use of iodized salt did not statistically significantly influence microbial populations in the fermentation. Thus, there is no basis for the popular held belief that the use of iodized salt inhibits the growth of the bacteria important for the sauerkraut fermentation. A statistically near significant effect (p = 0.06), however, was noted for the effect of iodine on yeasts and mould populations in the fermentations performed without starter cultures. As sauerkraut is usually produced without starters, this should be further investigated., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A short review is given of concepts which are used to evaluate effects from combined-acting agents. To explore those effects exactly a high multiplicity of experiments must be performed, as an algebraic derivation from the effects of the single-acting agents is not usually possible. For practical purposes (as, for instance, to establish threshold limit values with respect to occupational health standards) a more pragmatic concept is proposed. Accordingly, an experimental setup has been developed which enables us to expose four groups of rodents simultaneously to two different single-acting chemical and/or physical stress parameters, both separately and in combination, and to control conditions.