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Customized voltage waveforms composed of a number of frequencies and used as the excitation of radio-frequency plasmas can control various plasma parameters such as energy distribution functions, homogeneity of the ion flux, or ionization dynamics. So far this technology, while being extensively studied in academia, has yet to be established in applications. One reason for this is the lack of a suitable multi frequency matching network that allows for maximum power absorption for each excitation frequency that is generated and transmitted via a single broadband amplifier. In this work, a method is introduced for designing such a network based on network theory and synthesis. Using this method, a circuit simulation is established that connects an exemplary matching network to an equivalent circuit plasma model of a capacitive radio-frequency discharge. It is found that for a range of gas pressures and number of excitation frequencies the matching conditions can be satisfied, which proves the functionality and feasibility of the proposed concept. Based on the proposed multi frequency impedance matching, tailored voltage waveforms can be used at an industrial level. [ABSTRACT FROM AUTHOR]

Background: Type III interferons (IFNs) (λ1-3) activate similar signaling cascades as type I IFNs (α and β) via different receptors. Since IFN-α and lymphotoxin-β activate cytosine deamination and subsequent purging of nuclear hepatitis B virus (HBV) DNA, we investigated whether IFN-β and -λ may also induce these antiviral effects in differentiated HBV-infected hepatocytes.Methods: After determining the biological activity of IFN-α2, -β1, -λ1, and -λ2 in differentiated hepatocytes, their antiviral effects were analyzed in HBV-infected primary human hepatocytes and HepaRG cells.Results: Type I and III IFNs reduced nuclear open-circle DNA and covalently closed circular DNA (cccDNA) levels in HBV-infected cells. IFN-β and -λ were at least as efficient as IFN-α. Differential DNA-denaturing polymerase chain reaction and sequencing analysis revealed G-to-A sequence alterations of HBV cccDNA in IFN-α, -β, and -λ-treated liver cells indicating deamination. All IFNs induced apolipoprotein B messenger RNA-editing enzyme-catalytic polypeptide-like (APOBEC) deaminases 3A and 3G within 24 hours of treatment, but IFN-β and -λ induced longer-lasting expression of APOBEC deaminases in comparison to IFN-α.Conclusions: IFN-β, IFN-λ1, and IFN-λ2 induce cccDNA deamination and degradation at least as efficiently as IFN-α, indicating that these antiviral cytokines are interesting candidates for the design of new therapeutic strategies aiming at cccDNA reduction and HBV cure. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics including electron heating in helicon plasma sources, the use of optical emission spectroscopy, and plasma breakdown in high voltage open discharges.

There are conflicting data about the frequency and role of regulatory T cells (Tregs) during the course of HIV infection. Peripheral blood of a large cohort of HIV-infected patients (n = 131) at different stages of disease, including 15 long-term nonprogressors and 21 elite controllers, was analyzed to determine the frequency and phenotype of Tregs, defined as CD4+, CD25high, CD127low, FoxP3high cells. A significantly increased relative frequency of Tregs within the CD4+ compartment of HIV+ patients compared to that of healthy controls (P < 0.0001) was observed. Additionally, the relative frequency of Tregs directly correlated with HIV viral load and inversely with CD4+ counts. However, the absolute Treg number was reduced in HIV-infected patients versus healthy controls (P < 0.0001), with the exception of elite controllers (P > 0.05). The loss of absolute Treg numbers coincided with rising markers of immune activation (P < 0.0006). The initiation of antiviral therapy significantly increased absolute Treg numbers (P < 0.0031). We find that the expression of CD39, a newly defined ectonucleotidase with immunomodulatory functions on Tregs, correlated with progressive HIV disease, HIV viral load, and immune activation. Of note, when tested in peripheral blood mononuclear cells of healthy volunteers, the in vitro capacity to suppress T-cell proliferation was limited to CD4+, CD25high, CD39+ T cells. Interestingly, Tregs of elite controllers exhibited not only the highest expression of CCR5, CTLA-4, and ICOS but also the lowest level of CD39. The data presented here reconcile the seemingly contradictory results of previous studies looking at Tregs in HIV and highlight the complexity of Treg-mediated immunoregulation during human viral infections. [ABSTRACT FROM AUTHOR]

We monitored expression of PD-1 (a mediator of T-cell exhaustion and viral persistence) on hepatitis C virus (HCV)-specific CD8+ and CD4+ T cells from blood and liver during acute and chronic infections and after the resolved infection stage. PD-1 expression on HCV-specific T cells was high early in acute infection irrespective of clinical outcome, and most cells continued to express PD-1 in resolved and chronic stages of infection; intrahepatic expression levels were especially high. Our results suggest that an analysis of PD-1 expression alone is not sufficient to predict infection outcome or to determine T-cell functionality in HCV infection. [ABSTRACT FROM AUTHOR]

Background & aims: To explore the humoral and T‐cell response to the third COVID‐19 vaccination in autoimmune hepatitis (AIH). Methods: Anti‐SARS‐CoV‐2 antibody titers were prospectively determined in 81 AIH patients and 53 healthy age‐ and sex‐matched controls >7 days (median 35) after the first COVID‐19 booster vaccination. The spike‐specific T‐cell response was assessed using an activation‐induced marker assay (AIM) in a subset of patients. Results: Median antibody levels were significantly lower in AIH compared to controls (10 908 vs. 25 000 AU/ml, p <.001), especially in AIH patients treated with MMF (N = 14, 4542 AU/ml, p =.004) or steroids (N = 27, 7326 AU/ml, p =.020). Also, 48% of AIH patients had antibody titers below the 10% percentile of the healthy controls (9194 AU/ml, p <.001). AIH patients had a high risk of failing to develop a spike‐specific T‐cell response (15/34 (44%) vs. 2/16 (12%), p =.05) and showed overall lower frequencies of spike‐specific CD4 + T cells (median: 0.074% vs 0.283; p =.01) after the booster vaccination compared to healthy individuals. In 34/81 patients, antibody titers before and after booster vaccination were available. In this subgroup, all patients but especially those without detectable/low antibodies titers (<100 AU/ml) after the second vaccination (N = 11/34) showed a strong, 148‐fold increase. Conclusion: A third COVID‐19 vaccination efficiently boosts antibody levels and T‐cell responses in AIH patients and even seroconversion in patients with the absent immune response after two vaccinations, but to a lower level compared to controls. Therefore, we suggest routinely assessing antibody levels in AIH patients and offering additional booster vaccinations to those with suboptimal responses. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology worldwide. In mice and humans, NAFLD progression is characterized by the appearance of TREM2-expressing macrophages in the liver. However, their mechanistic contributions to disease progression have not been completely elucidated. Here, we show that TREM2+ macrophages prevent the generation of a pro-inflammatory response elicited by LPS-laden lipoproteins in vitro. Further, Trem2 expression regulates bone-marrow-derived macrophages (BMDMs) and Kupffer cell capacity to phagocyte apoptotic cells in vitro, which is dependent on CD14 activation. In line with this, loss of Trem2 resulted in an increased pro-inflammatory response, which ultimately aggravated liver fibrosis in murine models of NAFLD. Similarly, in a human NAFLD cohort, plasma levels of TREM2 were increased and hepatic TREM2 expression was correlated with higher levels of liver triglycerides and the acquisition of a fibrotic gene signature. Altogether, our results suggest that TREM2+ macrophages have a protective function during the progression of NAFLD, as they are involved in the processing of pro-inflammatory lipoproteins and phagocytosis of apoptotic cells and, thereby, are critical contributors for the re-establishment of liver homeostasis. [ABSTRACT FROM AUTHOR]

Background/Aims Bulevirtide (BLV) is an entry inhibitor for chronic hepatitis delta (CHD). In an ongoing Phase 3 study, BLV 2- or 10-mg monotherapy was effective and safe at 96 weeks (W). Here, we present 144W results. Methods 150 patients were randomised: Arm A (delayed treatment), observed for 48W followed by BLV 10 mg/d for 96W (n=51); Arm B, BLV 2 mg/d for 144W (n=49); Arm C, BLV 10 mg/d for 144W (n=50). Efficacy endpoints included virologic response (VR; undetectable HDV RNA or ≥2 log10 decline from baseline [BL]), alanine aminotransferase (ALT) normalisation, combined response (CR; VR+ALT normalisation), and undetectable HDV RNA (target not detected). Univariate logistic regression determined baseline predictors of undetectable HDV RNA at 144W for patients in Arms B/C who completed 144W and had BL HDV RNA ≥250 IU/mL. Predictors with p<.05 were significant. Results At 144W, 49/51, 45/49, and 44/50 patients in Arms A, B, and C remained in study. Arms B and C had similar rates of CR, VR, and ALT normalisation at 144W (Figure 1). Undetectable HDV RNA rates were 29% in Arm B and 50% in Arm C at 144W. Mean (SD) change from BL to 144W in hepatitis B surface antigen (HBsAg) was −0.36 (0.596) and − 0.19 (0.39) with BLV 2 and 10 mg. BL predictors of 144W undetectable HDV RNA included lower HDV RNA and lower HBsAg (Figure 2). There was no progression to liver-related outcomes over 144W except for 1 case of mild ascites in a patient with BL cirrhosis; there were no drug discontinuations, serious adverse events, or deaths attributed to BLV. Conclusion Long-term BLV remained safe and effective. Improvements in virologic and biochemical markers support the clinical benefits of long-term BLV therapy. [ABSTRACT FROM AUTHOR]

Background. The natural outcome of infection with hepatitis C virus (HCV) varies substantially among individuals. However, little is known about host and viral factors associated with a self-limiting or chronic evolution of HCV infection. Methods. From 1 January 2001 through 31 December 2008, a consecutive series of 65 patients from Rio de Janeiro, Brazil, with a well-documented diagnosis of acute HCV infection, acquired via various routes, were enrolled in this study. Patients were prospectively followed up for a median of 40 months after the estimated date of HCV infection with serial measurements of serum alanine aminotransferase, HCV RNA, and anti-HCV antibodies. Spontaneous viral clearance (SVC) was defined as undetectable levels of HCV RNA in serum, in the absence of treatment, for 3 consecutive HCV polymerase chain reaction tests within the first 6 months of follow-up. Cox proportional hazards regression was used to identify host and viral predictors of SVC. Results. The cumulative rate of SVC was 44.6% (95% confidence interval, 32.3%-57.5%). Compared with chronic HCV evolution, patients with self-limiting disease had significantly lower peak levels of anti-HCV antibodies (median, 109.0 vs 86.7 optical density-to-cutoff ratio [od/co]; P < .02), experienced disease symptoms more frequently (69.4% vs 100%; P < .001), and had lower viral load at first clinical presentation (median, 4.3 vs 0.0 log copies; P=.01). In multivariate analyses, low peak anti-HCV level (!93.5 od/co) was the only independent predictor for SVC; the hazard ratio compared with high anti-HCV levels (⩾93.5 od/co) was 2.62 (95% confidence interval, 1.11-6.19; P=.03). Conclusion. Our data suggest that low levels of anti-HCV antibodies during the acute phase of HCV infection are independently related to spontaneous viral clearance. [ABSTRACT FROM AUTHOR]

We provide detailed clinical, virological, and immunological data of a B-cell–depleted patient treated with obinutuzumab for follicular lymphoma with protracted coronavirus disease 2019 (COVID-19) and viremia. A sustained response was achieved after 2 courses of remdesivir and subsequent convalescent plasma therapy. Immunocompromised patients might require combined and prolonged antiviral treatment regimens. [ABSTRACT FROM AUTHOR]

Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and muscle function remains poorly understood. Here, we took a complementary interorgan approach to investigate skeletal muscle wasting in CKD. We identified increased production and elevated blood levels of soluble pro-cachectic factors, including activin A, directly linking experimental and human CKD to skeletal muscle wasting programs. Single-cell sequencing data identified the expression of activin A in specific kidney cell populations of fibroblasts and cells of the juxtaglomerular apparatus. We propose that persistent and increased kidney production of pro-cachectic factors, combined with a lack of kidney clearance, facilitates a vicious kidney/muscle signaling cycle, leading to exacerbated blood accumulation and, thereby, skeletal muscle wasting. Systemic pharmacological blockade of activin A using soluble activin receptor type IIB ligand trap as well as muscle-specific adeno-associated virus-mediated downregulation of its receptor ACVR2A/B prevented muscle wasting in different mouse models of experimental CKD, suggesting that activin A is a key factor in CKD-induced cachexia. In summary, we uncovered a crosstalk between kidney and muscle and propose modulation of activin signaling as a potential therapeutic strategy for skeletal muscle wasting in CKD. [ABSTRACT FROM AUTHOR]

Background Micro-elimination of the hepatitis C virus (HCV) includes treatment in populations at risk of ongoing HCV transmission, such as men who have sex with men (MSM) or people who inject drugs (PWID). We analyzed the HCV reinfection incidence rates of participants in the German hepatitis C cohort (GECCO) and compared our data to previous findings from the interferon era. Methods Patients with HCV reinfections in the multi-centric GECCO cohort were compared to patients in whom no reinfection occurred. The HCV reinfection incidence rate in MSM was also compared to the incidence rate in the interferon era (using data from the European Acquired Immunodeficiency Syndrome Treatment Network [NEAT]). Results Between January 2014 and April 2018, 48 HCV reinfections occurred in 2298 individuals (2%), with 2346 cured HCV episodes. The median time to reinfection was 500 days (range 16–1160) and the overall HCV reinfection incidence rate was 1.89 per 100 person-years (py; 95% confidence interval [CI], 1.41–2.48). In a multivariate analysis, the transmission risk in MSM was the only independent risk factor of HCV reinfection (odds ratio, 39.3; 95% CI, 4.57–334.40; P =.001). The incidence rate in MSM was 9.02 (95% CI, 6.48–12.26) per 100 py, compared to 1.14 per 100 py in PWID (95% CI,.56–2.09). The incidence rate for a first HCV reinfection in MSM was similar in the direct-acting antiviral era, compared to the interferon era, with a hazard ratio of 1.05 (95% CI,.64–1.74; P =.831). Conclusions HCV reinfection remains a frequent finding among MSM in Germany. In addition to behavioral interventions, early HCV treatment and retreatment should be implemented for this subgroup to prevent HCV transmission. [ABSTRACT FROM AUTHOR]

The spatial structures of plasma parameters in a radio-frequency capacitive discharge plasma with a ring-shaped hollow electrode operated in argon were measured at various oxygen gas concentrations for plasma processing by moving a cylindrical Langmuir probe. Their distinctive profiles are obtained around the ring-shaped hollow trench. The electron temperature Te at the hollow trench of radial position r  =  37.5 mm has a peak value at an O2 gas concentration of 0%, whereas at O2 gas concentrations of 5 and 10% Te decreases everywhere except for positions close to the hollow trench. The plasma potential Vs at an O2 gas concentration of 0% is higher than that at O2 gas concentrations of 5% and 10%. The electron density ne has a peak value at the hollow trench at all O2 gas concentrations and decreases with increasing O2 gas concentration. Their axial profiles indicate unique distributions around the hollow inlet at a radial position of r  =  37.5 mm, while at a radial position of r  =  0 the profiles are almost uniform. It is found that a double layer is formed from the axial profiles of the plasma potential at r  =  37.5 mm for all oxygen gas concentrations. [ABSTRACT FROM AUTHOR]

Anemia is a common complication of malaria that is characterized by the loss of infected and uninfected erythrocytes. In mouse malaria models, clearance of uninfected erythrocytes is promoted by autoimmune anti-phosphatidylserine (PS) antibodies produced by T-bet+B-cells, which bind to exposed PS in erythrocytes, but the mechanism in patients is still unclear. In Plasmodium falciparum patients with anemia, we show that atypical memory FcRL5+T-bet+ B-cells are expanded and associate both with higher levels of anti-PS antibodies in plasma and with the development of anemia in these patients. No association of anti-PS antibodies or anemia with other B-cell subsets and no association of other antibody specificities with FcRL5+T-bet+ B- cells is observed, revealing high specificity in this response. We also identify FcRL5+T-bet+ B-cells as producers of anti-PS antibodies in ex vivo cultures of naıve human peripheral blood mononuclear cells (PBMC) stimulated with P.-falciparum-infected erythrocyte lysates. These data define a crucial role for atypical memory B-cells and anti-PS autoantibodies in human malarial anemia. [ABSTRACT FROM AUTHOR]

Background: This study aimed to comprehensively define the breadth and specificity of the hepatitis delta virus (HDV)-specific T-cell response in patients at different stages of chronic coinfection with hepatitis B virus (HBV).Methods: Following in vitro stimulation with an overlapping set of 21 HDV-specific 20mer peptides and exogenous interleukin 2, HDV-specific CD4+ and CD8+ T-cell responses of 32 HDV-infected patients were analyzed by enzyme-linked immunospot analysis and intracellular cytokine staining for interferon γ production at the single-peptide level. Additionally, HLA-binding studies were performed both in silico and in vitro.Results: We were able to detect ≥1 T-cell response in >50% our patients. Interestingly, there was no significant difference between the breadth of the response in patients positive and those negative for HDV by PCR. HDV-specific T-cell responses focused on 3 distinct HDV-specific epitopes that were each detected in 12%-21% of patients-2 HLA class II-restricted epitopes (amino acids 11-30 and 41-60) and 1 major histocompatibility complex class I-restricted epitope (amino acids 191-210). In in vitro HLA-binding assays, the 2 CD4+ T-cell specificities (amino acids 11-30 and 41-60) showed promiscuous binding to multiple HLA-DR molecules.Conclusions: This comprehensive characterization of HDV T-cell epitopes provides important information that will facilitate further studies of HDV immunopathogenesis. [ABSTRACT FROM AUTHOR]

The expression pattern of the ectonucleotidases CD39 and CD73 on natural killer (NK) cells was examined in peripheral blood mononuclear cell of 61 HIV-1-infected patients. Increased frequencies of CD39+CD56bright NK cells were detectable in untreated HIV pa- tients, which was associated with high viral load, low CD4+ T-cell count, and CD8+ T-cell activation. Additionally, levels of CD39 on NK cells were inducible by in vitro stimulation of NK cells, correlating with aryl hydrocarbon receptor and interleukin 10 expression. Here, we provide the first evidence of increased CD39+CD56bright NK cell frequencies during HIV infection, which might have consequences for NK cell function and HIV pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa is highly effective, but can be associated with frequent side-effects. We investigated the safety and efficacy of an interferon-free regimen for treatment of acute HCV infection.Methods: In this prospective, open-label, multicentre, single-arm pilot study, we enrolled adults (≥18 years) with acute HCV genotype 1 monoinfection from ten centres in Germany. Patients were given ledipasvir (90 mg) plus sofosbuvir (400 mg) as a fixed-dose combination tablet once daily for 6 weeks. The primary efficacy outcome was the proportion of patients with sustained virological response (defined as undetectable HCV RNA 12 weeks after the end of treatment; other primary outcomes were safety and tolerability of ledipasvir plus sofosbuvir. The primary analysis population consisted of all patients who received at least one dose of study drug. Safety was also assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02309918.Findings: Between Nov 19, 2014, and Nov 10, 2015, we enrolled 20 patients. Median HCV RNA viral load at baseline was 4·04 log10 IU/mL (1·71-7·20); 11 patients were infected with HCV genotype 1a and nine patients with genotype 1b. All patients achieved a sustained virological response 12 weeks after the end of treatment (20 [100%] of 20 patients). Treatment was well tolerated; there were no drug-related serious adverse events. Up to 12 weeks after treatment, 22 possible or probable drug-related adverse events were reported. There was one serious adverse event, which was judged unrelated to the study drug; one patient was admitted to hospital for surgery of a ruptured cruciate ligament.Interpretation: Treatment for 6 weeks with ledipasvir plus sofosbuvir was well tolerated and highly effective in patients with acute HCV genotype 1 monoinfection. Short-duration treatment of acute hepatitis C might prevent the spread of HCV in high-risk populations.Funding: Gilead Sciences, HepNet Study-House/German Liver Foundation, and German Centre for Infection Research (DZIF). [ABSTRACT FROM AUTHOR]

Background. Shortening the duration of treatment with HCV direct-acting antivirals (DAAs) leads to substantial cost reductions. According to the label, sofosbuvir and ledipasvir can be prescribed for 8 weeks (SL8) in noncirrhotic women or men with HCV genotype 1 and low viral loads. However, real-world data about the efficacy and safety of SL8 are largely missing. Methods. Interim results from an ongoing prospective, multicenter cohort of 9 treatment centers in Germany (GECCO). All patients started on treatment with HCV DAAs since January 2014 were included. This report describes safety and efficacy outcomes in 210 patients with HCV monoinfection and 35 with human immunodeficiency virus (HIV)-HCV coinfection given SL8 in a realworld setting. Results. Of 1353 patients included into the GECCO cohort until December 2015, a total of 1287 had complete data sets for this analysis; 337 (26.2%) fulfilled the criteria for SL8 according to the package insert, but only 193 (57.2%) were eventually treated for 8 weeks. Another 52 patients did not fulfill the criteria but were treated for 8 weeks. SL8 was generally well tolerated. The overall sustained virologic response rate 12 weeks after the end of treatment was 93.5% (186 of 199). The on-treatment response rate was 99.4% (159 of 160) in HCV-monoinfected and 96.4% (27 of 28) in HIV-HCV-coinfected patients. Ten patients were lost to follow-up. Conclusions. SL8 seems highly effective and safe in well-selected HCV-monoinfected and HIV-HCV-coinfected patients in a real-world setting. [ABSTRACT FROM AUTHOR]

Background: Interferon gamma release assays (IGRA) have been developed to support easy and fast diagnosis of diseases like tuberculosis, and CMV in transplant patients. IGRAs focus on cellular immunity especially memory T cells and thus also allow rapid screening prior to complex flow cytometric testing. Here, we describe a novel, sensitive whole blood based cytokine release assay capable of assessing T cell responsiveness to HBV antigens in Hepatitis B patients and assessing hepatitis B vaccination status in healthy individuals. Methods: Seventy two chronic Hepatitis B patients (CHB), 8 acute hepatitis B patients (AHB) and 80 healthy controls (HC) were tested by ELISA for IFNγ- and IL2-secretion in whole blood after challenge with synthetic peptide libraries of hepatitis B core antigen (HBcAg) or hepatitis B surface antigen (HBsAg). Results: The developed IGRA test reliably differentiated between Hepatitis B patients, vaccinees and unvaccinated healthy controls. Treatment naïve and treated CHB patients showed a weaker IFNγ response to HBcAg (16 ± 5 and 35 ± 28 pg/ml, respectively) compared to the AHB group (82 ± 39 pg/ml), whereas HC remained unresponsive (6 ± 1 pg/ml). IL2 levels after HBcAg challenge were also higher in the AHB group compared to naive and treated CHB as well as HC (47 ± 21 vs. 12 ± 3, 15 ± 10 and 12 ± 9 pg/ml, respectively). HBsAg stimulation led to increased IFNγ and IL2 levels in the AHB group (33 ± 12 and 22 ± 12 pg/ml) and even higher levels in HC due to a high hepatitis B vaccination rate (41 ± 10 and 167 ± 58 pg/ml). Naive and treated CHB patients developed no or only weaker IFNγ or IL2 responses to HBsAg (5 ± 2 and 12 ± 7 pg/ml, for naive CHB, 12 ± 10 and 18 ± 15 pg/ml, for treated CHB). For HC, IL2 release after HBsAg stimulation depicted hepatitis B vaccination status with a diagnostic sensitivity and specificity of 85 % and 90 %. Conclusion: Our novel whole blood based cytokine release assay constitutes an easy and robust tool for screening HBV specific cellular immunity as alternative to flow cytometry or ELISPOT assays. [ABSTRACT FROM AUTHOR]

Current hepatitis C virus (HCV) treatment guidelines recommend treating HCV/human immunodeficiency virus (HIV)-coinfected individuals similar to HCV-monoinfected individuals. Recently inferior response rates to direct acting antiviral (DAA) therapy in HCV/HIV coinfection have been reported. Our German hepatitis C cohort (GECCO) cohort data show that coinfected patients with liver cirrhosis are less likely to achieve viral eradication. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells are characterized by the combined expression of the semi-invariant T cell receptor (TCR) Vα7.2, the lectin receptor CD161, as well as IL-18R, and play an important role in antibacterial host defense of the gut. The current study characterized CD161+ MAIT and CD161–TCRVα7.2+ T cell subsets within a large cohort of HIV patients with emphasis on patients with slow disease progression and elite controllers. Mononuclear cells from blood and lymph node samples as well as plasma from 63 patients and 26 healthy donors were analyzed by multicolor flow cytometry and ELISA for IL-18, sCD14 and sCD163. Additionally, MAIT cells were analyzed after in vitro stimulation with different cytokines and/or fixed E.coli. Reduced numbers of CD161+ MAIT cells during HIV infection were detectable in the blood and lymph nodes of all patient groups, including elite controllers. CD161+ MAIT cell numbers did not recover even after successful antiretroviral treatment. The loss of CD161+ MAIT cells was correlated with higher levels of MAIT cell activation; an increased frequency of the CD161–TCRVα7.2+T cell subset in HIV infection was observed. In vitro stimulation of MAIT cells with IL-18 and IL-12, IL-7 and fixed E.coli also resulted in a rapid and additive reduction of the MAIT cell frequency defined by CD161, IL-18R and CCR6. In summary, the irreversible reduction of the CD161+ MAIT cell subset seems to be an early event in HIV infection that is independent of later stages of the disease. This loss appears to be at least partially due to the distinctive vulnerability of MAIT cells to the pronounced stimulation by microbial products and cytokines during HIV-infection. [ABSTRACT FROM AUTHOR]

Current German and European HIV guidelines recommend early evaluation of HCV treatment in all HIV/HCV co-infected patients. However, there are still considerable barriers to initiate HCV therapy in everyday clinical practice. This study evaluates baseline characteristics, "intention-to-treat" pattern and outcome of therapy of HCV/HIV co-infected patients in direct comparison to HCV mono-infected patients in a "real-life" setting. Methods A large, single-center cohort of 172 unselected HCV patients seen at the Infectious Diseases Unit at the University Medical Center Hamburg-Eppendorf from 2000-2011, 88 of whom HCV/HIV co-infected, was retrospectively analyzed by chart review with special focus on demographic, clinical and virologic aspects as well as treatment outcome. Results Antiviral HCV combination therapy with PEG-interferon plus weight-adapted ribavirin was initiated in 88/172 (52%) patients of the entire cohort and in n = 36 (40%) of all HCV/HIV co-infected patients (group A) compared to n = 52 (61%) of the HCV mono-infected group (group B) (p = 0.006). There were no significant differences of the demographics or severity of the liver disease between the two groups with the exception of slightly higher baseline viral loads in group A. A sustained virologic response (SVR) was observed in 50% (n = 18) of all treated HIV/HCV co-infected patients versus 52% (n = 27) of all treated HCV monoinfected patients (p = 0.859). Genotype 1 was the most frequent genotype in both groups (group A: n = 37, group B: n = 49) and the SVR rates for these patients were only slightly lower in the group of co-infected patients (group A: n = 33%, group B: 40% p = 0.626). During the course of treatment HCV/HIV co-infected patients received less ribavirin than mono-infected patients. Conclusion Overall, treatment was only initiated in half of the patients of the entire cohort and in an even smaller proportion of HCV/HIV co-infected patients despite comparable outcome (SVR) and similar baseline characteristics. In the light of newer treatment options, greater efforts to remove the barriers to treatment that still exist for a great proportion of patients especially with HIV/HCV co-infection have to be undertaken. [ABSTRACT FROM AUTHOR]

Background The combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the treatment of patients infected with HCV genotype 1 has led to significantly increased rates of sustained virological response (SVR) in phase III trials. There is only limited data regarding the safety and efficacy in a "real-life" cohort. Methods We analyzed a cohort of 110 unselected HCV patients who started triple therapy from September 2011 to February 2013 by chart review with focus on the individual course of treatment, complications and outcome. We excluded 8 patients from analysis because of HIV-coinfection (N = 6) or status post liver transplant (N = 2). Importantly, 41 patients displayed F3 or F4 fibrosis, 10 patients had a history of treatment with protease/polymerase inhibitors and 15 patients were prior partial- or null-responder. Results SVR12 was achieved in 62 of the 102 patients (60.8%). A high rate of serious adverse events (N = 30) was observed in 22 patients including 2 fatalities in cirrhotic diabetes patients. Age >50 years, liver cirrhosis, bilirubin >1.1 mg/dl (P < 0.01, each), platelets <100,000/μl (P = 0.01), ASAT >100 U/l (P = 0.03) and albumin ≤35 g/l (P = 0.04) at baseline were associated with occurence of a SAE. Conclusions The frequency of SVR in a "real-life" treatment setting is slightly lower as compared to the results of the phase III trials for telaprevir or boceprevir. Importantly, we observed a high frequency of SAE in triple therapy, especially in patients with liver cirrhosis. [ABSTRACT FROM AUTHOR]

HIV targets CD4 T cells, which are required for the induction of high-affinity antibody responses and the formation of long-lived B cell memory. The depletion of antigen-specific CD4 T cells during HIV infection is therefore believed to impede the development of protective B cell immunity. Although several different HIVrelated B cell dysfunctions have been described, the role of CD4 T follicular helper (TFH) cells in HIV infection remains unknown. Here, we assessed HIV-specific TFH responses in the lymph nodes of treatment-naive and antiretroviral-treated HIV-infected individuals. Strikingly, both the bulk TFH and HIV-specific TFH cell populations were significantly expanded in chronic HIV infection and were highly associated with viremia. In particular, GAG-specific TFH cells were detected at significantly higher levels in the lymph nodes compared with those of GP120-specific TFH cells and showed preferential secretion of the helper cytokine IL-21. In addition, TFH cell expansion was associated with an increase of germinal center B cells and plasma cells as well as IgG1 hypersecretion. Thus, our study suggests that high levels of HIV viremia drive the expansion of TFH cells, which in turn leads to perturbations of B cell differentiation, resulting in dysregulated antibody production. [ABSTRACT FROM AUTHOR]

Background: The anti-HCV antibody response has not been well characterized during the early phase of HCV infection and little is known about its relationship to the clinical course during this period. Methods: We analyzed serial anti-HCV antibodies longitudinally obtained from a prospective cohort of 65 patients with acute HCV infection by using a microparticle enzyme immunoassay AxSYM HCV 3.0 (Abbott Diagnostics) during the first 12 months from HCV acquisition in Rio de Janeiro,Brazil. Spontaneous viral clearance (SVC) was defined as undetectable HCV RNA in serum, in the absence of treatment, for three consecutive HCV PCR tests within 12-months of follow-up. Results:Baseline antibody values were similar among patient groups with self-limiting HCV evolution (n = 34) and persistent viremia (n = 31) [median (interquartile range) signal/cut-off ratio (s/co) 78.7 (60.7-93.8) vs. 93.9 (67.8- 111.9), p = 0.26]. During 12-months follow-up, patients with acute spontaneous resolving HCV infection showed significantly lower serial antibody response in comparison to individuals progressing to chronic infection [median (interquartile range) s/co 62.7 (35.2-85.0) vs. 98.4 (70.4-127.4), p < 0.0001]. In addition, patients with self-limiting HCV evolution exhibited an expeditious, sharp decline of serial antibody values after SVC in comparison to those measured before SVC [median (interquartile range) s/co 56.0 (25.4-79.3) vs. 79.4 (66.3-103.0), p < 0.0001]. Conclusion: Our findings indicate a rapid short-term decline of antibody values in patients with acute spontaneous resolving HCV infection. [ABSTRACT FROM AUTHOR]

Background. The Centers for Disease Control and Prevention has emphasized the need for interventional programs regarding hepatitis C virus (HCV) infection for injection drug users, the group of persons who are at highest risk of acquiring acute infection. Methods. We designed a pilot study to assess the feasibility of identifying injection drug users with acute HCV infection in correctional and detoxification facilities. On-site medical providers were educated regarding risk factors and signs and symptoms of infection and were instructed to refer all patients with hepatitis to our specialty clinic. Results. Over a 30-month period, 21 patients received a diagnosis of acute hepatitis C, 3 received a diagnosis of hepatitis B, and 1 received a diagnosis of hepatitis A. Of the 21 patients with acute hepatitis C, 19 were identified in the prison setting shortly after incarceration. Of the 17 patients who were observed serially (mean duration of observation, 6.3 months), 8 had spontaneous virologic clearance. Early therapy with pegylated interferon was initiated for 5 patients with persistent viremia and led to a sustained virologic response in 2 individuals. All patients agreed to undergo human immunodeficiency virus counseling and testing, as well as to receive immunization for hepatitis A and B. Conclusions. Incarceration presents a unique opportunity to identify injection drug users with acute HCV infection, to initiate counseling regarding other bloodborne pathogens, and to facilitate immunizations and HCV treatment. [ABSTRACT FROM AUTHOR]

Examines the biochemical properties of minimal functional domain with adenosine triphosphate-binding (ATP) activity of the nucleoside triphosphate of the hepatitis C virus (HCV). Proteolysis for greater fragment of HCV polyprotein; Analysis on the kinetics of ATP binding; Capability to bind with five stress-fluorosulfonylbenzoyladenosine.

• Four rapid antigen tests showed moderate sensitivity (< = 55 %) for SARS-CoV-2. • All tests were able to detect high infectious samples with high reliability (95 %). • Handling of all the assays poses to users to significant risk for contamination. SARS-CoV-2 molecular diagnostics is facing material shortages and long turnaround times due to exponential increase of testing demand. We evaluated the analytic performance and handling of four rapid Antigen Point of Care Tests (AgPOCTs) I-IV (Distributors: (I) Roche, (II) Abbott, (III) MEDsan and (IV) Siemens). 100 RT-PCR negative and 84 RT-PCR positive oropharyngeal swabs were prospectively collected and used to determine performance and accuracy of these AgPOCTs. Handling was evaluated by 10 healthcare workers/users through a questionnaire. The median duration from symptom onset to sampling was 6 days (IQR 2–12 days). The overall respective sensitivity were 49.4 % (CI95 %: 38.9–59.9), 44.6 % (CI95 %: 34.3–55.3), 45.8 % (CI95 %: 35.5–56.5) and 54.9 % (CI95 %: 43.4−65.9) for tests I, II, III and IV, respectively. In the high viral load subgroup (containing >106 copies of SARS-CoV-2 /swab, n = 26), AgPOCTs reached sensitivities of 92.3 % or more (range 92.3 %–100 %). Specificity was 100 % for tests I, II (CI95 %: 96.3–100 for both tests) and IV (CI95 %: 96.3–100) and 97 % (CI95 %: 91.5–98.9) for test III. Regarding handling, test I obtained the overall highest scores, while test II was considered to have the most convenient components. Of note, users considered all assays, with the exception of test I, to pose a significant risk for contamination by drips or spills. Besides some differences in sensitivity and handling, all four AgPOCTs showed acceptable performance in high viral load samples. However, due to the significantly lower sensitivity compared to RT-qPCR, a careful consideration of pro and cons of AgPOCT has to be taken into account before clinical implementation. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to a study conducted on spread of HIV virus in blood of African Americans is presented.

• Clinical performance of five different commercially available automated SARS-CoV-2 antibody tests. • No overlap of "false" positive samples between different serology assays was observed. • The ability to rule out acute SARS-CoV-2 infection at hospital admission with serology is limited. The global market for SARS-CoV-2-immunoassays is becoming ever more crowded with antibody-tests of various formats, targets and technologies, careful evaluation is crucial for understanding the implications of individual test results. Here, we evaluate the clinical performance of five automated immunoassays on a set of clinical samples. Serum/plasma samples of 75 confirmed COVID-19 patients and 320 pre-pandemic serum samples of healthy blood donors were subjected to two IgG and three total antibody SARS-CoV-2-immunoassays. All test setups were automated workflows. Positivity of assays (onset of symptoms > 10 days) ranged between 68.4 % and 81.6 % (Diasorin 68.4 %, Euroimmun 70.3 %, Siemens 73.7 %, Roche 79.0 % and Wantai 81.6 %). All examined assays demonstrated high specificity of >99 % (Euroimmun, Diasorin: 99.1 %, Wantai: 99.4 %) but only two reached levels above 99.5 % (Roche: 99.7 %, Siemens 100 %). Interestingly, there was no overlap in false positive results between the assays. The strongest correlation of quantitative results was observed between the Diasorin and Euroimmun IgG tests (r2 = 0.76). Overall, we observed no difference in the distribution of test results between female and male patients (p-values: 0.18−0.87). A significant difference between severely versus critically ill patients was demonstrated for the Euroimmun, Diasorin, Wantai and Siemens assays (p-values:0.041). All assays showed good clinical performance. Our data confirm that orthogonal test strategies as recommended by the CDC can enhance clinical specificity. However, the suboptimal rates of test positivity found at time of hospitalization in this cohort underline the importance of molecular diagnostics to rule out/confirm active infection with SARS-CoV-2. [ABSTRACT FROM AUTHOR]

The majority of cells with latent human immunodeficiency virus 1 infection are located in lymphoid tissues that are difficult to access. In the current study, we used single-genome near-full-length proviral sequencing to evaluate intact and defective proviruses in blood and lymph node CD4 T cells enriched for specific functional polarizations. We observed minor variations between the frequencies of proviral sequences within individual CD4 T-cell subsets and across tissue compartments. However, we noted multiple clonal clusters of identical intact or defective proviral sequences from distinct compartments and CD4 T-cell subpopulations, suggesting frequent interchanges between viral reservoir cells in blood and tissues. [ABSTRACT FROM AUTHOR]

Single frequency, geometrically symmetric Radio-Frequency (RF) driven atmospheric pressure plasmas exhibit temporally and spatially symmetric patterns of electron heating, and consequently, charged particle densities and fluxes. Using a combination of phase-resolved optical emission spectroscopy and kinetic plasma simulations, we demonstrate that tailored voltage waveforms consisting of multiple RF harmonics induce targeted disruption of these symmetries. This confines the electron heating to small regions of time and space and enables the electron energy distribution function to be tailored. [ABSTRACT FROM AUTHOR]