Documents published in Scipedia

• The Effect of Latency Reversal Agents on Primary CD8 + T Cells: Implications for Shock and Kill Strategies for Human Immunodeficiency Virus Eradication

  V. Walker-Sperling, C. Pohlmeyer, P. Tarwater, J. Blankson

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Shock and kill strategies involving the use of small molecules to induce viral transcription in resting CD4 + T cells (shock) followed by immune mediated clearance of the reactivated cells (kill), have been proposed as a method of eliminating latently infected CD4 + T cells. The combination of the histone deacetylase (HDAC) inhibitor romidepsin and protein kinase C (PKC) agonist bryostatin-1 is very effective at reversing latency in vitro. However, we found that primary HIV-1 specific CD8 + T cells were not able to eliminate autologous resting CD4 + T cells that had been reactivated with these drugs. We tested the hypothesis that the drugs affected primary CD8 + T cell function and found that both agents had inhibitory effects on the suppressive capacity of HIV-specific CD8 + T cells from patients who control viral replication without antiretroviral therapy (elite suppressors/controllers). The inhibitory effect was additive and multi-factorial in nature. These inhibitory effects were not seen with prostratin, another PKC agonist, either alone or in combination with JQ1, a bromodomain-containing protein 4 inhibitor. Our results suggest that because of their adverse effects on primary CD8 + T cells, some LRAs may cause immune-suppression and therefore should be used with caution in shock and kill strategies.

  Abstract
  Shock and kill strategies involving the use of small molecules to induce viral transcription in resting CD4 + T cells (shock) followed by immune mediated clearance of the [...]

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• LEDGIN-mediated Inhibition of Integrase–LEDGF/p75 Interaction Reduces Reactivation of Residual Latent HIV

  L. Vranckx, J. Demeulemeester, S. Saleh, A. Boll, G. Vansant, R. Schrijvers, C. Weydert, E. Battivelli, E. Verdin, A. Cereseto, F. Christ, R. Gijsbers, Z. Debyser

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Persistence of latent, replication-competent Human Immunodeficiency Virus type 1 (HIV-1) provirus is the main impediment towards a cure for HIV/AIDS (Acquired Immune Deficiency Syndrome). Therefore, different therapeutic strategies to eliminate the viral reservoirs are currently being explored. We here propose a novel strategy to reduce the replicating HIV reservoir during primary HIV infection by means of drug-induced retargeting of HIV integration. A novel class of integration inhibitors, referred to as LEDGINs, inhibit the interaction between HIV integrase and the LEDGF/p75 host cofactor, the main determinant of lentiviral integration site selection. We show for the first time that LEDGF/p75 depletion hampers HIV-1 reactivation in cell culture. Next we demonstrate that LEDGINs relocate and retarget HIV integration resulting in a HIV reservoir that is refractory to reactivation by different latency-reversing agents. Taken together, these results support the potential of integrase inhibitors that modulate integration site targeting to reduce the likeliness of viral rebound.

  Abstract
  Persistence of latent, replication-competent Human Immunodeficiency Virus type 1 (HIV-1) provirus is the main impediment towards a cure for HIV/AIDS (Acquired Immune Deficiency [...]

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• What Lies Beneath: Antibody Dependent Natural Killer Cell Activation by Antibodies to Internal Influenza Virus Proteins

  H. Vanderven, F. Ana-Sosa-Batiz, S. Jegaskanda, S. Rockman, K. Laurie, I. Barr, W. Chen, B. Wines, P. Hogarth, T. Lambe, S. Gilbert, M. Parsons, S. Kent

  Collection of EBioMedicine (2017).

  
  

  Abstract

  The conserved internal influenza proteins nucleoprotein (NP) and matrix 1 (M1) are well characterised for T cell immunity, but whether they also elicit functional antibodies capable of activating natural killer (NK) cells has not been explored. We studied NP and M1-specific ADCC activity using biochemical, NK cell activation and killing assays with plasma from healthy and influenza-infected subjects. Healthy adults had antibodies to M1 and NP capable of binding dimeric FcγRIIIa and activating NK cells. Natural symptomatic and experimental influenza infections resulted in a rise in antibody dependent NK cell activation post-infection to the hemagglutinin of the infecting strain, but changes in NK cell activation to M1 and NP were variable. Although antibody dependent killing of target cells infected with vaccinia viruses expressing internal influenza proteins was not detected, opsonising antibodies to NP and M1 likely contribute to an antiviral microenvironment by stimulating innate immune cells to secrete cytokines early in infection. We conclude that effector cell activating antibodies to conserved internal influenza proteins are common in healthy and influenza-infected adults. Given the significance of such antibodies in animal models of heterologous influenza infection, the definition of their importance and mechanism of action in human immunity to influenza is essential.

  Abstract
  The conserved internal influenza proteins nucleoprotein (NP) and matrix 1 (M1) are well characterised for T cell immunity, but whether they also elicit functional antibodies [...]

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• Catecholamines Facilitate Fuel Expenditure and Protect Against Obesity via a Novel Network of the Gut-Brain Axis in Transcription Factor Skn-1 -deficient Mice

  S. Ushiama, Y. Ishimaru, M. Narukawa, M. Yoshioka, C. Kozuka, N. Watanabe, M. Tsunoda, N. Osakabe, T. Asakura, H. Masuzaki, K. Abe

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Taste signals and nutrient stimuli sensed by the gastrointestinal tract are transmitted to the brain to regulate feeding behavior and energy homeostasis. This system is referred to as the gut-brain axis. Here we show that both brush cells and type II taste cells are eliminated in the gastrointestinal tract of transcription factor Skn-1 knockout (KO) mice. Despite unaltered food intake, Skn-1 KO mice have reduced body weight with lower body fat due to increased energy expenditure. In this model, 24-h urinary excretion of catecholamines was significantly elevated, accompanied by increased fatty acid β-oxidation and fuel dissipation in skeletal muscle and impaired insulin secretion driven by glucose. These results suggest the existence of brain-mediated energy homeostatic pathways originating from brush cells and type II taste cells in the gastrointestinal tract and ending in peripheral tissues, including the adrenal glands. The discovery of food-derived factors that regulate these cells may open new avenues the treatment of obesity and diabetes. Taste signals and nutrient stimuli sensed by the gastrointestinal tract are transmitted to the brain to regulate feeding behavior and energy homeostasis along the gut-brain axis. We propose the concept that taste-receiving cells in the oral cavity and/or food-borne chemicals-receiving brush cells in the gut are involved in regulation of the body weight and adiposity via the brain. The discovery of food-derived factors that regulate these cells may open new avenues for the treatment of obesity and diabetes.

  Abstract
  Taste signals and nutrient stimuli sensed by the gastrointestinal tract are transmitted to the brain to regulate feeding behavior and energy homeostasis. This system is referred [...]

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• Low Circulating Amino Acids and Protein Quality: An Interesting Piece in the Puzzle of Early Childhood Stunting

  R. Uauy, D. Suri, S. Ghosh, A. Kurpad, I. Rosenberg

  Collection of EBioMedicine (2017).

  
  

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• A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics

  K. Tschapalda, Y. Zhang, L. Liu, K. Golovnina, T. Schlemper, T. Eichmann, M. Lal-Nag, U. Sreenivasan, J. McLenithan, S. Ziegler, C. Sztalryd, A. Lass, D. Auld, B. Oliver, H. Waldmann, Z. Li, M. Shen, M. Boxer, M. Beller

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Excess lipid storage is an epidemic problem in human populations. Thus, the identification of small molecules to treat or prevent lipid storage-related metabolic complications is of great interest. Here we screened > 320.000 compounds for their ability to prevent a cellular lipid accumulation phenotype. We used fly cells because the multifarious tools available for this organism should facilitate unraveling the mechanism-of-action of active small molecules. Of the several hundred lipid storage inhibitors identified in the primary screen we concentrated on three structurally diverse and potent compound classes active in cells of multiple species (including human) and negligible cytotoxicity. Together with Drosophila in vivo epistasis experiments, RNA-Seq expression profiles suggested that the target of one of the small molecules was diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in the production of triacylglycerols and prominent human drug target. We confirmed this prediction by biochemical and enzymatic activity tests.

  Abstract
  Excess lipid storage is an epidemic problem in human populations. Thus, the identification of small molecules to treat or prevent lipid storage-related metabolic complications [...]

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• A Nexus Consisting of Beta-Catenin and Stat3 Attenuates BRAF Inhibitor Efficacy and Mediates Acquired Resistance to Vemurafenib

  T. Sinnberg, E. Makino, M. Krueger, A. Velic, B. Macek, U. Rothbauer, N. Groll, O. Pötz, S. Czemmel, H. Niessner, F. Meier, K. Ikenberg, C. Garbe, B. Schittek

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Acquired resistance to second generation BRAF inhibitors (BRAFis), like vemurafenib is limiting the benefits of long term targeted therapy for patients with malignant melanomas that harbor BRAF V600 mutations. Since many resistance mechanisms have been described, most of them causing a hyperactivation of the MAPK- or PI3K/AKT signaling pathways, one potential strategy to overcome BRAFi resistance in melanoma cells would be to target important common signaling nodes. Known factors that cause secondary resistance include the overexpression of receptor tyrosine kinases (RTKs), alternative splicing of BRAF or the occurrence of novel mutations in MEK1 or NRAS. In this study we show that β-catenin is stabilized and translocated to the nucleus in approximately half of the melanomas that were analyzed and which developed secondary resistance towards BRAFi. We further demonstrate that β-catenin is involved in the mediation of resistance towards vemurafenib in vitro and in vivo . Unexpectedly, β-catenin acts mainly independent of the TCF/LEF dependent canonical Wnt-signaling pathway in resistance development, which partly explains previous contradictory results about the role of β-catenin in melanoma progression and therapy resistance. We further demonstrate that β-catenin interacts with Stat3 after chronic vemurafenib treatment and both together cooperate in the acquisition and maintenance of resistance towards BRAFi.

  Abstract
  Acquired resistance to second generation BRAF inhibitors (BRAFis), like vemurafenib is limiting the benefits of long term targeted therapy for patients with malignant melanomas [...]

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• Diagnostic Performance of Bronchoalveolar Lavage Fluid CD4/CD8 Ratio for Sarcoidosis: A Meta-analysis

  Y. Shen, C. Pang, Y. Wu, D. Li, C. Wan, Z. Liao, T. Yang, L. Chen, F. Wen

  Collection of EBioMedicine (2017).

  
  

  Abstract

  The usefulness of bronchoalveolar lavage fluid (BALF) CD4/CD8 ratio for diagnosing sarcoidosis has been reported in many studies with variable results. Therefore, we performed a meta-analysis to estimate the overall diagnostic accuracy of BALF CD4/CD8 ratio based on the bulk of published evidence. Studies published prior to June 2015 and indexed in PubMed, OVID, Web of Science, Scopus and other databases were evaluated for inclusion. Data on sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were pooled from included studies. Summary receiver operating characteristic (SROC) curves were used to summarize overall test performance. Deekss funnel plot was used to detect publication bias. Sixteen publications with 1885 subjects met our inclusion criteria and were included in this meta-analysis. Summary estimates of the diagnostic performance of the BALF CD4/CD8 ratio were as follows: sensitivity, 0.70 (95%CI 0.64–0.75), specificity, 0.83 (95%CI 0.78–0.86), PLR, 4.04 (95%CI 3.13–5.20), NLR, 0.36 (95%CI 0.30–0.44), and DOR, 11.17 (95%CI 7.31–17.07). The area under the SROC curve was 0.84 (95%CI 0.81–0.87). There was no evidence of publication bias. Measuring the BALF CD4/CD8 ratio may assist in the diagnosis of sarcoidosis when interpreted in parallel with other diagnostic factors.

  Abstract
  The usefulness of bronchoalveolar lavage fluid (BALF) CD4/CD8 ratio for diagnosing sarcoidosis has been reported in many studies with variable results. Therefore, we performed [...]

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• Ethnicity matters: A Systematic Review and Meta-Analysis of the Non-Linear Relationship Between Alcohol Consumption and Prevalence and Incidence of Hepatic Steatosis

  M. Roerecke, R. Nanau, J. Rehm, M. Neuman

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Fatty liver (hepatic steatosis) is one of the most common diseases globally, with increasing prevalence. The role of alcohol consumption in the development of hepatic steatosis has not been systematically examined. We searched Medline, Embase, and ProQuest Dissertations & Theses Global for original data on the relationship between alcohol consumption and hepatic steatosis measured by non-invasive imagery, excluding studies conducted in participants < 18 years, or subgroups related to viral and drug-induced liver disease. We identified 18 articles reporting adjusted data (Japan = 11, other high-income countries = 7). Random-effect categorical meta-analyses (< 20 g/day pure alcohol consumption vs non-drinkers) and dose-response meta-analyses for the whole range of alcohol consumption were conducted. In total, 99, 370 participants and 25, 662 cases of hepatic steatosis were included. In Japan, low alcohol consumption was consistently associated with substantially reduced incidence and prevalence of hepatic steatosis compared to non-drinkers (RR for < 20 g pure alcohol/day = 0.75, 95% CI: 0.71–0.79, I2 = 0%). No overall association was found in other countries (RR = 1.05, 95% CI: 0.86–1.30, I2 = 84%). Dose-response analyses in Japan (up to 80 g/day) showed an inverse relationship in men and a J-shape in women. Alcohol consumption showed a complex association with hepatic steatosis with substantial differences by ethnicity and sex. Low alcohol consumption was beneficial in Japan with good epidemiological evidence, whereas there was no association in other countries. However, heterogeneity was large in countries other than Japan. More and higher quality research in diverse ethnic populations is needed to further clarify this relationship.

  Abstract
  Fatty liver (hepatic steatosis) is one of the most common diseases globally, with increasing prevalence. The role of alcohol consumption in the development of hepatic steatosis [...]

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• One of the immune activation profiles observed in HIV-1-infected adults with suppressed viremia is linked to metabolic syndrome: The ACTIVIH study

  C. Psomas, M. Younas, C. Reynes, R. Cezar, P. Portalès, E. Tuaillon, A. Guigues, C. Merle, N. Atoui, C. Fernandez, V. Moing, C. Barbuat, G. Marin, N. Nagot, A. Sotto, J. Eliaou, R. Sabatier, J. Reynes, P. Corbeau

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Immune activation in HIV-1-infected individuals is reduced under antiretroviral therapies, but persists, resulting in various morbidities. To better characterize this phenomenon, using a panel of 68 soluble and cell surface markers, we measured the level of activation in circulating CD4+ and CD8+ T cells, B cells, monocytes, NK cells, polynuclear and endothelial cells as well as of inflammation and fibrinolysis in 120 virologic responders over 45 years of age. As compared with age- and sex-matched uninfected individuals, we observed a persistence of activation in all the cell subpopulations analyzed, together with marks of inflammation and fibrinolysis. Two independent hierarchical clustering analyses allowed us to identify five clusters of markers that varied concurrently, and five patient groups, each with the same activation profile. The five groups of patients could be characterized by a marker of CD4+ T cell, CD8+ T cell, NK cell, monocyte activation or of inflammation, respectively. One of these profiles was strongly associated with marks of metabolic syndrome, particularly with hyperinsulinemia (OR 12.17 [95% CI 1.79–82.86], p = 0.011). In conclusion, our study unveils biomarkers linked to metabolic syndrome that could be tested as predictive markers, and opens the way to new therapeutic approaches tailored to each patient group.

  Abstract
  Immune activation in HIV-1-infected individuals is reduced under antiretroviral therapies, but persists, resulting in various morbidities. To better characterize this phenomenon, [...]

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