Differential Trends in the Codon Usage Patterns in HIV-1 Genes

Host-pathogen interactions underlie one of the most complex evolutionary phenomena resulting in continual adaptive genetic changes, where pathogens exploit the host's molecular resources for growth and survival, while hosts try to eliminate the pathogen. Deciphering the molecular basis of host–pathogen interactions is useful in understanding the factors governing pathogen evolution and disease propagation. In host-pathogen context, a balance between mutation, selection, and genetic drift is known to maintain codon bias in both organisms. Studies revealing determinants of the bias and its dynamics are central to the understanding of host-pathogen evolution. We considered the Human Immunodeficiency Virus (HIV) type 1 and its human host to search for evolutionary signatures in the viral genome. Positive selection is known to dominate intra-host evolution of HIV-1, whereas high genetic variability underlies the belief that neutral processes drive inter-host differences. In this study, we analyze the codon usage patterns of HIV-1 genomes across all subtypes and clades sequenced over a period of 23 years. We show presence of unique temporal correlations in the codon bias of three HIV-1 genes illustrating differential adaptation of the HIV-1 genes towards the host preferred codons. Our results point towards gene-specific translational selection to be an important force driving the evolution of HIV-1 at the population level

IFITM proteins inhibit HIV-1 protein synthesis

Interferon induced transmembrane proteins (IFITMs) inhibit the cellular entry of a broad range of viruses, but it has been suspected that for HIV-1 IFITMs may also inhibit a post-integration replicative step. We show that IFITM expression reduces HIV-1 viral protein synthesis by preferentially excluding viral mRNA transcripts from translation and thereby restricts viral production. Codon-optimization of proviral DNA rescues viral translation, implying that IFITM-mediated restriction requires recognition of viral RNA elements. In addition, we find that expression of the viral accessory protein Nef can help overcome the IFITM-mediated inhibition of virus production. Our studies identify a novel role for IFITMs in inhibiting HIV replication at the level of translation, but show that the effects can be overcome by the lentiviral protein Nef.Wellcome Trust-University of Edinburgh Institutional Strategic Support Fun

Brain Natriuretic Peptide mediates the prognostic role of renal function toward 10-year cardiovascular mortality in patients with Acute Coronary Syndrome: the HHF study (2006–2016)

Background/Introduction: Risk stratification in chronic heart failure (HF) remains a challenge. Renal function and B-natriuretic peptide (BNP) might confer predictive value towards long-term mortality in HF patients after an acute coronary syndrome (ACS). Methods: From May 2006 to March 2009, 1,000 consecutive patients who were hospitalized with ACS diagnosis were enrolled in the study. In 2016, the 10-year follow-up (2006 -2016) was performed in 745 participants. GFR was evaluated through the MDRD formula. HF phenotype was defined according to baseline ejection fraction (EF); HF with reduced EF (i.e. <40%) (HFrEF), preserved EF (i.e. ≥50%) (HFpEF) and mid-range EF (i.e. 40 –49%) (HFmrEF). Results: 10-year mortality was 21%. Deceased patients presented significantly lower GFR and higher BNP values at the baseline, compared with their alive counterparts (p < 0.001 for both). By multivariable logistic regression analysis, GFR independently predicted all-cause mortality (OR = 0.98, p = 0.04). After adjusting for baseline BNP, GFR lost its predictive role while BNP was independently associated with 10-year mortality (OR = 1.39 for a 2-fold increase, p = 0.001). A significant interaction was observed between EF and BNP levels on the tested outcome (p for interaction < 0.001). In stratified analysis, BNP predicted all cause death only in HFmrEF (OR=1.43, p = 0.04) and in HFpEF (OR=1.80, p = 0.01). Conclusion: BNP mediates the predictive role of GFR towards long-term mortality in ACS-induced HF patients with retained systolic performance of the left ventricle (HFmrEF and HFpEF). © 2017 Hellenic Society of Cardiolog

Effectiveness and Safety of Micafungin in Managing Invasive Fungal Infections among Patients in Greece with Hematologic Disorders: The ASPIRE Study

Introduction: Invasive candidiasis (IC) can be a life-threatening infection in immunocompromised patients, particularly those with cancer, hematologic diseases and/or hematopoietic stem cell transplantation (HSCT) recipients. The objective of this study was to evaluate the effectiveness of micafungin in patients with hematologic malignancies or HSCT recipients, relevant to clinical presentation of IC, in real-life practice in Greece. Methods: ASPIRE was a phase IV, multicenter, non-interventional, prospective cohort study, conducted at ten tertiary hospitals in Greece, in adults with hematologic disease. Micafungin treatment for IC or prophylaxis for Candida infection was administered per standard clinical practice until a clinical outcome (success or failure) was reached. Treatment success was defined by the EORTC/MSG criteria for invasive fungal infections (IFI) and was assessed by the investigator. Treatment discontinuation and safety were also evaluated. Results: One hundred forty-three patients were enrolled. Median age was 62; 85 (59.4%) patients were male, and 133 (93.0%) had Greek ethnicity. One hundred twenty-six (88.1%) patients had hematologic malignancies, and 21 (14.7%) had received HSCT. Prophylaxis was administered to 74 (51.7%) patients [median (range) dose: 50 (50–150) mg/day] with no signs of IFI. Overall, 52 (36.4%) patients with possible IFI at baseline received micafungin treatment [100 (50–125) mg/day] versus 12 (17.2%) with probable [100 (75–150) mg/day] and 5 (3.5%) with confirmed [125 (100–150) mg/day] IFI. Treatment success was 91.6% (95% CI 85.80–95.59; n = 131) overall and 90.5% (n = 67) in patients receiving prophylaxis. Median time on treatment was 13 days. Treatment discontinuation (n = 26; 18.2%) was not related to adverse events. No treatment-related serious adverse events were reported. Conclusion: Micafungin treatment for IC or prophylaxis for Candida infection was effective and well tolerated in patients with hematologic disorders in clinical practice in Greece. These results demonstrate that micafungin could be used more widely for prophylaxis. Further work is required to determine the efficacy and safety of micafungin for the management of IFIs in hematologic settings. Funding: Astellas Pharma Inc. © 2019, The Author(s)

Pseudomonas aeruginosa bacteraemia in patients with hematologic malignancies: risk factors, treatment and outcome

Our aims were to identify factors associated with Pseudomonas aeruginosa (PA) bloodstream infection (BSI) in patients with hematological malignancies and evaluate the outcome of the affected patients. Consecutive patients with hematological malignancies who developed PA BSI were identified. Subsequently, two case–control studies were performed to evaluate the risk factors (i) for PA BSI and (ii) for carbapenem resistant (CR) PA BSI. Patients' outcome was evaluated at 28 days after the onset of bacteraemia. A total of 64 patients with PA BSI (45 caused by CS and 19 by CR organisms) and 128 without PA BSI were enrolled. Patients with rapidly fatal disease, steroid use, neutropenia or prior surgery were more likely to develop PA BSI, whereas patients with previous hospitalization and prior use of fluoroquinolones were more likely to develop CR PA BSI. The 28-day mortality rate was 35.9%. Severity of sepsis was the only independent predictor of adverse outcome. © 2017 Elsevier Inc

Carbapenemase-producing Klebsiella pneumoniae bloodstream infections in neutropenic patients with haematological malignancies or aplastic anaemia: Analysis of 50 cases

Carbapenemase-producing Klebsiella pneumoniae (CP-Kp) are currently among the most important nosocomial pathogens in many geographic regions. A retrospective study was conducted between 2010 and 2014 in four hospitals located in a high-prevalence area (Athens, Greece) to describe the clinical features, treatment and outcomes of neutropenic patients with haematological diseases complicated with CP-Kp bloodstream infections. A total of 50 patients were identified, including 48 with haematological malignancies and 2 with aplastic anaemia. All patients had neutropenia (<500 cells/mm3), of whom 40 had <100 neutrophils/mm3. The probable source of bacteraemia was identified in 9 patients; in the remaining 41 patients the bacteraemia was considered primary. For definitive treatment, 30 patients received combination therapy (two or more active drugs), 10 received monotherapy (one active drug) and 4 received therapy with no active drug; the remaining 6 patients died within 48 h after the onset of bacteraemia. The 14-day all-cause mortality rate was 50%, 38% and 33% for those who received one, two or three active drugs respectively. In the Cox proportional hazards model, unresolved neutropenia [hazard ratio (HR) = 19.28, 95% confidence interval (CI) 2.31-160.69; P = 0.006], septic shock (HR = 3.04, 95% CI 1.06-8.78; P = 0.04) and treatment with one active drug (HR for monotherapy versus combination therapy = 3.95, 95% CI 1.23-12.65; P = 0.02) were independent predictors of death, whilst combination therapy was associated with lower mortality. These findings may assist physicians in making treatment decisions for neutropenic patients with CP-Kp infections. © 2016 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved