Comparative analyses of clinical features reveal the severity of human adenovirus type 55 and type 7 in acute respiratory tract infections

Introduction. Human adenovirus (HAdV) is an important pathogen in acute respiratory tract infections (ARTIs) and HAdV genotypes are associated with disease severity. Hypothesis. Comparative analyses of clinical features could reveal the severity of different HAdV genotypes in ARTIs. Aim. This study aimed to investigate the molecular epidemiology of HAdV infections and explore the correlations between clinical features and HAdV genotypes. Methodology. A retrospective study was conducted on ARTIs at Beijing Chao-Yang Hospital during the period 2011–2016. A standardized data form was used to record the clinical information. HAdV was detected by FQ-PCR from respiratory specimens, and genotypes were determined by entire hexon gene sequencing. Results. A total of 8044 samples were collected, of which 296 (3.7 %) were HAdV-positive. Patients ≤44 years old were more likely to be positive for HAdV. There were three peak periods of adenoviral infections, with detection rates of 13.03, 9.39 and 10.38 %, respectively. Six HAdV genotypes (HAdV-55, -7, -3, -14, -50, -2) were identified, with HAdV-55 and HAdV-7 being the most prevalent (50.6 and 21.5 %). Compared with HAdV-7 and other types, patients infected with HAdV-55 had a longer duration of fever (P=0.0428). Infections with HAdV-55 and HAdV-7 were more severe compared to those caused by other types, with higher rates of oxygen therapy and mechanical ventilation (P=0.0172 and P=0.0144). All five deaths were caused by HAdV‐55. Conclusion. This study describes the epidemiological characteristics of HAdV infections in North China, revealing the higher severity of HAdV-55 and HAdV-7 in ARTIs. Thus, strengthened surveillance of HAdV genotypes is warranted.

High-Throughput Screening and Identification of Human Adenovirus Type 5 Inhibitors

Human adenovirus infections can develop into diffuse multi-organ diseases in young children and immunocompromised patients, and severe cases can lead to death. However, there are no approved antiviral drugs available to treat adenovirus diseases. In this study, a chemiluminescence-based, high-throughput screening (HTS) assay was developed and applied to screen human adenovirus 5(HAdV5)inhibitors from 1,813 approved drug library and 556 traditional Chinese medicine-sourced small-molecule compounds. We identified three compounds with in vitro anti-HAdV5 activities in the low-micromolar range (EC50 values 0.3-4.5 μM, selectivity index values 20-300) that also showed inhibitory effects on HAdV3. Cardamomin (CDM) had good anti-HAdV5 activity in vitro. Furthermore, three dilutions of CDM (150, 75, and 37.5 mg/kg/d) administered to BALB/c mouse models inhibited HAdV5-fluc infection at 1 day post-infection by 80% (p < 0.05), 76% (p < 0.05), and 58% (p < 0.05), respectively. HE-staining of pathological tissue sections of mice infected with a wildtype adenoviral strain showed that CDM had a protective effect on tissues, especially in the liver, and greatly inhibited virus-induced necrosis of liver tissue. Thus, CDM inhibits adenovirus replication in vivo and in vitro. This study established a high-throughput screening method for anti-HAdV5 drugs and demonstrated CDM to be a candidate for HAdV5 therapy, potentially providing a new treatment for patients infected with adenoviruses.

Human Adenovirus Species D Interactions with Corneal Stromal Cells

Notable among the many communicable agents known to infect the human cornea is the human adenovirus, with less than ten adenoviruses having corneal tropism out of more than 100 known types. The syndrome of epidemic keratoconjunctivitis (EKC), caused principally by human adenovirus, presents acutely with epithelial keratitis, and later with stromal keratitis that can be chronic and recurrent. In this review, we discuss the current state of knowledge regarding the molecular biology of adenovirus infection of corneal stromal cells, among which the fibroblast-like keratocyte is the most predominant, in order to elucidate basic pathophysiologic mechanisms of stromal keratitis in the human patient with EKC.

Core-Shell Imprinted Particles for Adenovirus Binding

Virus-imprinted polymers were synthesized via surface imprinting strategies to produce core-shell imprinted particles selective for human adenovirus type 5. High binding affinity of the target virus towards the resulting imprinted layer was confirmed and unspecific binding was reduced in presence of blocking agents, i.e., via bovine serum albumin and skim milk in combination with Tween 20. In addition, the imprinted materials were applied for adenovirus extraction from cell culture supernatants. High levels of virus binding with negligible binding of matrix proteins confirmed the suitability of these materials for binding and extraction of the target virus from complex matrices.

A Recombinant Human Adenovirus Type 5 (H101) Combined With Chemotherapy for Advanced Gastric Carcinoma: A Retrospective Cohort Study

BackgroundThis retrospective cohort study aimed to evaluate the clinical outcomes of H101 combined with chemotherapy for advanced gastric carcinoma (GC) patients.MethodsThe advanced GC patients, who were treated with H101 and/or chemotherapy, were enrolled and divided into three groups according to treatment method. The clinical characteristics of patients, clinical short-term and long-term outcomes, followed up, and complication were analyzed.ResultsA total of 95 patients (30 patients in group A were treated with H101, 33 in group B patients were treated with chemotherapy, 32 patients in group C were treated with H101 combined with chemotherapy) were retrospectively reviewed. The disease control rate (DCR) and overall response rate (ORR) were significantly greater in group C (81.3% and 50.0%) than in groups A (63.3% and 30.0%) and B (66.7% and 33.3%, all p < 0.05). The 1- and 2-year survival rates and progression-free survival were significantly greater in group C than in groups A and B (all p < 0.05). There was no significant difference in complication among the three groups. At dose levels of 0.5 × 1012 vp/day, 1.0 × 1012 vp/day, and 1.5 × 1012 vp/day, complications were not increased as increased of dose.ConclusionsH101 combined with chemotherapy may be a potential therapeutic option for patients with advanced GC, and prospective studies with proper assessment of toxicity will be needed in the future.

Human Adenovirus Type 5 Infection Leads to Nuclear Envelope Destabilization and Membrane Permeability Independently of Adenovirus Death Protein

The human adenovirus type 5 (HAdV5) infects epithelial cells of the upper and lower respiratory tract. The virus causes lysis of infected cells and thus enables spread of progeny virions to neighboring cells for the next round of infection. The mechanism of adenovirus virion egress across the nuclear barrier is not known. The human adenovirus death protein (ADP) facilitates the release of virions from infected cells and has been hypothesized to cause membrane damage. Here, we set out to answer whether ADP does indeed increase nuclear membrane damage. We analyzed the nuclear envelope morphology using a combination of fluorescence and state-of-the-art electron microscopy techniques, including serial block-face scanning electron microscopy and electron cryo-tomography of focused ion beam-milled cells. We report multiple destabilization phenotypes of the nuclear envelope in HAdV5 infection. These include reduction of lamin A/C at the nuclear envelope, large-scale membrane invaginations, alterations in double membrane separation distance and small-scale membrane protrusions. Additionally, we measured increased nuclear membrane permeability and detected nuclear envelope lesions under cryoconditions. Unexpectedly, and in contrast to previous hypotheses, ADP did not have an effect on lamin A/C reduction or nuclear permeability.