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Adenovirus infections [keywords]
- Ganciclovir Inhibits Human Adenovirus Replication and Pathogenicity in Permissive Immunosuppressed Syrian Hamsters. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2014 Sep 15.
Adenovirus infections of immunocompromised patients can develop into deadly multi-organ or systemic disease. The virus is especially threatening for pediatric allogeneic hematopoietic stem cell transplant recipients; according to some studies, 10% or more of these patients succumb to disease resulting from adenovirus infection. At present, there is no drug approved for treatment or prevention of adenovirus infections. Compounds that are approved to treat other virus infections are used off-label to combat adenovirus, but only anecdotal evidence exists as to the efficacy of these drugs. Ganciclovir, a drug approved for the treatment of herpesvirus infection, was reported previously to be effective against human adenoviruses in vitro. To model adenovirus infections in immunocompromised humans, we examined ganciclovir's efficacy in immunosuppressed Syrian hamsters intravenously infected with type 5 human adenovirus (Ad5). This animal model is permissive for Ad5 replication, and develops symptoms similar to those seen in humans. We demonstrate that ganciclovir suppresses Ad5 replication in the liver of infected hamsters, and that it mitigates the consequences of Ad5 infections in these animals when administered prophylactically or therapeutically. We show that ganciclovir inhibits Ad5 DNA synthesis and late gene expression. The mechanism of action for the drug is not clear; preliminary data suggest that it exerts its anti-adenoviral effect by directly inhibiting the adenoviral DNA polymerase. While more extensive studies are required, we believe that ganciclovir is a promising drug candidate to treat adenovirus infections. Brincidofovir, a drug with proven activity against Ad5 was used as a positive control in the prophylactic experiment.
- The use of a multiplex real-time PCR assay for diagnosing acute respiratory viral infections in children attending an emergency unit. [JOURNAL ARTICLE]
- J Clin Virol 2014 Sep 3.
The use of a multiplex molecular technique to identify the etiological pathogen of respiratory viral infections might be a support as clinical signs are not characteristic.The aim of the study was to evaluate a multiplex molecular real-time assay for the routine diagnosis of respiratory viruses, to analyze the symptoms associated with the pathogens detected and to determine the spread of virus during the period.Respiratory samples were collected from children presenting with respiratory symptoms and attending the emergency unit during the 2010-2011 winter seasons. Samples were tested with the multiplex RespiFinder(®) 15 assay (PathoFinder™) which potentially detects 15 viruses.857 (88.7%) of the 966 samples collected from 914 children were positive for one (683 samples) or multiple viruses (174 samples). The most prevalent were the respiratory syncytial virus (39.5%) and the rhinovirus (24.4%). Influenza viruses were detected in 139 (14.4%) samples. Adenovirus was detected in 93 (9.6%) samples, coronaviruses in 88 (9.1%), metapneumovirus in 51 (5.3%) and parainfluenzae in 47 (4.9%). Rhinovirus (40%) was the most prevalent pathogen in upper respiratory tract infections while respiratory syncytial virus (49.9%) was the most prevalent in lower respiratory tract infections. Co-infections were associated with severe respiratory symptoms.The multiplex assay detected clinically important viruses in a single genomic test and thus will be useful for detecting several viruses causing respiratory tract disorders.
- Sheep Lung Segmental Delivery Strategy Demonstrates Adenovirus Priming of Local Lung Responses to Bacterial LPS and the Role of Elafin as a Response Modulator. [JOURNAL ARTICLE]
- PLoS One 2014; 9(9):e107590.
Viral lung infections increase susceptibility to subsequent bacterial infection. We questioned whether local lung administration of recombinant adenoviral vectors in the sheep would alter the susceptibility of the lung to subsequent challenge with bacterial lipopolysaccharide (LPS). We further questioned whether local lung expression of elafin, a locally produced alarm anti-LPS/anti-bacterial molecule, would modulate the challenge response. We established that adenoviral vector treatment primed the lung for an enhanced response to bacterial LPS. Whereas this local effect appeared to be independent of the transgene used (Ad-o-elafin or Ad-GFP), Ad-o-elafin treated sheep demonstrated a more profound lymphopenia in response to local lung administration of LPS. The local influence of elafin in modulating the response to LPS was restricted to maintaining neutrophil myeloperoxidase activity, and levels of alveolar macrophage and neutrophil phagocytosis at higher levels post-LPS. Adenoviral vector-bacterial synergism exists in the ovine lung and elafin expression modulates such synergism both locally and systemically.
- Symptomatic and asymptomatic respiratory viral infections in the first year of life: Association with acute otitis media development. [JOURNAL ARTICLE]
- Clin Infect Dis 2014 Sep 9.
Sensitive diagnostic assays have increased the detection of viruses in asymptomatic individuals. The clinical significance of asymptomatic respiratory viral infection in infants is unknown. High-throughput, quantitative PCR assays were used to detect 13 common respiratory viruses from nasopharyngeal specimens collected during 2028 visits from 362 infants followed from near birth up to 12 months of age. Specimens were collected at monthly interval (months 1-6 and month 9) and during upper respiratory tract infection (URI) episodes. Subjects were followed closely for acute otitis media (AOM) development. Viruses were detected in 76% of 394 URI specimens and 27% of asymptomatic monthly specimens. Rhinovirus was detected most often; multiple viruses were detected in 29% of the specimens. Generalized mixed model analyses associated symptoms with increasing age and female gender; detection of RSV, influenza, rhinovirus, metapneumovirus, and adenovirus were highly associated with symptoms. Increasing age was also associated with multiple virus detection. Overall, 403 asymptomatic viral infections in 237 infants were identified. Viral load was significantly higher in URI specimens than asymptomatic specimens but did not differentiate cases of URI with and without AOM complication. The rate of AOM complicating URI was 27%; no AOM occurred following asymptomatic viral infections. AOM development was associated with increasing age and infection with RSV, rhinovirus, enterovirus, adenovirus and bocavirus. Compared to symptomatic infection, asymptomatic viral infection in infants is associated with young age, male gender, low viral load, specific viruses and single virus detection. Asymptomatic viral infection did not result in AOM.
- Differential expression of THELPER 1 cytokines upon antigen stimulation predicts ex vivo proliferative potential and cytokine production of virus-specific T cells following re-stimulation. [JOURNAL ARTICLE]
- Transpl Infect Dis 2014 Sep 9.
Cytomegalovirus (CMV) and human adenovirus (ADV) infections are causes of morbidity after stem cell transplantation. Antigen (Ag)-specific T cells are essential for the control of viral infections. However, in vivo expansion potential of T-cell subpopulations is hardly predictable in humans. Furthermore, ex vivo identification of human T cells with repopulating capacity for adoptive T-cell transfer has been difficult.We analyzed Ag-specific T-cell populations, subdivided according to the expression of different THELPER- 1 (Th1) cytokines. Isolation by flow cytometry was based on interferon-gamma (IFN)-γ, interleukin (IL)-2, or tumor necrosis factor-alpha (TNF-α) secretion of T cells after ex vivo stimulation with the Ags hexon (for ADV) and pp65 (for CMV). Isolated T cells were expanded and examined for functional characteristics, expansion/differentiation potential, and naïve, effector memory, central memory, and late effector phenotypes.Isolation based on IFN-γ production provides a T-cell population with a mixture of early, central memory, and effector memory T cells, high expansion potential, and effective cytokine production. Selection of T cells with Ag-specific expression of IL-2 or TNF-α, however, results in a T-cell population with reduced proliferation and lower effector potential after expansion.We conclude that the exclusive secretion of IFN-γ in the human antiviral T-cell responses preferentially leads to higher repopulation capacities of antiviral T cells, compared to IL-2 or TNF-α secreting T-cell populations.
- Preferential infection of human Ad5-specific CD4 T cells by HIV in Ad5 naturally exposed and recombinant Ad5-HIV vaccinated individuals. [JOURNAL ARTICLE]
- Proc Natl Acad Sci U S A 2014 Sep 2.
Efficacy trials of adenovirus 5-vectored candidate HIV vaccines [recombinant Ad5 (rAd5)-HIV] were halted for futility due to lack of vaccine efficacy and unexpected excess HIV infections in the vaccine recipients. The potential immunologic basis for these observations is unclear. We comparatively evaluated the HIV susceptibility and phenotypes of human CD4 T cells specific to Ad5 and CMV, two viruses that have been used as HIV vaccine vectors. We show that Ad5-specific CD4 T cells, either induced by natural Ad5 exposure or expanded by rAd5 vaccination, are highly susceptible to HIV in vitro and are preferentially lost in HIV-infected individuals compared with CMV-specific CD4 T cells. Further investigation demonstrated that Ad5-specific CD4 T cells selectively display a proinflammatory Th17-like phenotype and express macrophage inflammatory protein 3α and α4β7 integrin, suggestive of gut mucosa homing potential of these cells. Analysis of HIV p24 and cytokine coexpression using flow cytometry revealed preferential infection of IL-17- and IL-2-producing, Ad5-specific CD4 T cells by HIV in vitro. Our data suggest a potential mechanism explaining the excess HIV infections in vaccine recipients after rAd5-HIV vaccination and highlight the importance of testing the HIV susceptibility of vaccine-generated, vector and insert-specific CD4 T cells in future HIV vaccine studies.
- A 5-year study of adenoviruses causing conjunctivitis in Izmir, Turkey. [JOURNAL ARTICLE]
- J Med Virol 2014 Sep 7.
Adenoviruses are a common cause of conjunctivitis. Genotypes are diverse and differ according to population and geographical distribution of the virus. There is limited data regarding ocular adenoviral infections and genotype distribution in Turkey. This study aimed to determine the adenovirus genotypes and their epidemiological features among patients with conjunctivitis between 2006 and 2010, in Izmir, Turkey. Adenoviral DNA was detected by PCR in 213 of 488 (44%) of the ocular samples collected from patients with viral conjunctivitis during the 5-year study period. Of these, 101 (47%) were randomly chosen and genotyped by sequence analysis. Seven genotypes were identified, including 3, 4, 8, 11, 19, 37, and 53. Genotype 8 and 4 were the dominant types detected in 67 (66.3%) and 25 (24.7%) of the samples, respectively. Other five genotypes (3, 11, 19, 37, 53) were detected in 9 (8.9%) samples. Genotype and seasonal differences observed throughout the study. Human adenoviruse (HAdV)-8 was the most frequent type, except 2008. The prevalence of genotype 4 increased starting from 2006, became dominant in 2008 and decreased in the following years. The peak season was mostly spring months, although it was possible to detect positive samples throughout the year. In conclusion, genotype 8 followed by genotype 4 was the most frequent adenoviral types causing conjunctivitis during the 5-year study period. Findings suggest that there is a slow shift between genotypes throughout the years. J. Med. Virol. © 2014 Wiley Periodicals, Inc.
- Gastrointestinal pathology in transplant patients. [JOURNAL ARTICLE]
- Histopathology 2014 Sep 6.
The assessment of gastrointestinal (GI) specimens from transplant patients is complicated by the wide range of, potentially rare, pathologies that may be found in this clinical setting. Acute GI graft versus host disease (GvHD) is characterised by epithelial cell apoptosis, although there is increasing recognition that acute and/or chronic inflammation may also be present. By contrast, there are thus far no histological features known to be specific to chronic GI GvHD. Mycophenolate mofetil colitis may mimic both GvHD and inflammatory bowel disease, whereas both CMV and adenovirus infections can cause gland apoptosis. Post-transplant lymphoproliferative disorder should be considered if a Crohn's like histological picture is seen, and granulomas in biopsies from umbilical cord blood recipients should raise a suspicion of cord colitis syndrome. Finally, the GI tract may be involved directly or indirectly by the disease that originally required haematopoietic stem cell or liver transplantation. This article is protected by copyright. All rights reserved.
- Markers of a recent bocavirus infection in children with Kawasaki disease: "A year prospective study" [JOURNAL ARTICLE]
- Pathol Biol (Paris) 2014 Sep 2.
Retrospective studies and case-reports have suggested the possible role of various viruses in the pathogenesis of the Kawasaki disease.To determine prospectively the incidence of Kawasaki diseases associated with a recent bocavirus infection in the course of a year.Thirty-two children with Kawasaki disease were enrolled in a 13 months prospective study to assess the frequency of human bocavirus type 1 infections. Seasonal shedding of virus, markers of recent infection such as viraemia, viral load, and serum interferon alpha were analyzed.Three of 32 (9%) children had HBoV-DNA in the serum suggesting a recent infection. HBoV-DNA was detected in naso-pharyngeal aspiration of 7/32 (21.8%) children with Kawasaki Disease and six of them (18%) had an increased viral load. No common respiratory viruses were isolated from the 32 patients with the exception of one adenovirus. The seven bocaviruses were identified during the winter-spring season. In addition, 4 of 7 of Kawasaki disease patients shedding bocavirus had detectable interferon alpha in the blood, indicating a possible active or recent viral infection.This study shows that a recent bocavirus infection is concomitant with the onset of some cases of Kawasaki disease. Bocavirus may be a cofactor in the pathogenesis of this disease as previously reported for other infectious agents.
- Detection of enteric viral and bacterial pathogens associated with paediatric diarrhoea in Goroka, Papua New Guinea. [JOURNAL ARTICLE]
- Int J Infect Dis 2014 Sep 1.
The aim of this study was to investigate the viral and bacterial causes of acute watery diarrhoea in hospitalized children in Papua New Guinea.A retrospective analysis was conducted on stool samples collected from 199 children (age <5 years) admitted to the paediatric ward of Goroka General Hospital from August 2009 through November 2010. A large range of viral and bacterial enteric pathogens were targeted using real-time PCR/RT-PCR assays.Young children were much more likely to be admitted with acute gastroenteritis, with 62.8% of patients aged <1 year and 88.4% aged <2 years. An enteric pathogen was detected in 69.8% (n=138) of patients. The most commonly detected pathogens were Shigella spp (26.6%), rotavirus (25.6%), adenovirus types 40/41 (11.6%), enterotoxigenic Escherichia coli (11.1%), enteropathogenic E. coli (8.5%), norovirus G2 (6.0%), and Campylobacter spp (4.0%). Norovirus G1, sapovirus, and Salmonella spp were also detected, but below our statistical limit of detection. Vibrio cholerae and astrovirus were not detected in any patients. Mixed infections were detected in 22.1% of patients, with Shigella and rotavirus most commonly detected in co-infections with other pathogens.This study demonstrates that Shigella and rotavirus are the major pathogens associated with acute paediatric gastroenteritis in this setting.