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Adenovirus infections [keywords]
- Performance of a multiplexed serological microarray for the detection of antibodies against central nervous system pathogens. [JOURNAL ARTICLE]
- J Microbiol Methods 2014 Mar 1.
Central nervous system (CNS) infections have multiple potential causative agents for which simultaneous pathogen screening can provide a useful tool. This study evaluated a multiplexed microarray for the simultaneous detection of antibodies against CNS pathogens. The performance of selected microarray antigens for the detection of IgG antibodies against herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), adenovirus, Mycoplasma pneumoniae and Borrelia burgdorferi sensu lato, was evaluated using serum sample panels tested with reference assays used in a routine diagnostic laboratory. The microarray sensitivity for HSV-1, HSV-2, VZV, adenovirus and M. pneumonia ranged from 77% to 100%, and the specificity ranged from 74% to 97%. Very variable sensitivities and specificities were found for borrelial antigens of three different VlsE protein IR(6) peptide variants (IR6p1, IR6p2, IR6p4) and three recombinant decorin binding proteins A (DbpA; DbpAIa, DbpA91, DbpAG40). For single antigens, good specificity was shown for antigens of IR6p4 and DbpAIa (96%), while DbpA91, IR6p1 and IR6p2 were moderately specific (88-92%). The analytical sensitivity of the microarray was dependent on the borrelial IgG concentration of the specimen. The overall performance and technical features of the platform showed that the platform supports both recombinant proteins, whole viruses and peptides as antigens. This study showed diagnostic potential for all six CNS pathogens, including Borrelia burgdorferi sensu lato, using glutaraldehyde based microarray, and further highlighted the importance of careful antigen selection and the requirement for the use of multiple borrelial antigens in order to increase specificity without a major lack of sensitivity.
- Detection of common respiratory viruses in tonsillar tissue of children with obstructive sleep apnea. [JOURNAL ARTICLE]
- Pediatr Pulmonol 2014 Feb 24.
Early life viral infection is associated with neurogenic inflammation that is present in lymphoid tissues of the upper airway in children with obstructive sleep apnea (OSA). We hypothesized that viral genomic material is present in tonsils of children with OSA. Therefore, we examined tonsils for the presence of respiratory viruses' nucleic acids in children with OSA, and in children without OSA (undergoing surgery for recurrent throat infections (RI)).Tonsillar tissue from patients with OSA and RI was subjected to multiplex quantitative real time reverse transcription PCR (mqRTPCR), analyzed for the presence of common respiratory viruses' genetic material.Fifty-six patients were included, of whom 34 had OSA (age (years ± S.D), 4.22 ± 1.14) and 22 with RI (4.35 ± 1.36). Respiratory viruses nucleic acids (24 detections) were observed in 17 (50%) OSA samples. In contrast, no virus was detected in RI samples (relative frequency P < 0.0001). Viruses detected, based on frequency were Rhinovirus, Adenovirus, human metapneumovirus (hMPV), respiratory syncytial virus (RSV), and corona virus.Respiratory viruses are detected in OSA hypertrophic tonsils, suggestive of their role in the evolution of tonsillar inflammation and hypertrophy. Early life viral infections may contribute to the pathogenesis of pediatric OSA. Pediatr Pulmonol. © 2014 Wiley Periodicals, Inc.
- The epidemiology and aetiology of infections in children admitted with clinical severe pneumonia to a university hospital in Rabat, Morocco. [JOURNAL ARTICLE]
- J Trop Pediatr 2014 Feb 25.
Objectives: Scarce and limited epidemiological, clinical and microbiological data are available regarding paediatric respiratory tract infections in the Kingdom of Morocco, a middle-income country in northwestern Africa. The results of hospital-based surveillance aiming at describing the aetiology and epidemiology of respiratory distress among children <5 years of age are presented.Methods: Children admitted to the Hôpital d'Enfants de Rabat, Morocco, and meeting the World Health Organization clinical criteria for severe pneumonia were recruited over a period of 14 months and were thoroughly investigated to ascertain a definitive diagnosis.Results: In total, 700 children were recruited for the study. Most frequent clinical diagnoses included wheezing-related conditions (bronchitis/asthma, 46%; bronchiolitis, 15%), while typical bacterial pneumonia was infrequent (only 19% of the cases). Invasive bacterial disease detected by classical microbiology or molecular methods was also uncommon, affecting only 3.5% of the patients, and with an overall low detection of pneumococcal or Haemophilus influenzae type b disease. Conversely, coverage of respiratory viral detection in the nasopharynx was almost universal among cases (92%), with the three most frequent viruses detected being rhinovirus (53%), respiratory syncytial virus (18%) and adenovirus (17%). The overall case fatality rate (CFR) among recruited patients with a known outcome was 4.1% (28/690).Conclusions: In Morocco, the epidemiological profile of paediatric acute respiratory infections is markedly shifted towards wheezing-related diseases and thus resembles that of high-income countries. However, the high associated CFRs found in this study call for an improvement in preventive and clinical management strategies.
- Orthopoxvirus inhibitors that are active in animal models: an update from 2008 to 2012. [JOURNAL ARTICLE]
- Future Virol 2013 Sep; 8(9):891-901.
Antiviral agents are being sought as countermeasures for the potential deliberate release of smallpox (variola) and monkeypox viruses, for the treatment of naturally acquired monkeypox virus infections, and as therapy for complications due to smallpox (live-attenuated vaccinia virus) vaccination or accidental infection after exposure to vaccinated persons. Reviews of the scientific literature spanning 1950-2008 have documented the progress made in developing small-animal models of poxvirus infection and identifying novel antiviral agents. Compounds of considerable interest include cidofovir, CMX001 and ST-246® (tecovirimat; SIGA Technologies, NY, USA). New inhibitors have been identified since 2008, most of which do not exhibit the kind of potency and selectivity required for drug development. Two promising agents include 4'-thioidoxuridine (a nucleoside analog) and mDEF201 (an adenovirus-vectored interferon). Compounds that have been effectively used in combination studies include vaccinia immune globulin, cidofovir, ST-246 and CMX001. In the future there may be an increase in experimental work using active compounds in combination.
- Recombinant adenovirus type 5 HIV gag/pol/nef vaccine in South Africa: unblinded, long-term follow-up of the phase 2b HVTN 503/Phambili study. [JOURNAL ARTICLE]
- Lancet Infect Dis 2014 Feb 19.
The HVTN 503/Phambili study, which assessed the efficacy of the Merck Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine in South Africa, was stopped when futility criteria in the Step study (assessing the same vaccine in the Americas, Caribbean, and Australia) were met. Here we report long-term follow-up data.HVTN 503/Phambili was a double-blind, placebo-controlled, randomised trial that recruited HIV-1 uninfected, sexually active adults aged 18-35 years from five sites in South Africa. Eligible participants were randomly assigned (1:1) by computer-generated random numbers to either vaccine or placebo, stratified by site and sex. Cox proportional hazards models were used to estimate HIV-1 infection in the modified intention-to-treat cohort, all of whom were unmasked early in follow-up. The trial is registered with ClinicalTrials.gov, number NCT00413725 and the South African National Health Research Database, number DOH-27-0207-1539.Between Jan 24, 2007, and Sept 19, 2007, 801 participants (26·7%) of a planned 3000 were randomly assigned (400 to vaccine, 401 to placebo); 216 (27%) received only one injection, 529 (66%) received only two injections, and 56 (7%) received three injections. At a median follow-up of 42 months (IQR 31-42), 63 vaccine recipients (16%) had HIV-1 infection compared with 37 placebo recipients (9%; adjusted HR 1·70, 95% CI 1·13-2·55; p=0·01). Risk for HIV-1 infection did not differ according to the number of vaccinations received, sex, circumcision, or adenovirus type 5 (Ad5) serostatus. Differences in risk behaviour at baseline or during the study, or annualised dropout rate (7·7% [95% CI 6·2-9·5] for vaccine recipients vs 8·8% [7·1-10·7] for placebo recipients; p=0·40) are unlikely explanations for the increased rate of HIV-1 infections seen in vaccine recipients.The increased risk of HIV-1 acquisition in vaccine recipients, irrespective of number of doses received, warrants further investigation to understand the biological mechanism. We caution against further use of the Ad5 vector for HIV vaccines.National Institute of Allergy and Infectious Diseases, Merck, and South African Medical Research Council.
- Adenovirus-based vaccines to rhesus lymphocryptovirus EBNA-1 induce expansion of specific CD8+ and CD4+ T cells in persistently infected rhesus macaques. [JOURNAL ARTICLE]
- J Virol 2014 Feb 12.
The impact of Epstein-Barr virus (EBV) on human health is substantial, but vaccines that prevent primary EBV infections or treat EBV-associated diseases are not yet available. The Epstein-Barr nuclear antigen 1 (EBNA-1) is an important target for vaccination because it is the only protein expressed in all EBV-associated malignancies. We have designed and tested two therapeutic EBV vaccines that target the rhesus (rh) lymphocryptovirus (LCV) EBNA-1 to determine if ongoing T cell responses during persistent rhLCV infection in rhesus macaques can be expanded upon vaccination. Vaccines were based on two serotypes of E1-deleted simian adenovirus and were administered in a prime-boost regimen. To further modulate the response, rhEBNA-1 was fused to herpes simplex virus glycoprotein D (gD), which acts to block an inhibitory signaling pathway during T cell activation. We found that vaccines expressing rhEBNA-1 with or without functional HSV-gD led to expansion of rhEBNA-1-specific CD8(+) and CD4(+) T cells in 33% and 83% of the vaccinated animals, respectively. Additional animals developed significant changes within T cell subsets without changes in total numbers. Vaccination did not increase T cell responses to rhBZLF-1, an immediate early lytic phase antigen of rhLCV, thus indicating that increases of rhEBNA-1-specific responses were a direct result of vaccination. Vaccine-induced rhEBNA-1-specific T cells were highly functional and produced various combinations of cytokines as well as the cytolytic molecule granzyme B. These results serve as an important proof-of-principle that functional EBNA-1-specific T cells can be expanded by vaccination.EBV is a common human pathogen that establishes a persistent infection through latency in B cells, where it occasionally reactivates. EBV infection is typically benign and is well controlled by the host adaptive immune system; however, it is considered carcinogenic due to its strong association with lymphoid and epithelial cell malignancies. Latent EBNA-1 is a promising target for a therapeutic vaccine, as it is the only antigen expressed in all EBV-associated malignancies. The goal was to determine if rhEBNA-1-specific T cells could be expanded upon vaccination of infected animals. Results were obtained with vaccines that target EBNA-1 of rhLCV, a virus closely related to EBV. We found that vaccination led to expansion of rhEBNA-1 immune cells that exhibited functions fit for controlling viral infection. This confirms that rhEBNA-1 is a suitable target for therapeutic vaccines. Future work should aim to generate more robust T cell responses through modified vaccines.
- [Identification and typing of adenovirus from acute respiratory infections in pediatric patients in Beijing from 2003 to 2012]. [English Abstract, Journal Article]
- Bing Du Xue Bao 2013 Nov; 29(6):615-20.
Adenovirus (ADV) is one of the most common causes of acute respiratory infections for infants and children. The objective of this study was to understand the prevalence of ADV in acute respiratory infections in infants and children in Beijing and the types of the circulating ADVs. Clinical specimens were collected from patients with acute respiratory infections in a consecutive period of 10 years from Jan 2003 to Dec 2012. ADVs were detected from the collected clinical specimens by tissue culture and/or immunofluorescence assay and typed by nested-PCR based on the sequence of hexon gene for ADV types 3 and 7. For those strains which could not be typed by the nest-PCR, the gene fragment was amplified by a universal primer pair for all ADV types from group A to F and the PCR products were sequenced directly and analyzed with sequence comparison. Out of 39214 clinical specimens collected, including 7198 throat swabs from outpatients and 32016 nasopharyngeal aspirates from hospitalized patients, 884 were ADV positive by tissue culture and/or immunofluorescence assay, the overall positive rate was 2.25% (884/39214). The positive rate of ADV from the hospitalized was 2.08% (665/32016), while from the outpatients was 3.04% (219/7198). The ADV positive rate for year 2010 was 3.69%, which was the highest among the 10 years. The types of the ADVs were tested for 848 out of the 884 patients by using the nest-PCR and sequence analysis. It was showed that AD3 was the most prevalent with the rate of 53.18% (451/848), followed by AD7 36.79% (312/848), AD2 3.78% (32/848), AD55 2.24% (19/848), AD1 2.0% (17/848), AD5 0.94% (8/848), AD14 0.47% (4/848), AD6 0.35% (3/848) and AD4 0.24% (2/848). AD3 was the most predominant in most of the years among these 10 years, except 2012, 2003 and 2007. AD7 was the most predominant in 2012, and AD3 and AD7 were co-circulated in 2003 and 2007. Among 26 ADV infected severe pneumonia cases with pulmonary failure, 23 (88.5%) were AD7 positive, while 12 ADV associated tonsillitis, 11 (91.7%) were AD 3. The ADV positive rates from age groups 0-3 years were higher than age groups older than 4 years. The ratio for ADV positive males to females was 1.9 to 1. Adenovirus is still an important pathogen of acute respiratory infection in infants and young children. Most of the ADV associated acute respiratory infections in children in Beijing from 2003 to 2012 were AD3 and AD7. Most of the severe lower respiratory infections were associated with AD7. AD55 generated by recombination of AD11 and AD14 emerged in 2006.
- Molecular detection and phylogenetic analysis of Kenyan human bocavirus isolates. [Journal Article]
- J Infect Dev Ctries 2014; 8(2):221-7.
The commonly expected causative agents associated with flu-like symptoms in Kenya are the classical viral pathogens identifiable as influenza virus, adenovirus, parainfluenza virus, enteroviruses, respiratory syncytial virus (RSV) and rhinovirus. However, newer agents have been identified globally that present with illnesses clinically indistinguishable from those caused by the classical pathogens; one of them is human bocavirus.A total of 384 specimens were analyzed, primarily to determine if the emerging human bocavirus (HBoV) infections exist in Kenya as coinfections with other respiratory viruses and to describe the genotype of the virus in circulation. In brief, viral nucleic acids were extracted from culture supernatants, amplified by PCR, and sequenced.HBoV DNA was amplified from 1.8% of screened specimens. Coinfection with parainfluenza virus, adenovirus, and enterovirus was 2.5%, 2%, and 1.4%, respectively. Multiple coinfections consisting of HBoV plus two other viruses were found in 3% of specimens. Isolation occurred in the months of January, March, April, August, and November. Retrospective review of clinical parameters indicated that all the individuals complained of non-specific symptoms, mainly fever, coughs, nasal stuffiness, runny noses, and vomiting. Phylogenetically, the GenBank deposited sequences of this study's isolates cluster closely to the reference strain NC_07455 (HBoV1).Coinfections with human bocavirus (HBoV1) occur in Kenya, and high incidence might primarily be during the early stages of children's lives.
- High prevalence and diversity of species D adenoviruses (HAdV-D) in human populations of four Sub-Saharan countries. [Journal Article, Research Support, Non-U.S. Gov't]
- Virol J 2014.:25.
Human adenoviruses of species D (HAdV-D) can be associated with acute respiratory illness, epidemic keratoconjunctivitis, and gastroenteritis, but subclinical HAdV-D infections with prolonged shedding have also been observed, particularly in immunocompromised hosts. To expand knowledge on HAdV-D in Sub-Saharan Africa, we investigated the prevalence, epidemiology and pathogenic potential of HAdV-D in humans from rural areas of 4 Sub-Saharan countries, Côte d'Ivoire (CI), Democratic Republic of the Congo (DRC), Central African Republic (CAR) and Uganda (UG).Stool samples were collected from 287 people living in rural regions in CI, DRC, CAR and UG. HAdV-D prevalence and diversity were determined by PCR and sequencing. A gene block, spanning the genes pV to hexon, was used for analysis of genetic distance. Correlation between adenovirus infection and disease symptoms, prevalence differences, and the effect of age and gender on infection status were analyzed with cross tables and logistic regression models.The prevalence of HAdV-D in the investigated sites was estimated to be 66% in CI, 48% in DRC, 28% in CAR (adults only) and 65% in UG (adults only). Younger individuals were more frequently infected than adults; there was no difference in HAdV-D occurrence between genders. No correlation could be found between HAdV-D infection and clinical symptoms. Highly diverse HAdV-D sequences were identified, among which a number are likely to stand for novel types.HAdV-D was detected with a high prevalence in study populations of 4 Sub-Saharan countries. The genetic diversity of the virus was high and further investigations are needed to pinpoint pathological potential of each of the viruses. High diversity may also favor the emergence of recombinants with altered tropism and pathogenic properties.
- Innate Immunity to Adenovirus. [JOURNAL ARTICLE]
- Hum Gene Ther 2014 Feb 10.
Human adenoviruses are the most widely used vectors in gene medicine, with applications ranging from oncolytic therapies to vaccinations, but adenovirus vectors are not without side effects. In addition, natural adenoviruses pose severe risks for immuno-compromised people, yet, infections are usually mild and self-limiting in immuno-competent individuals. Here we describe how adenoviruses are recognized by the host innate defense system during entry and replication in immune and non-immune cells. Innate defense protects the host, and at the same time, represents a major barrier to using adenoviruses as therapeutic interventions in humans. Innate response against adenoviruses involves intrinsic factors present at constant levels, and innate factors induced by the host cell upon viral challenge. These factors exert anti-viral effects by directly binding to viruses or viral components, or shield the virus, for example soluble factors, such as blood clotting components, the complement system, preexisting immunoglobulins or defensins. In addition, toll-like receptors and lectins in the plasma membrane and endosomes are intrinsic factors against adenoviruses. Important innate factors restricting adenovirus in the cytosol are tripartite motif-containing proteins (TRIM), nucleotide-binding oligomerization domain (NOD)-like inflammatory receptors and DNA sensors triggering interferon, such as DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 (DDX41) and cyclic guanosine monophosphate-adenosine monophosphate synthase (cGMP-AMP synthase, short cGAS). Adenovirus tunes the function of anti-viral autophagy, and counters innate defense by virtue of its early proteins E1A, E1B, E3 and E4 and two virus-associated noncoding RNAs VA-I and VA-II. We conclude by discussing strategies to engineer adenovirus vectors with attenuated innate responses and enhanced delivery features.