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Mammalian α-defensins are a family of abundant effector peptides of the mucosal innate immune system. Although primarily considered to be antimicrobial, α-defensins can increase rather than block infection by certain prominent bacterial and viral pathogens in cell culture and in vivo. We have shown previously that exposure of mouse and human adenoviruses (HAdVs) to α-defensins is able to overcome competitive inhibitors that block cell binding, leading us to hypothesize a defensin-mediated binding mechanism that is independent of known viral receptors. To test this hypothesis, we used genetic approaches to demonstrate that none of several primary receptors nor integrin co-receptors are needed for human α-defensin-mediated binding of HAdV to cells; however, infection remains integrin dependent. Thus, our studies have revealed a novel pathway for HAdV binding to cells that bypasses viral primary receptors. We speculate that this pathway functions in parallel with receptor-mediated entry and contributes to α-defensin-enhanced infection of susceptible cells. Remarkably, we also found that in the presence of α-defensins, HAdV tropism is expanded to non-susceptible cells, even when viruses are exposed to a mixture of both susceptible and non-susceptible cells. Therefore, we propose that in the presence of sufficient concentrations of α-defensins, such as in the lung or gut, integrin expression rather than primary receptor expression will dictate HAdV tropism in vivo. In summary, α-defensins may contribute to tissue tropism not only through the neutralization of susceptible viruses but also by allowing certain defensin-resistant viruses to bind to cells independently of previously described mechanisms. Author summary: In this study, we demonstrate a novel mechanism for binding of human adenoviruses (HAdVs) to cells that is dependent upon interactions with α-defensin host defense peptides but is independent of known viral receptors and co-receptors. To block normal receptor-mediated HAdV infection, we made genetic changes to both host cells and HAdVs. Under these conditions, α-defensins restored cell binding; however, infection still required the function of HAdV integrin co-receptors. This was true for multiple types of HAdVs that use different primary receptors and for cells that are either naturally devoid of HAdV receptors or were engineered to be receptor deficient. These observations suggest that in the presence of concentrations of α-defensins that would be found naturally in the lung or intestine, there are two parallel pathways for HAdV binding to cells that converge on integrins for productive infection. Moreover, these binding pathways function independently, and both operate in mixed culture. Thus, we have found that viruses can co-opt host defense molecules to expand their tropism. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdVs) are a diverse group of viruses associated with respiratory infections in humans worldwide. However, there is a lack of research on the genetic diversity and epidemiology of HAdVs in Pakistan. This study characterized HAdVs in pediatric patients with respiratory tract infections in Karachi, Pakistan, between 2022 and 2023. We analyzed 762 nasopharyngeal samples of children ≤ 5 years. DNA extraction, followed by PCR targeting E2B and hexon genes, was carried out. Data analysis was performed on SPSS 25.0, and phylogenetic analysis of hexon gene was performed on MEGA 11. HAdV was detected in 7.34% (56/762) of patients round the year, but at a significantly higher rate during the winter season. Age was insignificantly associated with HAdV incidence (p = 0.662), but more than 62.5% (35/56) of positive cases were younger than 10 months. The circulating HAdVs were identified as six different types from species B (78.57%) and C (21.42%), with the majority of isolates found to be like B3. HAdV was found to be co-infected with bocavirus (5.4%) and measles (7.14%). These findings revealed a high frequency and genetic diversity of respiratory HAdVs in Karachi, Pakistan. We conclude that periodic and continuous surveillance of adenoviruses and other respiratory pathogens is necessary to improve the prognosis and management of respiratory diseases, thereby reducing the child mortality rate in Pakistan. [ABSTRACT FROM AUTHOR]

Purpose: Human adenoviruses (HAdVs) have always been suggested as one of the main causes of gastroenteritis in children. However, no comprehensive report on the global epidemiology of these viruses in pediatric gastroenteritis is available. Methods: A systematic search was conducted to obtain published papers from 2003 to 2023 in three main databases PubMed, Scopus, and Web of Science. Results: The estimated global pooled prevalence of HAdV infection in children with gastroenteritis was 10% (95% CI: 9-11%), with a growing trend after 2010. The highest prevalence was observed in Africa (20%, 95% CI: 14–26%). The prevalence was higher in inpatients (11%; 95% CI: 8-13%) and patients aged 5 years old and younger (9%; 95% CI: 7-10%). However, no significant difference was observed between male and female patients (P = 0.63). The most prevalent species was found to be the species F (57%; 95% CI: 41-72%). The most common HAdVs observed in children with gastroenteritis were types 40/41, 38, and 2. Analysis of case-control studies showed an association between HAdV and gastroenteritis in children (OR: 2.28, 95% CI; 1.51–3.44). Conclusion: This study provided valuable insights into the importance of HAdVs in children with gastroenteritis, especially in hospitalized and younger children. The results can be used in future preventive measurements and the development of effective vaccines. [ABSTRACT FROM AUTHOR]

Background Human adenoviruses (HAdVs) can cause outbreaks of flu-like illness in university settings. Most infections in healthy young adults are mild; severe illnesses rarely occur. In Fall 2022, an adenovirus outbreak was identified in university students. Methods HAdV cases were defined as university students 17–26 years old who presented to the University Health Service or nearby emergency department with flu-like symptoms (eg, fever, cough, headache, myalgia, nausea) and had confirmed adenovirus infections by polymerase chain reaction (PCR). Demographic and clinical characteristics were abstracted from electronic medical records; clinical severity was categorized as mild, moderate, severe, or critical. We performed contact investigations among critical cases. A subset of specimens was sequenced to confirm the HAdV type. Results From 28 September 2022 to 30 January 2023, 90 PCR-confirmed cases were identified (51% female; mean age, 19.6 years). Most cases (88.9%) had mild illness. Seven cases required hospitalization, including 2 critical cases that required intensive care. Contact investigation identified 44 close contacts; 6 (14%) were confirmed HAdV cases and 8 (18%) reported symptoms but never sought care. All typed HAdV-positive specimens (n = 36) were type 4. Conclusions While most students with confirmed HAdV had mild illness, 7 otherwise healthy students had severe or critical illness. Between the relatively high number of hospitalizations and proportion of close contacts with symptoms who did not seek care, the true number of HAdV cases was likely higher. Our findings illustrate the need to consider a wide range of pathogens, even when other viruses are known to be circulating. [ABSTRACT FROM AUTHOR]

Recombinant adenoviruses are widely used in clinical and laboratory applications. Despite the wide variety of available sero- and genotypes, only a fraction is utilized in vivo. As adenoviruses are a large group of viruses, displaying many different tropisms, immune epitopes, and replication characteristics, the merits of translating these natural benefits into vector applications are apparent. This translation, however, proves difficult, since while research has investigated the application of these viruses, there are no universally applicable rules in vector design for non-classical adenovirus types. In this paper, we describe a generalized workflow that allows vectorization, rescue, and cloning of all adenoviral species to enable the rapid development of new vector variants. We show this using human and simian adenoviruses, further modifying a selection of them to investigate their gene transfer potential and build potential vector candidates for future applications. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdVs) are causative agents of morbidity and mortality throughout the world. These double-stranded DNA viruses are phylogenetically classified into seven different species (A-G). HAdV-G52, originally isolated in 2008 from a patient presenting with gastroenteritis, is the sole human-derived member of species G. Phylogenetic analysis previously suggested that HAdV-G52 may have a simian origin, indicating a potential zoonotic spillover into humans. However, evidence of HAdV-G52 in either human or simian populations has not been reported since. Here, we describe the isolation and in vitro characterization of rhesus (rh)AdV-69, a novel simian AdV with clear evidence of recombination with HAdV-G52, from the stool of a rhesus macaque. Specifically, the rhAdV-69 hexon capsid protein is 100% identical to that of HAdV-G52, whereas the remainder of the genome is most similar to rhAdV-55, sharing 95.36% nucleic acid identity. A second recombination event with an unknown adenovirus (AdV) is evident at the short fiber gene. From the same sample, we also isolated a second, highly related recombinant AdV (rhAdV-68) that harbors a distinct hexon gene but nearly identical backbone compared to rhAdV-69. In vitro, rhAdV-68 and rhAdV-69 demonstrate comparable growth kinetics and tropisms in human cell lines, nonhuman cell lines, and human enteroids. Furthermore, we show that coinfection of highly related AdVs is not unique to this sample since we also isolated coinfecting rhAdVs from two additional rhesus macaque stool samples. Our data collectively contribute to elucidating the origins of HAdV-G52 and provide insights into the frequency of coinfections and subsequent recombination in AdV evolution. IMPORTANCE Understanding the host origins of adenoviruses (AdVs) is critical for public health as transmission of viruses from animals to humans can lead to emergent viruses. Recombination between animal and human AdVs can also produce emergent viruses. HAdV-G52 is the only human-derived member of the HAdV G species. It has been suggested that HAdV-G52 has a simian origin. Here, we isolated from a rhesus macaque, a novel rhAdV, rhAdV-69, that encodes a hexon protein that is 100% identical to that of HAdV-G52. This observation suggests that HAdV-G52 may indeed have a simian origin. We also isolated a highly related rhAdV, differing only in the hexon gene, from the same rhesus macaque stool sample as rhAdV-69, illustrating the potential for co-infection of closely related AdVs and recombination at the hexon gene. Furthermore, our study highlights the critical role of whole-genome sequencing in understanding AdV evolution and monitoring the emergence of pathogenic AdVs. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdV) are classified as DNA tumor viruses due to their potential to mediate oncogenic transformation in non-permissive mammalian cells and certain human stem cells. To achieve transformation, the viral early proteins of the E1 and E4 regions must block apoptosis and activate proliferation: the former predominantly through modulating the cellular tumor suppressor p53 and the latter by activating cellular pro-survival and pro-metabolism protein cascades, such as the phosphoinositide 3-kinase (PI3K-Akt) pathway, which is activated by HAdV E4orf1. Focusing on HAdV-C5, we show that E4orf1 is necessary and sufficient to stimulate Akt activation through phosphorylation in H1299 cells, which is not only hindered but repressed during HAdV-C5 infection with a loss of E4orf1 function in p53-positive A549 cells. Contrary to other research, E4orf1 localized not only in the common, cytoplasmic PI3K-Akt-containing compartment, but also in distinct nuclear aggregates. We ident ified a novel inhibitory mechanism, where p53 selectively targeted E4orf1 to destabilize it, also stalling E4orf1-dependent Akt phosphorylation. Co-IP and immunofluorescence studies showed that p53 and E4orf1 interact, and since p53 is bound by the HAdV-C5 E3 ubiquitin ligase complex, we also identified E4orf1 as a novel factor interacting with E1B-55K and E4orf6 during infection; overexpression of E4orf1 led to less-efficient E3 ubiquitin ligase-mediated proteasomal degradation of p53. We hypothesize that p53 specifically subverts the pro-survival function of E4orf1-mediated PI3K-Akt activation to protect the cell from metabolic hyper-activation or even transformation. IMPORTANCE Human adenoviruses (HAdV) are nearly ubiquitous pathogens comprising numerous subtypes that infect various tissues and organs. Among many encoded proteins that facilitate viral replication and subversion of host cellular processes, the viral E4orf1 protein has emerged as an intriguing yet under-investigated player in the complex interplay between the virus and its host. Nonetheless, E4orf1 has gained attention as a metabolism activator and oncogenic agent, while recent research is showing that E4orf1 may play a more important role in modulating the cellular pathways such as phosphoinositide 3-kinase-Akt-mTOR. Our study reveals a novel and general impact of E4orf1 on host mechanisms, providing a novel basis for innovative antiviral strategies in future therapeutic settings. Ongoing investigations of the cellular pathways modulated by HAdV are of great interest, particularly since adenovirus-based vectors actually serve as vaccine or gene vectors. HAdV constitute an ideal model system to analyze the underlying molecular principles of virus-induced tumorigenesis. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive type of pancreatic cancer, which rapidly develops resistance to the current standard of care. Several oncolytic Human AdenoViruses (HAdVs) have been reported to re-sensitize drug-resistant cancer cells and in combination with chemotherapeutics attenuate solid tumour growth. Obstacles preventing greater clinical success are rapid hepatic elimination and limited viral replication and spread within the tumour microenvironment. We hypothesised that higher intratumoural levels of the virus could be achieved by altering cellular epigenetic regulation. Here we report on the screening of an enriched epigenetics small molecule library and validation of six compounds that increased viral gene expression and replication. The greatest effects were observed with three epigenetic inhibitors targeting bromodomain (BRD)-containing proteins. Specifically, BRD4 inhibitors enhanced the efficacy of Ad5 wild type, Ad∆∆, and Ad-3∆-A20T in 3-dimensional co-culture models of PDAC and in vivo xenografts. RNAseq analysis demonstrated that the inhibitors increased viral E1A expression, altered expression of cell cycle regulators and inflammatory factors, and attenuated expression levels of tumour cell oncogenes such as c-Myc and Myb. The data suggest that the tumour-selective Ad∆∆ and Ad-3∆-A20T combined with epigenetic inhibitors is a novel strategy for the treatment of PDAC by eliminating both cancer and associated stromal cells to pave the way for immune cell access even after systemic delivery of the virus. [ABSTRACT FROM AUTHOR]

Adenoviruses (AdVs) are being developed for oncolytic or vaccination therapy against existing and emerging conditions. Well-characterized replication-competent human and human primate AdVs expressing multiple payloads are desirable, but their replication in rodent models is limited. To score the timing of adenoviral gene expression in cell cultures, we developed fully replication-competent transcriptional reporter viruses for HAdV-C5, -B3, and -B35. The picornavirus-derived 2A sequence, which induces cotranslational peptide splitting and reinitiation (skipping), was linked to GFP and the fused sequence was inserted C-terminal of the early gene E1A, the intermediate early gene protein IX and the late fiber gene. The 2A peptide induced ribosomal skipping during translation of the messenger RNA (mRNA) and gave rise to GFP from the corresponding viral promoters, as shown by immunoblotting and flow cytometry analyses of human and rodent cells. In human cells, both species B and C AdV exhibited highest reporter expression for fiber, followed by protein IX and lowest for E1A. Inoculation with either HAdV-C5 or -B3/35 viruses encoding protein IX- or fiber-GFP gave rise to higher GFP levels in hamster than mouse cells. Remarkably, despite rather low 2A ribosomal skipping efficiency of ∼50% for E1A-2A-GFP, protein IX-2A-GFP, and fiber-2A-GFP, unprocessed protein IX-2A-GFP and fiber-2A-GFP fusion proteins were efficiently incorporated into HAdV-B3 virions, respectively. These data indicate that the B3 C-termini of protein IX and fiber can be considered for retargeting engineered oncolytic or vaccination vectors, or for antigen display. The variable expression levels of transgenes from different subviral promoters may be used to improve oncolytic AdV vectors expressing therapeutic genes. [ABSTRACT FROM AUTHOR]

Background: Under the pressure of Human Adenovirus (HAdV)–associated acute respiratory infection (ARI) outbreak in children in Northern Vietnam in the end of 2022, this study was initiated to identify the HAdV subtype(s) and examine the associated clinical features and risk factors of more severe cases. Methods: This study evaluated pediatric patients with ARI which had tested positive for HAdV between October and November 2022 using a multiplex real-time PCR panel. Nasopharyngeal aspirates or nasal swab samples were used for sequencing to identify HAdV subtypes. Clinical data were collected retrospectively. Results: Among 97 successfully sequenced samples, the predominant subtypes were HAdV-B3 (83%), HAdV-B7 (16%) and HAdV-C2 (1%). Lower respiratory manifestations were found in 25% of the patients of which 5% were diagnosed with severe pneumonia. There was no significant association between HAdV subtype and clinical features except higher white blood cell and neutrophil counts in those detected with HAdV-B3 (p<0.001). Co-detection of HAdV with ≥1 other respiratory viruses was found in 13/24(54%) of those with lower respiratory manifestations and 4/5(80%) of those with severe pneumonia (odds ratio (95% confidence interval) vs. those without = 10.74 (2.83, 48.17) and 19.44 (2.12, 492.73) respectively after adjusting for age, sex, birth delivery method, day of disease). Conclusion: HAdV-B3 and HAdV-B7 were predominant in the outbreak. Co-detection of HAdV together with other respiratory viruses was a strong risk factor for lower respiratory tract illnesses and severe pneumonia. The findings advocate the advantages of multi-factor microbial panels for the diagnosis and prognosis of ARI in children. Author summary: Human Adenoviruses (HAdV) is among the common causes of acute respiratory infection (ARI) in children. HAdV may cause severe or deadly diseases in both immunocompetent and immunocompromised individuals. There are many HAdV subtypes and different HAdV subtypes may be associated with different diseases or disease manifestations. In the second half of 2022, for the first time in Northern Vietnam, there was a HAdV-associated ARI outbreak in children with an alarming number of severe cases and deaths. During the outbreak, the authors performed Sanger sequencing on nasal swab samples of 97 patients who tested positive for HAdV by multiplex real-time PCR panel (the PCR panel was designed to test for HAdV and 6 other respiratory viruses). Three HAdV subtypes were identified: B3 (83%), B7 (16%) and C2 (1%). Patient clinical characteristics were similar between the detected HAdV subtypes. Co-detection of HAdV with other respiratory viruses was associated with greater disease severity compared to HAdV detection alone. This is probably the first study describing the clinical features and HAdV molecular subtypes associated with an ARI outbreak in children in Vietnam. The findings demonstrate the usefulness of multi-factor microbial panels for the diagnosis and prognosis of ARI in children. [ABSTRACT FROM AUTHOR]

Enteric adenovirus types F40 and 41 (EAdVs) are a leading cause of diarrhea and diarrhea-associated death in young children and have recently been proposed to cause acute hepatitis in children. EAdVs have a unique capsid architecture and exhibit — unlike other human adenoviruses — a relatively strict tropism for gastrointestinal tissues with, to date, understudied infection mechanism and unknown target cells. In this study, we turn to potentially limiting host factors by comparing EAdV entry in cell lines with respiratory and intestinal origin by cellular perturbation, virus particle tracking, and transmission electron microscopy. Our analyses highlight kinetic advantages for EAdVs in duodenal HuTu80 cell infection and reveal a larger fraction of mobile particles, faster virus uptake, and infectious particle entry in intestinal cells. Moreover, EAdVs display a dependence on clathrin- and dynamin-dependent pathways in intestinal cells. Detailed knowledge of virus entry routes and host factor requirements is essential to understanding pathogenesis and developing new countermeasures. Hence, this study provides novel insights into the entry mechanisms of a medically important virus with emerging tropism in a cell line originating from a relevant tissue. IMPORTANCE Enteric adenoviruses have historically been difficult to grow in cell culture, which has resulted in lack of knowledge of host factors and pathways required for infection of these medically relevant viruses. Previous studies in non-intestinal cell lines showed slow infection kinetics and generated comparatively low virus yields compared to other adenovirus types. We suggest duodenum-derived HuTu80 cells as a superior cell line for studies to complement efforts using complex intestinal tissue models. We show that viral host cell factors required for virus entry differ between cell lines from distinct origins and demonstrate the importance of clathrin-mediated endocytosis. [ABSTRACT FROM AUTHOR]

Background: Human adenoviruses (HAdV) have been known to cause a range of diseases, including respiratory tract infections (RTIs). However, there is limited information available regarding the genotype diversity and epidemiology of HAdV associated with RTIs in Nanning. Methods: Between June 2019 and December 2021, throat swab, nasal swab, or nasopharyngeal swab samples were obtained from individuals hospitalized with respiratory tract infections (RTIs). Statistical software was used to analyze the epidemiological data. The highly conserved 132-bp gene region of the HAdV hexon was targeted for the detection of HAdV using a qPCR assay. An 875-bp hexon gene fragment was subjected to phylogenetic analysis. Results: Significant variations were observed in the age and gender distribution of HAdV-positive patients (P = 0.004 and P = 0.025, respectively). The age distribution of HAdV-positive patients showed that 67.89% of those who tested positive were the age group of 0–6 years. Furthermore, the prevalence of HAdV detection was highest during spring and autumn, with a peak in February. Additionally, genotyping of the 36 HAdV-positive samples with 875-bp fragments identified the presence of circulating HAdV species B, C, and E in Nanning between 2019 and 2021. Conclusions: This study identified an association between HAdV prevalence and age as well as season. Among hospitalized patients with RTIs in Nanning, HAdV-B, HAdV-C, and HAdV-E were found to be co-circulating. The most commonly detected genotypes were HAdV-C1, HAdV-C6, and HAdV-E4. [ABSTRACT FROM AUTHOR]

Epidemic keratoconjunctivitis (EKC) is a hazardous and highly contagious disease, with the potential to cause epidemic outbreaks in hospitals and other community settings. There are currently no approved drugs for human adenovirus (HAdV), the causative agent of EKC. To establish a novel drug screening system for ocular HAdV infections, we employed CRL11516, a non-cancerous but immortalized human corneal epithelial cell line. Brincidoforvir and 3′-deoxy-3′-fluorothymidine inhibit replication of HAdV species C type 1 (C1), C2, E4, and C6 to the same extent. This alternative assay system may allow for the evaluation of anti-HAdV activity and cell cytotoxicity of compounds within 2 days and without the need of the rabbit eye infection model. • A human epithelial cell line, CRL-11516, support infection of human adenoviruses. • Potency of anti-adenoviral agents can be evaluated within 2 days. • The assay system is a useful model of adenoviral keratoconjunctivitis in vitro. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdVs) are widespread pathogens causing a variety of diseases. A well-controlled expression of virus capsid mRNAs originating from the major late transcription unit (MLTU) is essential for forming the infectious virus progeny. However, regulation of the MLTU mRNA metabolism has mainly remained enigmatic. In this study, we show that the cellular RNA-binding protein FXR1 controls the stability of the HAdV-5 MLTU mRNAs, as depletion of FXR1 resulted in increased steady-state levels of MLTU mRNAs. Surprisingly, the lack of FXR1 reduced viral capsid protein accumulation and formation of the infectious virus progeny, indicating an opposing function of FXR1 in HAdV-5 infection. Further, the long FXR1 isoform interfered with MLTU mRNA translation, suggesting FXR1 isoform-specific functions in virus-infected cells. We also show that the FXR1 protein interacts with N6-methyladenosine (m6A)-modified MLTU mRNAs, thereby acting as a novel m6A reader protein in HAdV-5 infected cells. Collectively, our study identifies FXR1 as a regulator of MLTU mRNA metabolism in the lytic HAdV-5 life cycle. IMPORTANCE Human adenoviruses (HAdVs) are common pathogens causing various self-limiting diseases, such as the common cold and conjunctivitis. Even though adenoviruses have been studied for more than 6 decades, there are still gaps in understanding how the virus interferes with the host cell to achieve efficient growth. In this study, we identified the cellular RNA-binding protein FXR1 as a factor manipulating the HAdV life cycle. We show that the FXR1 protein specifically interferes with mRNAs encoding essential viral capsid proteins. Since the lack of the FXR1 protein reduces virus growth, we propose that FXR1 can be considered a novel cellular proviral factor needed for efficient HAdV growth. Collectively, our study provides new detailed insights about the HAdV-host interactions, which might be helpful when developing countermeasures against pathogenic adenovirus infections and for improving adenovirus-based therapies. [ABSTRACT FROM AUTHOR]

Background and Objectives: Human rhinoviruses (HRVs) and human adenoviruses (HAdVs) are among the most prevalent viruses in hospitalized patients with severe acute respiratory infection (SARI). This study aimed to evaluate the molecular characterization of HRV and HAdV in hospitalized patients with SARI, who aged ≤ 18 years in Tehran, Iran. Materials and Methods: To detect these two viruses, a conventional nested RT-PCR (Reverse transcription-polymerase chain reaction) assay was performed on 264 throat swabs collected from December 2018 to March 2019. The epidemiological data were analyzed and phylogenetic trees were constructed. Results: Of 264 cases with SARI, 36 (13.6%) and 28 (10.6%) were positive for HAdV and HRV respectively. Of 21 HRV sequenced samples, HRV-A (42.9%), HRV-B (9.5%) and HRV-C (47.6%) and of 36 HAdV sequenced samples, HAdV-C6 (38.9%), HAdV-B7 (22.2%), HAdV-B3 (11.1%), HAdV-B16 (5.6%), HAdV-C5 (13.9%), HAdV-C57 (5.6%), HAdV-E4 (2.8%); were detected in children with SARI. Some viral genotypes appeared to cause more severe disease, which may lead to hospitalization. Conclusion: Large-scale studies are recommended to investigate the epidemiology and molecular characterizations through surveillance networks to provide useful information on etiology, seasonality, and demographic associations in patients with SARI. [ABSTRACT FROM AUTHOR]

In the 1990s, adenovirus became one of the first virus types to be genetically engineered to selectively destroy cancer cells. In the intervening years, the field of "oncolytic viruses" has slowly progressed and culminated in 2015 with the FDA approval of Talimogene laherparepvec, a genetically engineered herpesvirus, for the treatment of metastatic melanoma. Despite the slower progress in translating oncolytic adenovirus to the clinic, interest in the virus remains strong. Among all the clinical trials currently using viral oncolytic agents, the largest proportion of these are using recombinant adenovirus. Many trials are currently underway to use oncolytic virus in combination with immune checkpoint inhibitors (ICIs), and early results using oncolytic adenovirus in this manner are starting to show promise. Many of the existing strategies to engineer adenoviruses were designed to enhance selective tumor cell replication without much regard to interactions with the immune system. Adenovirus possesses a wide range of viral factors to attenuate both innate anti-viral pathways and immune cell killing. In this review, we summarize the strategies of oncolytic adenoviruses currently in clinical trials, and speculate how the mutational backgrounds of these viruses may impact upon the efficacy of these agents in oncolytic and immunotherapy. Despite decades of research on human adenoviruses, the interactions that these viruses have with the immune system remains one of the most understudied aspects of the virus and needs to be improved to rationally design the next generation of engineered viruses. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdV) are one of the most important pathogens detected in acute respiratory diseases in pediatrics and immunocompromised patients. In 1953, Wallace Rowe described it for the first time in oropharyngeal lymphatic tissue. To date, more than 110 types of HAdV have been described, with different cellular tropisms. They can cause respiratory and gastrointestinal symptoms, even urinary tract inflammation, although most infections are asymptomatic. However, there is a population at risk that can develop serious and even lethal conditions. These viruses have a double-stranded DNA genome, 25–48 kbp, 90 nm in diameter, without a mantle, are stable in the environment, and resistant to fat-soluble detergents. Currently the diagnosis is made with lateral flow immunochromatography or molecular biology through a polymerase chain reaction. This review aimed to highlight the HAdV variability and the pandemic potential that a HAdV3 and 7 recombinant could have considering the aggressive outbreaks produced in health facilities. Herein, we described the characteristics of HAdV, from the infection to treatment, vaccine development, and the evaluation of the social determinants of health associated with HAdV, suggesting the necessary measures for future sanitary control to prevent disasters such as the SARS-CoV-2 pandemic, with an emphasis on the use of recombinant AdV vaccines to control other potential pandemics. [ABSTRACT FROM AUTHOR]

Fowl adenovirus 4 (FAdV-4) has the potential to be constructed as a gene transfer vector for human gene therapy or vaccine development to avoid the pre-existing immunity to human adenoviruses. To enhance the transduction of FAdV-4 to human cells, CELO fiber1 knob (CF1K) was chosen to replace the fiber2 knob in FAdV-4 to generate recombinant virus F2CF1K-CG. The original FAdV4-CG virus transduced 4% human 293 or 1% HEp-2 cells at the multiplicity of infection of 1000 viral particles per cell. In contrast, F2CF1K-CG could transduce 98% 293 or 60% HEp-2 cells under the same conditions. Prokaryotically expressed CF1K protein blocked 50% transduction of F2CF1K-CG to 293 cells at a concentration of 1.3 µg/mL while it only slightly inhibited the infection of human adenovirus 5 (HAdV-5), suggesting CF1K could bind to human cells in a manner different from HAdV-5 fiber. The incorporation of CF1K had no negative effect on the growth of FAdV-4 in the packaging cells. In addition, CF1K-pseudotyped HAdV-41 could transduce HEp-2 and A549 cells more efficiently. These data indicated that CF1K had the priority to be considered when there is a need to modify adenovirus tropism. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdVs) are prevalent worldwide and are a common cause of respiratory tract infection in people of all ages. However, little is known about HAdV infection among children with severe acute respiratory infection (SARI). The present study retrospectively analysed the molecular typing and epidemiological characteristics of HAdV‐positive samples from children with SARI from January 2017 to December 2021 in Huzhou. The results showed that 89 (8·27%) of 1078 SARI paediatric patients were positive for HAdVs. Children <5 years of age accounted for 87·64% of the positive cases. The peak seasons for HAdV infection were the first quarter and the fourth quarter. In addition, HAdV‐B and HAdV‐C were circulating among paediatric patients with SARI, of which the B3 genotype (n = 30, 51·72%) was the most prevalent and was detected every year, indicating that B3 is the main epidemic strain in the Huzhou area, followed by C1 (n = 9, 15·52%), C2 (n = 7, 12·07%) and B7 (n = 5, 8·62%). These findings provide a benchmark for future epidemiology and prevention strategies for HAdVs. [ABSTRACT FROM AUTHOR]

It is well established that human adenoviruses such as species C, types 2 and 5 (HAdV-C2 and HAdV-C5), induce a nearly complete shutoff of host-cell protein synthesis in the infected cell, simultaneously directing very efficient production of viral proteins. Such preferential expression of viral over cellular genes is thought to be controlled by selective nucleocytoplasmic export and translation of viral mRNA. While detailed knowledge of the regulatory mechanisms responsible for the translation of viral mRNA is available, the viral or cellular mechanisms of mRNA biogenesis are not completely understood. To identify parameters that control the differential export of viral and cellular mRNAs, we performed global transcriptome analyses (RNAseq) and monitored temporal nucleocytoplasmic partitioning of viral and cellular mRNAs during HAdV-C5 infection of A549 cells. Our analyses confirmed previously reported features of the viral mRNA expression program, as a clear shift in viral early to late mRNA accumulation was observed upon transition from the early to the late phase of viral replication. The progression into the late phase of infection, however, did not result in abrogation of cellular mRNA export; rather, viral late mRNAs outnumbered viral early and most cellular mRNAs by several orders of magnitude during the late phase, revealing that viral late mRNAs are not selectively exported but outcompete cellular mRNA biogenesis. [ABSTRACT FROM AUTHOR]

Porcine adenoviruses (PAdVs) are distributed in pig populations and classified into five immunologically distinct serotypes (PAdV-1 to 5). In this study, a PAdV was isolated from a fecal sample of wild boar for the first time. Whole-genome analysis revealed that this strain (Ino5) has sequence homology (approximately > 93%) throughout the genome with the PAdV-5 strain HNF-70 that was isolated from a pig in Japan in 1987, except for the hexon, E3 612R, and fiber coding regions. Two possible recombination breakpoints were detected in the hexon and E3 612R regions, which were found to have reduced GC content. Structural prediction analysis showed that a part of the hexon protein corresponding to the tower region of Ino5 had structural differences when compared with HNF-70, suggesting antigenic heterogeneity between these strains. PAdVs were detected in 1.77% (2/113) and 12% (12/100) of the fecal samples from wild boars and pigs collected in Japan by PCR, respectively. Phylogenetic analyses of the hexon and fiber genes revealed that some samples showed different grouping in the hexon and fiber genes, suggesting that these viruses have recombination events. These findings suggest that the PAdV-5 has evolved with homologous recombination events in the same manner as human adenoviruses among not only pig populations, but also wild boars in Japan. [ABSTRACT FROM AUTHOR]

Background and Objectives: Adenovirus species B, C, D, and E are the most common causes of ocular manifestations caused by adenoviruses. FDA-approved treatment agents for adenovirus infections are not available. Cell-mediated immunity is the major protective mechanism versus human adenoviruses (HAdVs) infection and T cells specific for peptide epitopes from nonstructural proteins can prevent adenoviral dissemination. E1A CR2 region of HAdVs Epitopes predicted for reinforcing cytotoxic T lymphocytes (CTLs) in the EKC patients. Among human adenoviruses E1 protein, four distinct E1A regions had a significantly higher level of homology than the rest of E1A protein. E1A protein inhibits IFN signal transduction. Epitope-based vaccines are designed to have flexible and simple methods to synthesize a vaccine, using an adjuvant to trigger fast immune responses. CTL epitopes were applied to create a multiepitope vaccine. Conserve region1 (CR1) and CR3 have less antigenicity compared to CR2. Additionally, CR3 in HAdV-D8 contains three toxic areas. CR4 similar to the two regions CR1 and CR3 do not show acceptable antigenic properties. Materials and Methods: Bioinformatics’ tools were used to predict, refine and validate the 3D structure of the construct. Effective binding was predicted by protein-protein docking of the epitope vaccine with MHC-I molecules and revealed the safety and efficacy of the predicted vaccine construct. Results: In silico analysis show that rising levels of cytotoxic CD8 + T cells, TH1 cells, macrophages, and neutrophils are linked to IFN-dominant TH1-type responses, which are detected in putative immune individuals. Conclusion: Combined with 3D protein modeling, this study predicted the epitopes of E1A CR2 protein in HAdVs. [ABSTRACT FROM AUTHOR]

Adenoviruses (AdVs) are widespread in vertebrates. They infect the respiratory and gastrointestinal tracts, the eyes, heart, liver, and kidney, and are lethal to immunosuppressed people. Mastadenoviruses infecting mammals comprise several hundred different types, and many specifically infect humans. Human adenoviruses are the most widely used vectors in clinical applications, including cancer treatment and COVID‐19 vaccination. AdV vectors are physically and genetically stable and generally safe in humans. The particles have an icosahedral coat and a nucleoprotein core with a DNA genome. We describe the concept of AdV cell entry and highlight recent advances in cytoplasmic transport, uncoating, and nuclear import of the viral DNA. We highlight a recently discovered "linchpin" function of the virion protein V ensuring cytoplasmic particle stability, which is relaxed at the nuclear pore complex by cues from the E3 ubiquitin ligase Mind bomb 1 (MIB1) and the proteasome triggering disruption. Capsid disruption by kinesin motor proteins and microtubules exposes the linchpin and renders protein V a target for MIB1 ubiquitination, which dissociates V from viral DNA and enhances DNA nuclear import. These advances uncover mechanisms controlling capsid stability and premature uncoating and provide insight into nuclear transport of nucleic acids. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdV) are a prevalent cause of diarrhea in children all over the world. Adenoviral infections are responsible for 2% to 10% of diarrheic cases. A long-term investigation was required to gain better knowledge about the incidence of HAdV in Egypt. Herein, we conducted 5 years of detection, isolation, and genotyping of HAdV in fecal and sewage samples from 2016 to 2020, in Cairo, Egypt using molecular and cell culture assays. Human adenoviruses were identified in 35 of 447 fecal samples (7.8%), but only 53.3% (64/120) of the sewage samples. Children under the age of two had the highest positive rate for HAdV infection (77.1%). Species F of HAdV was the most common prevalent genotype in fecal and sewage samples, at 88.5% and 85.9%, respectively. The most prevalent genotypes detected in fecal samples were HAdV-41 (71.2%), HAdV-40 (17.2%), HAdV-6 (5.7%), and HAdV-1 (5.7%). In contrast, the most common genotypes in sewage samples were HAdV-41 (64%), HAdVs-40 (21.8%), HAdV-6 (7.8%), HAdV-1 (4.7%), and HAdV-2 (1.6%). HAdV was detected in all months of the year, with a peak period for clinical samples from December to February (p < 0.001), which matched Egypt's rainy season, while the monthly distribution of HAdV in sewage samples remained consistent throughout the year, with no statistically significant peak period. Interestingly, the HAdV-type 41 genotype was the most common genotype during all of the years of this study. Throughout a 5-year period, our work revealed the infection rate, seasonal distribution, virus isolates, and genetic diversity of HAdV infections in environmental and clinical samples in Cairo, Egypt. Non-enteric adenovirus types (1, 2 and 6), as well as enteric adenovirus (41 and 40), may play a key role in gastroenteritis in Egypt. [ABSTRACT FROM AUTHOR]

The adenoviruses (AdVs) isolated from humans are taxonomically grouped in seven different species in the Mastadenovirus genus (HAdV-A through G). AdVs isolated from apes are often included in one of the human AdV species. Here we describe the sequence analyses of ten new AdVs that are related to the HAdV-C species and that were isolated from healthy western lowland gorillas, bonobos, chimpanzees, and orangutans kept in Dutch zoos. We analyzed these viruses and compared their genome sequences to those of human- and ape-derived AdV sequences in the NCBI GenBank database. Our data demonstrated that the ape-derived viruses clustering to HAdV-C are markedly distinct from the human HAdV-C species in the size and nucleotide composition (%GC) of their genome, differ in the amino-acid sequence of AdV proteins, and have longer RGD-loops in their penton-base proteins. The viruses form three well-separated clades (the human, the gorilla, and the combined group of the bonobo and chimpanzee viruses), and we propose that these should each be given species-level ranks. The Ad-lumc005 AdV isolated from orangutans was found to be very similar to the gorilla AdVs, and bootstrap inference provided evidence of recombination between the orangutan AdV and the gorilla AdVs. This suggests that this virus may not be a genuine orangutan AdV but may have been transferred from a gorilla to an orangutan host. [ABSTRACT FROM AUTHOR]

Background: Human adenoviruses typically cause self-limited respiratory, gastrointestinal, and conjunctival infections in healthy children. In late 2021 and early 2022, several previously healthy children were identified with acute hepatitis and human adenovirus viremia.Methods: We used International Classification of Diseases, 10th Revision, codes to identify all children (<18 years of age) with hepatitis who were admitted to Children's of Alabama hospital between October 1, 2021, and February 28, 2022; those with acute hepatitis who also tested positive for human adenovirus by whole-blood quantitative polymerase chain reaction (PCR) were included in our case series. Demographic, clinical, laboratory, and treatment data were obtained from medical records. Residual blood specimens were sent for diagnostic confirmation and human adenovirus typing.Results: A total of 15 children were identified with acute hepatitis - 6 (40%) who had hepatitis with an identified cause and 9 (60%) who had hepatitis without a known cause. Eight (89%) of the patients with hepatitis of unknown cause tested positive for human adenovirus. These 8 patients plus 1 additional patient referred to this facility for follow-up were included in this case series (median age, 2 years 11 months; age range, 1 year 1 month to 6 years 5 months). Liver biopsies indicated mild-to-moderate active hepatitis in 6 children, some with and some without cholestasis, but did not show evidence of human adenovirus on immunohistochemical examination or electron microscopy. PCR testing of liver tissue for human adenovirus was positive in 3 children (50%). Sequencing of specimens from 5 children showed three distinct human adenovirus type 41 hexon variants. Two children underwent liver transplantation; all the others recovered with supportive care.Conclusions: Human adenovirus viremia was present in the majority of children with acute hepatitis of unknown cause admitted to Children's of Alabama from October 1, 2021, to February 28, 2022, but whether human adenovirus was causative remains unclear. Sequencing results suggest that if human adenovirus was causative, this was not an outbreak driven by a single strain. (Funded in part by the Centers for Disease Control and Prevention.). [ABSTRACT FROM AUTHOR]

Human adenovirus (HAdV) infection is a major cause of respiratory disease, yet no antiviral drugs have been approved for its treatment. Herein, we evaluated the antiviral and anti-inflammatory effects of cyclin-dependent protein kinase (CDK) inhibitor indirubin-3′-monoxime (IM) against HAdV infection in cells and a transgenic mouse model. After evaluating its cytotoxicity, cytopathic effect reduction, antiviral replication kinetics, and viral yield reduction assays were performed to assess the anti-HAdV activity of IM. Quantitative real-time polymerase chain reaction (qPCR), quantitative reverse transcription PCR (qRT-PCR), and western blotting were used to assess the effects of IM on HAdV DNA replication, transcription, and protein expression, respectively. IM significantly inhibited HAdV DNA replication as well as E1A and Hexon transcription, in addition to significantly suppressing the phosphorylation of the RNA polymerase II C-terminal domain (CTD). IM mitigated body weight loss, reduced viral burden, and lung injury, decreasing cytokine and chemokine secretion to a greater extent than cidofovir. Altogether, IM inhibits HAdV replication by downregulating CTD phosphorylation to suppress viral infection and corresponding innate immune reactions as a promising therapeutic agent. [Display omitted] • CDK inhibitor IM inhibited HAdV replication in vitro with low cytotoxicity. • IM suppressed HAdV E1A transcription by downregulating phosphorylated CTD. • IM alleviated HAdV infection in the tri-receptor transgenic mouse model. • IM curbed inflammatory responses induced by HAdV infection in mice. [ABSTRACT FROM AUTHOR]

Background and Objectives: Human adenovirus type 8 is a highly contagious eye disease and is considered as the most common epidemic keratoconjunctivitis worldwide. The virus may alter the course of detection as mutations and recombination in surface antigens are associated with binding and pathogenesis in human adenovirus. The recognition of new recombinant human adenovirus has been based on sequencing of three genes, penton base, hexon and fiber. Materials and Methods:50 suspected samples of ocular keratoconjunctivitis were selected over 6 months. Following DNA extraction from isolates positive for cytopathic effect in each well, the complete sequences of hexon, fiber, and penton regions were performed on the genome of human adenovirus isolates using PCR. The sequences of capsid genes, including hexon, fiber, and penton were assessed to observe the evidence of recombination at the molecular level using genetic tools. Results: The results of nucleotide and amino acid sequence of 5/ 50 patients with epidemic keratoconjunctivitis positive for hypervariable region of hexon (132 -449), hypervariable of knob fiber (183 -362) and hypervariable penton (106 -466) aa aa aa isolates showed nucleotide and amino acid identity of 98% and 99.41%, 99% and 100%, 95% and 99.72% with hexon, fiber and penton of human adenovirus 8 subtypes. The results of phylogenetic tree and Simplot of the entire sequences and hypervariable regions of isolated hexon, fiber and penton showed all the isolates of human adenovirus from Ahvaz, Iran, were clustered with human adenovirus 8A, B, E, P and J, subtypes isolated strains from different regions of the world. Conclusion: The results of this study revealed that the human adenovirus isolates from patients with epidemic keratoconjunctivitis were closed to human adenovirus 8A, B, E, P and J subtypes. To determine the emergence of new human adenovirus D8 subtypes strain, analysis of complete genome sequence of human adenovirus was required. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdV) express either one or two virus-associated RNAs (VA RNAI or VA RNAII). The structure of VA RNA resembles human precursor microRNAs (pre-miRNA), and, like human pre-miRNA, VA RNA can be processed by DICER into small RNAs that resemble human miRNA. VA RNA-derived miRNA (mivaRNA) can mimic human miRNA post-transcriptional gene repression by binding to complementary sequences in the 3′ UTR of host mRNA. HAdV14 is a member of the B2 subspecies of species B adenovirus, and the emergent strain HAdV14p1 is associated with severe respiratory illness that can lead to acute respiratory distress syndrome. Utilizing small RNA sequencing, we identified four main mivaRNAs generated from the HAdV14/p1 VA RNA gene, two from each of the 5′ and 3′ regions of the terminal stem. There were temporal expression changes in the abundance of 5′ and 3′ mivaRNAs, with 3′ mivaRNAs more highly expressed early in infection and 5′ mivaRNAs more highly expressed later in infection. In addition, there are differences in expression between the emergent and reference strains, with HAdV14 expressing more mivaRNAs early during infection and HAdV14p1 having higher expression later during infection. HAdV14/p1 mivaRNAs were also shown to repress gene expression in a luciferase gene reporter system. Our results raise the question as to whether differential expression of mivaRNAs during HAdV14p1 infection could play a role in the increased pathogenesis associated with the emergent strain. [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory infections (SARI) threaten human health and cause a large number of hospitalizations every year. However, as one of the most common pathogen that cause acute respiratory tract infection, the molecular epidemiological information relating to human adenoviruses (HAdVs) among patients with SARI is limited. Here, we evaluate the epidemiological and molecular characteristics of HAdV infections among hospitalized patients with SARI from January 2017 to December 2019 in Huzhou, China. Methods: From January 2017 to December 2019, a total of 657 nasopharyngeal swabs collected from inpatients with SARI were screened for HAdV and other common respiratory viruses by multiplex real-time PCR. All samples that tested positive for HAdV were further typed by sequencing partial sequences of hexon gene. Genotypes of HAdV were confirmed by phylogenetic analysis. Epidemiological data were analyzed using Microsoft Excel 2010 and service solutions (SPSS) 21.0 software. Results: 251 (38.20%) samples were positive for at least one respiratory virus. HAdV was the second common viral pathogen detected, with a detection rate of 7.08%. Infection with HAdV was found in all age groups tested (0<2, 2<5, 5<15, 15<50, 50<65, ≥65). Children under 15 years old accounted for 84.62% (44/52) of the infections. Higher activity of HAdV infection could be seen in spring-early autumn season. Seven different types of HAdV belonging to 4 species (HAdV-A, B, C, E) were identified in hospitalized SARI cases, with HAdV-B3 as the most prevalent HAdV types, followed by HAdV-B7 and HAdV-E4. HAdV-B3 was the most frequently detected genotype in 2017 and 2019, accounting for 75.00% (9/12) and 63.64% (7/11) of typed HAdV infections in 2017 and 2019, respectively. No predominant strain was responsible for HAdV infections in 2018, although HAdV-B7 (28.57%, 2/7) and HAdV-C1 (28.57%, 2/7) were the major causative genotypes. Conclusions: This study revealed the prevalence and the molecular epidemiological characteristics of HAdV infections among hospitalized patients with SARI in Huzhou from January 2017 to December 2019. The HAdV prevalence is related to age and season. As the most prevalent HAdV types, HAdV-B3 was co-circulating with other types and presented an alternate prevalence pattern. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdV) are known to cause a wide range of diseases including acute respiratory infections, conjunctivitis, and acute gastroenteritis. In this study, we aimed to determine the serotypes of HAdV in patients with influenza-like illness (ILI) in the Philippines from 2006-2012 and to describe the demographic and epidemiological characteristics of patients who tested positive for HAdV. Between 2006 and 2012, the Philippine National Influenza Centre detected HAdV in 1294 samples of patients with ILI. Serotype determination was done in select samples using microneutralization, polymerase chain reaction (PCR), and sequencing methods. A total of 8 serotypes were identified (HAdV 1–7 and 11), with HAdV-2 (27.8%), and HAdV-3 (27.8%) being the most prevalent. The majority of HAdV infections were found in children below 5 years of age (79.9%). The identification of HAdV circulating serotypes may serve as guide for designing disease intervention and control strategies and will provide important information regarding the contribution of this virus to respiratory infections, particularly in children, which remain a public health burden in the Philippines. [ABSTRACT FROM AUTHOR]

RNA molecules can adopt specific RNA triplex structures to execute critical biological functions. Human adenoviruses (HAdVs) are abundant pathogens encoding the essential, noncoding virus-associated RNA I (VA RNAI). Here, we employ a triplex-specific probing assay, based on the intercalating and cleaving agent benzoquinoquinoxaline 1, 10-phenanthroline (BQQ–OP), to unravel a potential RNA triplex formation in VA RNAI. The BQQ–OP cleavage of the pathogenic HAdV type 4 (HAdV-4) VA RNAI indicates that a potential triplex is formed involving the highly conserved stem 4 of the central domain and side stem 7. Further, the integrity of the HAdV-4 VA RNAI side stem 7 contributes to a potential triplex formation in vitro and virus growth in vivo. Collectively, we propose that the HAdV-4 VA RNAI can potentially form a biologically relevant triplex structure. [ABSTRACT FROM AUTHOR]

• The incidence of seasonal respiratory viruses fell significantly in the autumn peak. • The median age of children with respiratory illnesses increased in 2020. • Intensive care unit (ICU) admission rate was comparable between SARS-CoV-2 and other respiratory viruses. • Interference is possible between SARS-CoV-2 and human rhinoviruses, human adenoviruses, and human metapneumoviruses. • Increased body mass index (BMI) correlates with increased risk of ICU admission in children. This study aimed to estimate the impact of the COVID-19 pandemic on the circulation of non-SARS-CoV-2 respiratory viruses and the clinical characteristics of COVID-19 in hospitalized children. A total of 226 and 864 children admitted to the Children's City Clinical Hospital with acute respiratory infection in September to November of 2018 and 2020 in Moscow were tested for respiratory viruses using multiplex polymerase chain reaction (PCR) and Mycoplasma pneumoniae / Chlamydia pneumoniae using enzyme-linked immunosorbent assay. The detection rate of non-SARS-CoV-2 viruses in 2020 was lower than in 2018, 16.9% versus 37.6%. An increase in the median age of children with respiratory viruses was observed during the pandemic (3 years vs 1 year). There was no significant difference in the frequency of intensive care unit (ICU) admission in children with SARS-CoV-2 and other respiratory virus infections (2.7% vs 2.9%). SARS-CoV-2 and human rhinoviruses, human metapneumoviruses, and human adenoviruses showed significantly lower than expected co-detection rates during co-circulation. An increase in body mass index (BMI) or bacterial coinfection leads to an increased risk of ICU admission and a longer duration of COVID-19 in children. The COVID-19 pandemic led to significant changes in the epidemiological characteristics of non-SARS-CoV-2 respiratory viruses during the autumn peak of the 2020 pandemic, compared with the same period in 2018. [ABSTRACT FROM AUTHOR]

The use of human adenoviruses (hAds) as oncolytic agents has demonstrated considerable potential. However, their efficacy in clinical studies is generally moderate and often varies between patients. This may, in part, be attributable to variable pre-existing neutralizing immunity in patients, which can impact the antitumor efficacy and lead to response heterogeneity. Our aim was to isolate new Ads for the development of oncolytic vectors with low prevalence of neutralizing immunity in the human population. To this end, we isolated a collection of new nonhuman primate (nhp) Ads from stool samples of four great ape species held captive. We elected 12 isolates comprising the broadest genetic variability for further characterization. For three new nhpAds, all classified as the human adenovirus B (HAdV-B) species, no neutralizing activity could be detected when exposed to a preparation of immunoglobulins isolated from a pool of >1,000 donors as a surrogate of population immunity. In addition, the nhpAds of the HAdV-B species showed enhanced oncolytic potency compared to nhpAds of the HAdV-C species as well as to human adenovirus type 5 (HAdV-C5) in vitro when tested in a panel of 29 human cancer cell lines. Next-generation sequencing of the viral genomes revealed higher sequence similarity between hAds and nhpAds of HAdV-B compared to HAdV-C, which might underlie the differences in oncolytic ability. As a proof-of-concept, the Rb-binding domain of the E1A protein of the gorilla-derived HAdV-B nhpAd-lumc007 was deleted, thereby creating a new oncolytic derivative, which demonstrated increased oncolytic potential compared to HAdV-C5. Collectively, our data demonstrate that nhpAds of the HAdV-B species can serve as an alternative for the development of potent oncolytic Ad vectors with limited pre-existing neutralizing immunity in humans. [ABSTRACT FROM AUTHOR]

Over the past decades, studies on the biology of human adenoviruses (HAdVs) mainly focused on the HAdV prototype species C type 5 (HAdV-C5) and revealed fundamental molecular insights into mechanisms of viral replication and viral cell transformation. Recently, other HAdV species are gaining more and more attention in the field. Reports on large E1B proteins (E1B-55K) from different HAdV species showed that these multifactorial proteins possess strikingly different features along with highly conserved functions. In this work, we identified potential SUMO-conjugation motifs (SCMs) in E1B-55K proteins from HAdV species A to F. Mutational inactivation of these SCMs demonstrated that HAdV E1B55K proteins are SUMOylated at a single lysine residue that is highly conserved among HAdV species B to E. Moreover, we provide evidence that E1B-55K SUMOylation is a potent regulator of intracellular localization and p53-mediated transcription in most HAdV species. We also identified a lysine residue at position 101 (K101), which is unique to HAdV-C5 E1B-55K and specifically regulates its SUMOylation and nucleo-cytoplasmic shuttling. Our findings reveal important new aspects on HAdV E1B-55K proteins and suggest that different E1B-55K species possess conserved SCMs while their SUMOylation has divergent cellular effects during infection. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdVs) usually cause asymptomatic or mild infection, but infrequently, they are responsible for various severe syndromes including neurological disorders. Various research studies have investigated the association of HAdVs with acute flaccid paralysis (AFP). The purpose of this study was to investigate the genetic diversity of HAdVs and their association with AFP. Stool samples from patients ≤ 12 years of age with suspected AFP were collected from all over Pakistan within the framework of poliovirus surveillance. Poliovirus- and enterovirus-negative samples were screened for HAdVs. For virus isolation, the human epithelial cell line HEp-2c was used, culture-positive samples were screened by nested PCR assay, and partial hexon gene sequences were used for genotype identification. Out of 172 samples, 94 were positive by virus isolation, 89 were positive by PCR, and 32 isolates were genotyped successfully. Phylogenetic analysis showed that the HAdVs belonged to species A (HAdV-A12 and A31), B (HAdV-B3 and B7), C (HAdV-C1 and C6), D (HAdV-D19 and D93), and F (HAdV-F41), showing 99-100% nucleotide sequence identity and 98.3-100% amino acid sequence identity). Most of these genotypes have been reported previously in AFP cases, but this is the first report of the detection of HAdV-D93 in stool samples from AFP cases. The detection of a significant fraction of the HAdVs genotypes indicates that these genetically distinct genotypes are circulating in Pakistan and suggests their possible role in the pathogenesis of AFP. [ABSTRACT FROM AUTHOR]

Background Seasonal and epidemic conjunctivitis (pink eye) infections are highly contagious and impose a significant economic burden worldwide. Long-term visual impairment can occur. Methods This study used metagenomic deep sequencing to evaluate pathogens causing acute infectious conjunctivitis in Burkina Faso. Results We found that pathogens causing conjunctivitis in Burkina Faso are diverse, with human adenoviruses responsible for a small fraction of the samples tested. Conclusions These results are unexpected and suggest the importance of regional surveillance. [ABSTRACT FROM AUTHOR]

· Adenovirus genomes can be generated from enrichment bait sets containing just 14 references. · Highly specific enrichment can be observed in a variety of sample matrices including stool. · Adenovirus enrichment success is not influenced by type even for types not covered in the bait set. Background: Human Adenoviruses are a common cause of disease and can cause significant morbidity and mortality in immunocompromised patients. Nosocomial transmission events can occur with whole genome sequencing playing a crucial role. This study evaluates the performance of a custom designed SureSelectXT target enrichment assay based on 14 adenovirus genomes for sequencing direct from clinical samples. Methods: Modifications were made to the SureSelectXT low input protocol to enhance performance for viral targets. Consensus sequences were generated using an in-house designed three stage bioinformatics pipeline. We assessed, percentage of on target reads, average depth of coverage and percentage genome coverage to determine assay performance across a range of sample matrices. Results: Whole genome sequences were successfully generated for 91.6 % of samples assessed. Adenovirus DNA concentration was a good indicator of enrichment success. Highly specific enrichment was observed with only 6 % of samples showing < 50 % on target reads. Respiratory and faecal samples performed well where bloods showed higher levels of non-specific enrichment likely confounded by low adenovirus DNA concentrations. Protocol performance did not appear impacted by Adenovirus type or species. Conclusion: Overall performance of this modified SureSelectXT protocol appears in line with previously published works although there are some confounding factors requiring further investigation. The use of a small RNA bait set has the potential to reduce associated costs which can be prohibitive. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdVs) are highly contagious pathogens of clinical importance, especially among the pediatric population. Studies on comparative viral genomic analysis of cases associated with severe and mild infections due to HAdV are limited. Using whole-genome sequencing (WGS), we investigated whether there were any differences between circulating HAdV strains associated with severe infections (meningitis, sepsis, convulsion, sudden infant death syndrome, death, and hospitalization) and mild clinical presentations in pediatric patients hospitalized between the years 1998 and 2017 in a tertiary care hospital group in Bern, Switzerland covering a population base of approx. 2 million inhabitants. The HAdV species implicated in causing severe infections in this study included HAdV species C genotypes (HAdV1, HAdV2, and HAdV5). Clustering of the HAdV whole-genome sequences of the severe and mild cases did not show any differences except for one sample (isolated from a patient presenting with sepsis, meningitis, and hospitalization) that formed its own cluster with HAdV species C genotypes. This isolate showed intertypic recombination events involving four genotypes, had the highest homology to HAdV89 at complete genome level, but possessed the fiber gene of HAdV1, thereby representing a novel genotype of HAdV species C. The incidence of potential recombination events was higher in severe cases than in mild cases. Our findings confirm that recombination among HAdVs is important for molecular evolution and emergence of new strains. Therefore, further research on HAdVs, particularly among susceptible groups, is needed and continuous surveillance is required for public health preparedness including outbreak investigations. [ABSTRACT FROM AUTHOR]

Background: Human adenovirus (HAdV) had been recognized as one of the most common enteric viruses associated with acute diarrhea in children. The present study was carried out to demonstrate the molecular and epidemiological characterization of HAdV Infections among children in Shandong province in China between July 2017 and June 2018. Methods: Fecal specimens were collected from children under 5 years old with acute diarrhea. DNA was extracted from the stool specimens and adenovirus DNA was detected by PCR amplification with specific primers. The amplification products were subjected to electrophoresis and visualized on a UV transilluminator. All positive RT-PCR amplification products were sequenced and the obtained sequences analyzed by MEGA (version 7.0). Demographic information and clinical manifestation data were also analyzed. Results: In total, 656 fecal specimens were collected and the overall positive rate of HAdV was 7.47%. HAdV infections were detected in all age groups, in which children aged 13–24 months presented the highest positive rate. Seasonal pattern could be observed with a peak in December, January and February. Diarrhea, vomiting, dehydration and fever were the main clinical manifestations, in which vomiting was the most common accompanied symptom. By phylogenetic analysis, four species (A, B, C, and F) were detected and seven different serotypes were identified. HAdV-41 (48.98%, 24/49) was the most common serotype followed by HAdV-3 (18.37%, 9/49), HAdV-31 (14.29%, 7/49), HAdV-7 (8.16%, 4/49), HAdV-40 (4.08%, 2/49), HAdV-1 (4.08%, 2/49) and HAdV-2 (2.04%, 1/49). Conclusion: This study indicated that HAdV infection was an important cause of acute diarrhea among children under 5 years old in Shandong province. The results will contribute to (a) increase understanding of the role of HAdV in diarrheal children and enhance identification of the predominant diarrhea pathogen for diagnosis; (b) avoid abuse of antibiotics; (c) monitor the change of prevalent HAdV serotypes and promote vaccine development and vaccination. [ABSTRACT FROM AUTHOR]

Background: Human adenoviruse (HAdV) is a major pathogen of paediatric respiratory tract infections (RTIs). Mutation or recombination of HAdV genes may cause changes in its pathogenicity and transmission. We described the epidemiology and genotypic diversity of HAdV in hospitalized children with RTIs in Beijing, China. Methods: Nasopharyngeal aspirates were collected from hospitalized children with RTIs from April 2018 to March 2019. HAdVs were detected by a quantitative real-time PCR, and the hexon gene was used for phylogenetic analysis. Results: Among 1572 samples, 90 (5.72%) were HAdV-positive. The HAdV detection rate was highest in November and July. Among HAdV-positive children, 61.11% (55/90) were co-infected with other respiratory viruses, the most common of which were human respiratory syncytial virus and human rhinovirus. The main diagnosis was bronchopneumonia, most patient have cough and fever. Children with a high viral load were more likely to have a high fever (P = 0.041) and elevated WBC count (P = 0.000). Of 55 HAdV-positive specimens, HAdV-B (63.64%), HAdV-C (27.27%), and HAdV-E (9.09%) were main epidemic species. Phylogenetic analysis indicated that hexon sequences of three samples were on the same branch with the recombinant HAdV strain (CBJ113), which was circulating in Beijing since 2016. Conclusion: The HAdV-B3 and HAdV-B7 are the main epidemic strains in Beijing, and the recombinant HAdV-C strain CBJ113 has formed an epidemic trend. [ABSTRACT FROM AUTHOR]

Background: Human Adenoviruses (HAdVs) cause a wide array of illnesses in all age groups. They particularly cause frequent morbidity among children. In China, human adenovirus types 3, 4, 7, 11, 14, 21, and 55 have caused at least seven outbreaks since 2000. However, limited studies are available regarding the epidemiological patterns and diversity of HAdVs types among hospitalized patients with respiratory tract infections (RTIs).Methods: To understand the epidemiology and subtype distribution of HAdV infections associated with RTIs in China, nasal swab (NS) clinical samples were collected from 4129 patients in a Guangzhou hospital between August 2017 and October 2019. PCR, sequencing, and phylogenetic analysis were performed on these specimens to identify HAdV subtypes.Results: HAdV was successfully sequenced in 99 (2.4%) of the 4129 NS specimens, with the highest HAdV prevalence (6.3%) found in children between the ages of 5 and 10 years. Among HAdV-positive specimens, the most prevalent genotypes identified were HAdV-B3 (55.6%) and HAdV-B7 (25.3%). The most common symptoms in the HAdV-infected patients were fever (100%), cough (80.8%), and rhinorrhea (71.8%). HAdV infections were detected throughout the year with a relatively higher prevalence in summer.Conclusion: All ages suffer adenovirus infections, but young children are at the greatest risk. This study data demonstrates that at least three species of HAdVs (species B, C, and E) are circulating in Guangzhou City, China. As antiviral therapies and type-specific vaccines become available, such epidemiological data will be useful in guiding therapy and public health interventions. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdVs) are a large family of DNA viruses that include more than 100 genotypes divided into seven species (A to G) and induce respiratory tract infections, gastroenteritis, and conjunctivitis. Genetically modified adenoviruses are also used as vaccines, gene therapies, and anticancer treatments. The APOBEC3s are a family of cytidine deaminases that restrict viruses by introducing mutations in their genomes. Viruses developed different strategies to cope with the APOBEC3 selection pressure, but nothing is known on the interplay between the APOBEC3s and the HAdVs. In this study, we focused on three HAdV strains: the B3 and C2 strains, as they are very frequent, and the A12 strain, which is less common but is oncogenic in animal models. We demonstrated that the three HAdV strains induce a similar APOBEC3B upregulation at the transcriptional level. At the protein level, however, APOBEC3B is abundantly expressed during HAdV-A12 and -C2 infection and shows a nuclear distribution. On the contrary, APOBEC3B is barely detectable in HAdV-B3-infected cells. APOBEC3B deaminase activity is detected in total protein extracts upon HAdV-A12 and -C2 infection. Bioinformatic analysis demonstrates that the HAdV-A12 genome bears a stronger APOBEC3 evolutionary footprint than that of the HAdV-C2 and HAdV-B3 genomes. Our results show that HAdV infection triggers the transcriptional upregulation of the antiviral innate effector APOBEC3B. The discrepancies between the APOBEC3B mRNA and protein levels might reflect the ability of some HAdV strains to antagonize the APOBEC3B protein. These findings point toward an involvement of APOBEC3B in HAdV restriction and evolution. IMPORTANCE The APOBEC3 family of cytosine deaminases has important roles in antiviral innate immunity and cancer. Notably, APOBEC3A and APOBEC3B are actively upregulated by several DNA tumor viruses and contribute to transformation by introducing mutations in the cellular genome. Human adenoviruses (HAdVs) are a large family of DNA viruses that cause generally asymptomatic infections in immunocompetent adults. HAdVs encode several oncogenes, and some HAdV strains, like HAdVA12, induce tumors in hamsters and mice. Here, we show that HAdV infection specifically promotes the expression of the APOBEC3B gene. We report that infection with the A12 strain induces a strong expression of an enzymatically active APOBEC3B protein in bronchial epithelial cells. We provide bioinformatic evidence that HAdVs' genomes and notably the A12 genome are under APOBEC3 selection pressure. Thus, APOBEC3B might contribute to adenoviral restriction, diversification, and oncogenic potential of particular strains. [ABSTRACT FROM AUTHOR]

Background: Viruses are responsible for a large proportion of acute respiratory tract infections (ARTIs). Human influenza, parainfluenza, respiratory-syncytial-virus, and adenoviruses are among the leading cause of ARTIs. Epidemiological evidence of those respiratory viruses is limited in the East Africa Community (EAC) region. This review sought to identify the prevalence of respiratory syncytial virus, parainfluenza, and adenoviruses among cases of ARTI in the EAC from 2007 to 2020. Methods: A literature search was conducted in Medline, Global Index Medicus, and the grey literature from public health institutions and programs in the EAC. Two independent reviewers performed data extraction. We used a random effects model to pool the prevalence estimate across studies. We assessed heterogeneity with the I2 statistic, and Cochran's Q test, and further we did subgroup analysis. This review was registered with PROSPERO under registration number CRD42018110186. Results: A total of 12 studies met the eligibility criteria for the studies documented from 2007 to 2020. The overall pooled prevalence of adenoviruses was 13% (95% confidence interval [CI]: 6–21, N = 28829), respiratory syncytial virus 11% (95% CI: 7–15, N = 22627), and parainfluenza was 9% (95% CI: 7–11, N = 28363). Pooled prevalence of reported ARTIs, all ages, and locality varied in the included studies. Studies among participants with severe acute respiratory disease had a higher pooled prevalence of all the three viruses. Considerable heterogeneity was noted overall and in subgroup analysis. Conclusion: Our findings indicate that human adenoviruses, respiratory syncytial virus and parainfluenza virus are prevalent in Kenya, Tanzania, and Uganda. These three respiratory viruses contribute substantially to ARTIs in the EAC, particularly among those with severe disease and those aged five and above. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdV) are one of the most frequent causes of respiratory infections around the world, causing mild to severe disease. In Argentina, many studies focused on the association of HAdV respiratory infection with severe disease and fatal outcomes leading to the discovery in 1984 of a genomic variant 7h associated with high fatality. Although several molecular studies reported the presence of at least 4 HAdV species (B, C, D and E) in Argentina, few sequences were available in the databases. In this study, sequences from the hexon gene region were obtained from 141 patients as a first approach to assess the genetic diversity of HAdVs circulating in Buenos Aires, Argentina. Phylogenetic analysis of these sequences and others recovered from public databases confirmed the circulation of the four above-mentioned species represented by 11 genotypes, with predominance in species B and C and shifts in their proportion in the studied period (2000 to 2018). The variants detected in Argentina, for most of the genotypes, were similar to those already described in other countries. However, uncommon lineages belonging to genotypes C2, C5 and E4 were detected, which might indicate the circulation of local variants and will deserve further studies of whole-genome sequences. [ABSTRACT FROM AUTHOR]

Currently, 90 different types of human adenoviruses (HAdV) are known, which have been classified into seven species from A to G and new adenovirus types continue to emerge. Antigenic diversity of viruses inhibits the process of creating universal vaccines and causes the development of resistance to direct-acting antiviral drugs. In addition to the rapid development of drug resistance, too narrow a range of existing drugs and a significant number of side effects limits the treatment of adenoviral infections. There is currently no specific etiotropic antiviral drug. Therefore, the development of new effective drugs and the selection of the optimal drug for the treatment of infections caused by adenoviruses remain relevant. The aim of the study was to investigate the antiviral properties of the drugs Nazoferon spray and Nazoferon drops in a model of human adenovirus serotype 3. Methods. Determination of cytotoxicity and antiviral action of drugs was performed by standard colorimetric method using MTT. The titer of the virus, synthesized in the presence of drugs was determined by the end point of dilution of the virus, which causes 50% development of the cytopathic effect of the virus on cells (СPE). Results. Low cytotoxicity of Nazoferon spray and Nazoferon drops (manufactured by JSC "Farmak", Ukraine) was shown, CC50 is 53854 IU/ml and 54357 IU/ml, respectively. Quantitative and qualitative composition of excipients had no cytotoxic effect. In prophylactic regimens, interferon preparations did not inhibit the reproduction of adenovirus in vitro. Taking into account that most of the virions remain associated with the cells during the reproduction of adenovirus in the cell, we used test to determine infectivity lysates of infected and treated cells. The infectious titer of the synthesized HAdV3 was reduced by 3.2 log10 and 3.7 log10 for Nazoferon spray and drops, respectively. Conclusions. Nazoferon spray and drops can be recommended as anti-adenoviral drugs that block the reproduction of adenovirus, and due to their bioavailability and low cost have significant advantages in the treatment of acute respiratory infections (ARIs) caused by human adenoviruses. [ABSTRACT FROM AUTHOR]

The use of infectivity assays in domestic wastewater samples is limited because of the concerns around cytotoxicity to host cells, thus, the UV inactivation efficiency of human adenoviruses (HAdVs) in wastewater remains unclear. In this study, a human adenovirus genotype five (HAdV-5) host cell line (A549 cells) was incubated with wastewater at varied dilutions from 1:1.5 to 1:4 (the ratio of wastewater to a mixture of wastewater and the cell culture medium) and the cytotoxicity was assessed by the cell morphology and viability. No change was observed in either cell viability or morphology in comparison with control samples, even at lowest dilution of 1:1.5, indicating the dilution allowed infectivity assays. The minimal degree of dilution to avoid cytotoxicity may differ with different water matrix. Consequently, the technique was applied to quantify spiked HAdV-5 after the UV disinfection of wastewater. A significant increase in UV disinfection efficiency was noted in wastewater and hydroxyl radicals (OH*) produced by the photosensitization of dissolved organic matter were suggested to be responsible for the enhancement. This study indicated that dilution can be a simple solution to avoid cytotoxicity, and UV inactivation may be enhanced in wastewater due to OH* radicals produced by UV radiation. [ABSTRACT FROM AUTHOR]

• Human adenoviruses 40/41 causing AGE showed a progressive increase from 2001 to 2013. • HAdV-F41 predominated over other adenovirus types. • It was a higher detection rate in rotavirus vaccinated than unvaccinated children. • Enteric adenovirus 40/41 showed high genetic similarity to worldwide strains. • Molecular characterization of HAdV provides critical epidemiological information. Human adenoviruses (HAdV) of species F are commonly involved in pediatric acute gastroenteritis (AGE). The real impact on Venezuelan health is unknown. To investigate the prevalence and molecular diversity of HAdV in Venezuela, 630 fecal samples collected from children with AGE in 3 cities, from 2001 to 2013, were tested by PCR. Species F and types F40/41 were identified by REA. HAdV was detected in 123 cases (19.5%), most from outpatient females under 24 months old. A progressive and substantial increase in the detection rate was observed over time, significantly higher in rotavirus vaccinated than unvaccinated children (28.4% vs. 9.5%, P = 0.00019). Phylogenetic analysis of 28 randomly selected genomes showed high similarity among HAdV-F40/41 and those worldwide. HAdV-F of type 41 prevailed (79.8%) and clustered into 2 intratypic major clades. The significant involvement of HAdV-F41 in AGE suggests the importance of actively monitoring viral agents other than rotavirus, especially after vaccine introduction. [ABSTRACT FROM AUTHOR]

Human adenovirus (HAdV) causes acute respiratory infections leading to mortality in children. This study analyzes the circulating respiratory HAdV genotypes in West Bengal, India during 2018-2022 among symptomatic patients. The overall positivity rate was 6.8%, out of which 26.4% were co-infected with other respiratory viruses. Children aged 2 to 5 years were mostly infected. Phylogenetic analysis revealed that the recombinant HAdV-B type 7/3, which has remarkable outbreak potential, predominantly circulated in this region followed by the non-recombinant HAdV-B type 3/3. Moreover, the amino acid sequences encoded by both the hexon and fiber genes of these two circulating strains possessed a few mutations that mostly diverged from the prototype strain, although the divergence was less pronounced in case of the amino acids encoded by the fiber gene of HAdV-B type 3/3. Overall, the results underscore the need for continuous surveillance of respiratory HAdV types to combat future possible epidemics. • The positivity of respiratory HAdV was 6.8% during Sep'2018 to Nov'2022 in West Bengal, India. • Highest HAdV positivity was observed in children belonging to 2-5 years of age. • Predominance of a recombinant HAdV-B 7/3 type over pure HAdV-B 3/3 type strain. [ABSTRACT FROM AUTHOR]

Human adenovirus species D (HAdV-D) types are currently being explored as vaccine vectors for coronavirus disease 2019 (COVID-19) and other severe infectious diseases. The efficacy of such vector-based vaccines depends on functional interactions with receptors on host cells. Adenoviruses of different species are assumed to enter host cells mainly by interactions between the knob domain of the protruding fiber capsid protein and cellular receptors. Using a cell-based receptor-screening assay, we identified CD46 as a receptor for HAdV-D56. The function of CD46 was validated in infection experiments using cells lacking and overexpressing CD46, and by competition infection experiments using soluble CD46. Remarkably, unlike HAdV-B types that engage CD46 through interactions with the knob domain of the fiber protein, HAdV-D types infect host cells through a direct interaction between CD46 and the hexon protein. Soluble hexon proteins (but not fiber knob) inhibited HAdV-D56 infection, and surface plasmon analyses demonstrated that CD46 binds to HAdV-D hexon (but not fiber knob) proteins. Cryoelectron microscopy analysis of the HAdV-D56 virion-CD46 complex confirmed the interaction and showed that CD46 binds to the central cavity of hexon trimers. Finally, soluble CD46 inhibited infection by 16 out of 17 investigated HAdV-D types, suggesting that CD46 is an important receptor for a large group of adenoviruses. In conclusion, this study identifies a noncanonical entry mechanism used by human adenoviruses, which adds to the knowledge of adenovirus biology and can also be useful for development of adenovirus-based vaccine vectors. [ABSTRACT FROM AUTHOR]