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PLoS Pathogens Sep 2023Viruses hijack host proteins to promote infection and dampen host defenses. Adenovirus encodes the multifunctional protein VII that serves both to compact viral genomes...
Viruses hijack host proteins to promote infection and dampen host defenses. Adenovirus encodes the multifunctional protein VII that serves both to compact viral genomes inside the virion and disrupt host chromatin. Protein VII binds the abundant nuclear protein high mobility group box 1 (HMGB1) and sequesters HMGB1 in chromatin. HMGB1 is an abundant host nuclear protein that can also be released from infected cells as an alarmin to amplify inflammatory responses. By sequestering HMGB1, protein VII prevents its release, thus inhibiting downstream inflammatory signaling. However, the consequences of this chromatin sequestration on host transcription are unknown. Here, we employ bacterial two-hybrid interaction assays and human cell culture to interrogate the mechanism of the protein VII-HMGB1 interaction. HMGB1 contains two DNA binding domains, the A- and B-boxes, that bend DNA to promote transcription factor binding while the C-terminal tail regulates this interaction. We demonstrate that protein VII interacts directly with the A-box of HMGB1, an interaction that is inhibited by the HMGB1 C-terminal tail. By cellular fractionation, we show that protein VII renders A-box containing constructs insoluble, thereby acting to prevent their release from cells. This sequestration is not dependent on HMGB1's ability to bind DNA but does require post-translational modifications on protein VII. Importantly, we demonstrate that protein VII inhibits expression of interferon β, in an HMGB1-dependent manner, but does not affect transcription of downstream interferon-stimulated genes. Together, our results demonstrate that protein VII specifically harnesses HMGB1 through its A-box domain to depress the innate immune response and promote infection.
Topics: Humans; Interferons; HMGB1 Protein; Nuclear Proteins; Chromatin; Adenoviridae
PubMed: 37703278
DOI: 10.1371/journal.ppat.1011633 -
The Science of the Total Environment Nov 2023Beach sand harbors a diverse group of microbial organisms that may be of public health concern. Nonetheless, little is known about the presence and distribution of...
Beach sand harbors a diverse group of microbial organisms that may be of public health concern. Nonetheless, little is known about the presence and distribution of viruses in beach sand. In this study, the first objective was to evaluate the presence of seven viruses (Aichi virus, enterovirus, hepatitis A virus, human adenovirus, norovirus, rotavirus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) in sands collected at public beaches. The second objective was to assess the spatial distribution of enteric viruses in beach sand. To that end, 27 beach sand samples from different beaches in Portugal were collected between November 2018 and August 2020 and analyzed for the presence of viruses. At seven beaches, samples were collected in the supratidal and intertidal zones. Results show that viruses were detected in 89 % (24/27) of the sand samples. Aichi virus was the most prevalent (74 %). Noroviruses were present in 19 % of the samples (norovirus GI - 15 %, norovirus GII - 4 %). Human adenovirus and enterovirus were detected in 48 % and 22 % of the samples, respectively. Hepatitis A virus and rotavirus were not detected. Similarly, SARS-CoV-2 in beach sand collected during the initial stages of the pandemic was also not detected. The detection of three or more viruses occurred in 15 % of the samples. Concentrations of viruses were as high as 7.2 log copies (cp)/g of sand. Enteric viruses were found in higher prevalence in sand collected from the supratidal zone compared to the intertidal zone. Human adenovirus was detected in 43 % of the supratidal and 14 % in the intertidal samples and Aichi virus in 57 % and 86 % of the intertidal and supratidal areas, respectively. Our findings suggest that beach sand can be a reservoir of enteric viruses, suggesting that it might be a vehicle for disease transmission, particularly for children, the elderly, and immunocompromised users.
Topics: Child; Humans; Aged; SARS-CoV-2; Sand; COVID-19; Enterovirus; Norovirus; Rotavirus; Adenoviruses, Human
PubMed: 37517729
DOI: 10.1016/j.scitotenv.2023.165836 -
Viruses Feb 2024Adenoviruses (Ad) have the potential to induce severe infections in vulnerable patient groups. Therefore, understanding Ad biology and antiviral processes is important... (Review)
Review
Adenoviruses (Ad) have the potential to induce severe infections in vulnerable patient groups. Therefore, understanding Ad biology and antiviral processes is important to comprehend the signaling cascades during an infection and to initiate appropriate diagnostic and therapeutic interventions. In addition, Ad vector-based vaccines have revealed significant potential in generating robust immune protection and recombinant Ad vectors facilitate efficient gene transfer to treat genetic diseases and are used as oncolytic viruses to treat cancer. Continuous improvements in gene delivery capacity, coupled with advancements in production methods, have enabled widespread application in cancer therapy, vaccine development, and gene therapy on a large scale. This review provides a comprehensive overview of the virus biology, and several aspects of recombinant Ad vectors, as well as the development of Ad vector, are discussed. Moreover, we focus on those Ads that were used in preclinical and clinical applications including regenerative medicine, vaccine development, genome engineering, treatment of genetic diseases, and virotherapy in tumor treatment.
Topics: Humans; Adenoviridae; Genetic Vectors; Genetic Therapy; Vaccines; Neoplasms; Oncolytic Virotherapy
PubMed: 38543743
DOI: 10.3390/v16030377 -
Human Vaccines & Immunotherapeutics Dec 2023Herpes zoster (HZ) results from waning immunity following childhood infection with varicella zoster virus (VZV) but is preventable by vaccination with recombinant HZ...
Herpes zoster (HZ) results from waning immunity following childhood infection with varicella zoster virus (VZV) but is preventable by vaccination with recombinant HZ vaccine or live HZ vaccine (two doses or one dose, respectively). Vaccine efficacy declines with age, live HZ vaccine is contraindicated in immunosuppressed individuals, and severe local reactogenicity of recombinant HZ vaccine is seen in up to 20% of older adults, indicating a potential need for new vaccines. Nonreplicating chimpanzee adenovirus (ChAd) vectors combine potent immunogenicity with well-established reactogenicity and safety profiles. We evaluated the cellular and humoral immunogenicity of ChAdOx1 encoding VZV envelope glycoprotein E (ChAdOx1-VZVgE) in mice using IFN-γ ELISpot, flow cytometry with intracellular cytokine staining, and ELISA. In outbred CD-1 mice, one dose of ChAdOx1-VZVgE (1 × 10 infectious units) elicited higher gE-specific T cell responses than two doses of recombinant HZ vaccine (1 µg) or one dose of live HZ vaccine (1.3 × 10 plaque-forming units). Antibody responses were higher with two doses of recombinant HZ vaccine than with two doses of ChAdOx1-VZVgE or one dose of live HZ vaccine. ChAdOx1-VZVgE boosted T cell and antibody responses following live HZ vaccine priming. The frequencies of polyfunctional CD4+ and CD8+ T cells expressing more than one cytokine (IFN-γ, TNF-α and IL-2) were higher with ChAdOx1-VZVgE than with the conventional vaccines. Results were similar in young and aged BALB/c mice. These findings support the clinical development of ChAdOx1-VZVgE for prevention of HZ in adults aged 50 years or over, including those who have already received conventional vaccines.
Topics: Animals; Mice; Herpesvirus 3, Human; Adenovirus Vaccines; Adenoviridae; Antibodies, Viral; Herpes Zoster; Herpes Zoster Vaccine; Vaccination; Cytokines; Immunogenicity, Vaccine
PubMed: 36785938
DOI: 10.1080/21645515.2023.2175558 -
Molecular Therapy : the Journal of the... Oct 2023Gliomas are the most prevalent and devastating primary malignant brain tumors in adults. Despite substantial advances in understanding glioma biology, there have been no... (Review)
Review
Gliomas are the most prevalent and devastating primary malignant brain tumors in adults. Despite substantial advances in understanding glioma biology, there have been no regulatory drug approvals in the US since bevacizumab in 2009 and tumor treating fields in 2011. Recent phase III clinical trials have failed to meet their prespecified therapeutic primary endpoints, highlighting the need for novel therapies. The poor prognosis of glioma patients, resistance to chemo-radiotherapy, and the immunosuppressive tumor microenvironment underscore the need for the development of novel therapies. Gene therapy-based immunotherapeutic strategies that couple the ability of the host immune system to specifically kill glioma cells and develop immunological memory have shown remarkable progress. Two adenoviral vectors expressing Ad-HSV1-TK/GCV and Ad-Flt3L have shown promising preclinical data, leading to FDA approval of a non-randomized, phase I open-label, first in human trial to test safety, cytotoxicity, and immune-stimulatory efficiency in high-grade glioma patients (NCT01811992). This review provides a thorough overview of immune-stimulatory gene therapy highlighting recent advancements, potential drawbacks, future directions, and recommendations for future implementation of clinical trials.
Topics: Animals; Humans; Brain Neoplasms; Rodentia; Adenoviridae; Glioma; Genetic Therapy; Thymidine Kinase; Genetic Vectors; Tumor Microenvironment
PubMed: 37574780
DOI: 10.1016/j.ymthe.2023.08.009 -
Pharmaceuticals (Basel, Switzerland) Oct 2023Human adenovirus type 7 (HAdV7) infection causes severe pneumonia, yet there are still no breakthroughs in treatment options for adenovirus, and the road to antiviral...
Human adenovirus type 7 (HAdV7) infection causes severe pneumonia, yet there are still no breakthroughs in treatment options for adenovirus, and the road to antiviral drug development faces major challenges. We attempted to find new drugs and we stumbled upon one: selenadiazole. Selenadiazole has been shown to have significant anti-tumor effects due to its unique chemical structure and drug activity. However, its effectiveness against viruses has not been evaluated yet. In our study, selenadiazole also showed superior antiviral activity. In vitro experiments, selenadiazole was able to inhibit adenovirus-mediated mitochondrial-oxidative-damage-related apoptosis, and in in vivo experiments, selenadiazole was able to inhibit apoptosis by modulating the apoptotic signaling pathway Bcl-2/Stat3/NF-κB, etc., and was able to largely attenuate adenovirus-infection-induced pneumonia and lung injury in mice. This study aims to describe a new antiviral treatment option from the perspective of anti-adenovirus-mediated oxidative stress and its associated apoptosis and to provide theoretical guidance for the treatment of clinical adenovirus infection to a certain extent.
PubMed: 37895944
DOI: 10.3390/ph16101474 -
Med (New York, N.Y.) Oct 2023RH5 is a leading blood-stage candidate antigen for a Plasmodium falciparum vaccine; however, its safety and immunogenicity in malaria-endemic populations are unknown. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
RH5 is a leading blood-stage candidate antigen for a Plasmodium falciparum vaccine; however, its safety and immunogenicity in malaria-endemic populations are unknown.
METHODS
A phase 1b, single-center, dose-escalation, age-de-escalation, double-blind, randomized, controlled trial was conducted in Bagamoyo, Tanzania (NCT03435874). Between 12 April and 25 October 2018, 63 healthy adults (18-35 years), young children (1-6 years), and infants (6-11 months) received a priming dose of viral-vectored ChAd63 RH5 or rabies control vaccine. Sixty participants were boosted with modified vaccinia virus Ankara (MVA) RH5 or rabies control vaccine 8 weeks later and completed 6 months of follow-up post priming. Primary outcomes were the number of solicited and unsolicited adverse events post vaccination and the number of serious adverse events over the study period. Secondary outcomes included measures of the anti-RH5 immune response.
FINDINGS
Vaccinations were well tolerated, with profiles comparable across groups. No serious adverse events were reported. Vaccination induced RH5-specific cellular and humoral responses. Higher anti-RH5 serum immunoglobulin G (IgG) responses were observed post boost in young children and infants compared to adults. Vaccine-induced antibodies showed growth inhibition activity (GIA) in vitro against P. falciparum blood-stage parasites; their highest levels were observed in infants.
CONCLUSIONS
The ChAd63-MVA RH5 vaccine shows acceptable safety and reactogenicity and encouraging immunogenicity in children and infants residing in a malaria-endemic area. The levels of functional GIA observed in RH5-vaccinated infants are the highest reported to date following human vaccination. These data support onward clinical development of RH5-based blood-stage vaccines to protect against clinical malaria in young African infants.
FUNDING
Medical Research Council, London, UK.
Topics: Adult; Child; Child, Preschool; Humans; Infant; Adenoviruses, Simian; Antibodies, Viral; Malaria Vaccines; Malaria, Falciparum; Rabies; Tanzania; Adolescent; Young Adult; Double-Blind Method
PubMed: 37572659
DOI: 10.1016/j.medj.2023.07.003 -
Journal of Medical Virology Oct 2023In the quest to eliminate measles virus (MV) and rubella virus (Ruv), every suspected case must be properly identified and diagnosed. Since 2017, in Milan (Italy), a...
In the quest to eliminate measles virus (MV) and rubella virus (Ruv), every suspected case must be properly identified and diagnosed. Since 2017, in Milan (Italy), a total of 978 measles and rubella suspected cases (fever and rash) were investigated and 310 were not laboratory confirmed (discarded cases). To improve surveillance activities, we investigated the presence in discarded cases of 8 other viral pathogens commonly associated with rash: human herpesvirus 6 (HHV-6) and 7 (HHV-7), parvovirus B19 (B19V), enterovirus (EV), Epstein-Barr virus (EBV), human adenovirus (HAdV), cytomegalovirus (HCMV), and SARS-CoV-2. Differential diagnosis was carried out on 289 discarded cases by multiplex real-time PCR assays. At least one pathogen was detected in 188 cases (65.1%) with HHV-7 being the most frequently detected virus. No difference in the number of detected infections overtime was observed and infections were identified in all age groups. As expected, most HHV-6, EV, HAdV, and HCMV-positive cases were found in children aged 0-4 years and HHV-7 was most frequent in the 15-39 age group. In light of the World Health Organization measles elimination goal, the introduction of laboratory methods for differential diagnosis is required for the final classification of clinically compatible cases. The used screening panel allowed us to increase the percentage of virus-positive cases to 87.5%, allowing us to clarify viral involvement and epidemiology, improve diagnosis, and strengthen surveillance activities. As all investigated pathogens were detected, this diagnostic panel was a suitable tool to complement MV and RuV surveillance activities.
Topics: Child; Humans; Adolescent; Young Adult; Adult; Diagnosis, Differential; Epstein-Barr Virus Infections; Antibodies, Viral; Immunoglobulin M; Herpesvirus 4, Human; Measles; Rubella; Measles virus; Enterovirus; Exanthema; Fever; Enterovirus Infections; Herpesvirus 6, Human; Adenoviruses, Human
PubMed: 37796084
DOI: 10.1002/jmv.29141 -
PloS One 2023Circulating tumor cells (CTCs) are present in the blood of cancer patients from the early stage of cancer development, and their presence has been correlated with...
Circulating tumor cells (CTCs) are present in the blood of cancer patients from the early stage of cancer development, and their presence has been correlated with patient prognosis and treatment responses. Accordingly, CTCs have been attracting attention as a novel biomarker for early detection of cancer and monitoring of treatment responses. However, since patients typically have only a few CTCs per milliliter of blood, development of an accurate and highly sensitive CTC detection method is crucial. We previously developed a CTC detection method using a novel conditionally replicating adenovirus (Ad) that expresses green fluorescence protein (GFP) in a tumor cell-specific manner by expressing the E1 gene using a tumor-specific human telomerase reverse transcriptase (hTERT) promoter (rAdF35-142T-GFP). CTCs were efficiently detected using rAdF35-142T-GFP, but GFP expression levels in the CTCs and production efficiencies of rAdF35-142T-GFP were relatively low. In this study, in order to overcome these problems, we developed four types of novel GFP-expressing conditionally replicating Ads and examined their ability to visualize CTCs in the blood samples of lung cancer patients. Among the four types of novel recombinant Ads, the novel conditionally replicating Ad containing the 2A peptide and the GFP gene downstream of the E1A gene and the adenovirus death protein (ADP) gene in the E3 region (rAdF35-E1-2A-GFP-ADP) mediated the highest number of GFP-positive cells in the human cultured tumor cell lines. Titers of rAdF35-E1-2A-GFP-ADP were significantly higher (about 4-fold) than those of rAdF35-142T-GFP. rAdF35-E1-2A-GFP-ADP and rAdF35-142T-GFP efficiently detected CTCs in the blood of lung cancer patients at similar levels. GFP+/CD45- cells (CTCs) were found in 10 of 17 patients (58.8%) for both types of recombinant Ads.
Topics: Humans; Neoplastic Cells, Circulating; Adenoviridae; Lung Neoplasms; Green Fluorescent Proteins; Tumor Cells, Cultured; Cell Line, Tumor
PubMed: 37856461
DOI: 10.1371/journal.pone.0286323 -
[Research and application of the SARS-CoV-2 vaccine based on adenovirus vector technology platform].Zhonghua Yu Fang Yi Xue Za Zhi [Chinese... Jul 2023During the global efforts to prevent and control the COVID-19 pandemic, extensive research and development of SARS-CoV-2 vaccines using various technical approaches have... (Review)
Review
During the global efforts to prevent and control the COVID-19 pandemic, extensive research and development of SARS-CoV-2 vaccines using various technical approaches have taken place. Among these, vaccines based on adenovirus vector have gained substantial knowledge and experience in effectively combating potential emerging infectious diseases, while also providing novel ideas and methodologies for vaccine research and development (R&D). This comprehensive review focuses on the adenovirus vector technology platform in vaccine R&D, emphasizing the importance of mucosal immunity induced by adenoviral vector-based vaccine for COVID-19 prevention. Furthermore, it analyzes the key technical challenges and obstacles encountered in the development of vaccines based on the adenovirus vector technology platform, with the aim of providing valuable insights and references for researchers and professionals in related fields.
Topics: Humans; COVID-19 Vaccines; Pandemics; COVID-19; SARS-CoV-2; Viral Vaccines; Adenoviridae; Technology
PubMed: 37198717
DOI: 10.3760/cma.j.cn112150-20230419-00309