scholarly journals HUMAN ADENOVIRUS TYPE 4 COMPRISES TWO MAJOR PHYLOGROUPS WITH DISTINCT REPLICATIVE FITNESS AND VIRULENCE PHENOTYPES

2021 ◽  
Author(s):  
Camden R. Bair ◽  
Wei Zhang ◽  
Gabriel Gonzalez ◽  
Arash Kamali ◽  
Daniel Stylos ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Genetic Variability ◽  
Rat Model ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Polymorphism Analysis ◽  
Cotton Rat ◽  
Replicative Fitness ◽  
Naturally Occurring

Human adenovirus type 4 (HAdV-E4) is the only type (and serotype) classified within species Human mastadenovirus E that has been isolated from a human host to the present. Recent phylogenetic analysis of whole genome sequences of strains representing the spectrum of intratypic genetic diversity described to date identified two major evolutionary lineages designated phylogroups (PG) I, and II, and validated the early clustering of HAdV-E4 genomic variants into two major groups by low resolution restriction fragment length polymorphism analysis. In this study we expanded our original analysis of intra- and inter-PG genetic variability, and used a panel of viruses representative of the spectrum of genetic diversity described for HAdV-E4 to examine the magnitude of inter- and intra-PG phenotypic diversity using an array of cell-based assays and a cotton rat model of HAdV respiratory infection. Our proteotyping of HAdV-E strains using concatenated protein sequences in selected coding regions including E1A, E1B-19K and -55K, DNA polymerase, L4-100K, various E3 proteins, and E4-34K confirmed that the two clades encode distinct variants/proteotypes at most of these loci. Our in vitro and in vivo studies demonstrated that PG I and PG II differ in their growth, spread, and cell killing phenotypes in cell culture and in their pulmonary pathogenic phenotypes. Surprisingly, the differences in replicative fitness documented in vitro between PGs did not correlate with the differences in virulence observed in the cotton rat model. This body of work is the first reporting phenotypic correlates of naturally occurring intratypic genetic variability for HAdV-E4. IMPORTANCE Human adenovirus type 4 (HAdV-E4) is a prevalent causative agent of acute respiratory illness of variable severity and of conjunctivitis and comprises two major phylogroups that carry distinct coding variations in proteins involved in viral replication and modulation of host responses to infection. Our data show that PG I and PG II are intrinsically different regarding their ability to grow and spread in culture and to cause pulmonary disease in cotton rats. This is the first report of phenotypic divergence among naturally occurring known genetic variants of a HAdV type of medical importance. This research reveals readily detectable phenotypic differences between strains representing phylogroups I and II, and it introduces a unique experimental system for the elucidation of the genetic basis of adenovirus fitness and virulence and thus for increasing our understanding of the implications of intratypic genetic diversity in the presentation and course of HAdV-E4-associated disease.

scholarly journals HUMAN ADENOVIRUS TYPE 4 COMPRISES TWO MAJOR PHYLOGROUPS WITH DISTINCT REPLICATIVE FITNESS AND VIRULENCE PHENOTYPES

2020 ◽  
Author(s):  
Camden R Bair ◽  
Wei Zhang ◽  
Gabriel Gonzalez ◽  
Arash Kamali ◽  
Daniel Stylos ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Genetic Variability ◽  
Rat Model ◽  
Phenotypic Diversity ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Polymorphism Analysis ◽  
Cotton Rat ◽  
Replicative Fitness

Human adenovirus type 4 (HAdV-E4) is the only type (and serotype) classified within species Human mastadenovirus E that has been isolated from a human host to the present. Recent phylogenetic analysis of whole genome sequences of strains representing the spectrum of intratypic genetic diversity described to date identified two major evolutionary lineages designated phylogroups (PG) I, and II, and validated the early clustering of HAdV-E4 genomic variants into two major groups by low resolution restriction fragment length polymorphism analysis. In this study we expanded our original analysis of intra- and inter-PG genetic variability, and used a panel of viruses representative of the spectrum of genetic diversity described for HAdV-E4 to examine the magnitude of inter- and intra-PG phenotypic diversity using an array of cell-based assays and a cotton rat model of HAdV respiratory infection. Our proteotyping of HAdV-E strains using concatenated protein sequences in selected coding regions including E1A, E1B-19K and -55K, DNA polymerase, L4-100K, various E3 proteins, and E4-34K confirmed that the two clades encode distinct variants/proteotypes at most of these loci. Our in vitro and in vivo studies demonstrated that PG I and PG II differ in their growth, spread, and cell killing phenotypes in cell culture and in their pulmonary pathogenic phenotypes. Surprisingly, the differences in replicative fitness documented in vitro between PGs did not correlate with the differences in virulence observed in the cotton rat model. This body of work is the first reporting phenotypic correlates of naturally occurring intratypic genetic variability for HAdV-E4.

scholarly journals In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1483
Author(s):  
Emily A. Bates ◽  
John R. Counsell ◽  
Sophie Alizert ◽  
Alexander T. Baker ◽  
Natalie Suff ◽  
...  
Keyword(s):  
Viral Vector ◽  
Ex Vivo ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Cell Types ◽  
In Vivo Evaluation ◽  
In Vivo Biodistribution ◽  
Adenovirus Type 5

The human adenovirus phylogenetic tree is split across seven species (A–G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of pre-existing immunity detected across screened populations. However, many aspects of the basic virology of species D—such as their cellular tropism, receptor usage, and in vivo biodistribution profile—remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49)—a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry, but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting, whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells, and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen, whilst avoiding liver interactions, such as intravascular vaccine applications.

scholarly journals In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications

2021 ◽  
Author(s):  
Emily A. Bates ◽  
John R. Counsell ◽  
Sophie Alizert ◽  
Alexander T. Baker ◽  
Natalie Suff ◽  
...  
Keyword(s):  
Viral Vector ◽  
Ex Vivo ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Cell Types ◽  
In Vivo Evaluation ◽  
In Vivo Biodistribution ◽  
Adenovirus Type 5

The human adenovirus phylogenetic tree is split across seven species (A-G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of preexisting immunity detected across screened populations. However, many aspects of the basic virology of species D, such as their cellular tropism, receptor usage and in vivo biodistribution profile, remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49), a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen whilst avoiding liver interactions, such as intravascular vaccine applications.

scholarly journals Human Adenovirus Type 55 Distribution, Regional Persistence, and Genetic Variability

2020 ◽  
Vol 26 (7) ◽  
pp. 1497-1505
Author(s):  
Jun Hang ◽  
Adriana E. Kajon ◽  
Paul C. F. Graf ◽  
Irina Maljkovic Berry ◽  
Yu Yang ◽  
...  
Keyword(s):  
Genetic Variability ◽  
Human Adenovirus ◽  
Adenovirus Type

Sequence Analysis of the Putative E3 Region of Bovine Adenovirus Type 2

Intervirology ◽  
1994 ◽  
Vol 37 (5) ◽  
pp. 277-286
Author(s):  
L.E. Esford ◽  
Y. Haj-Ahmad
Keyword(s):  
Dna Sequences ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Open Reading Frames ◽  
Bovine Adenovirus ◽  
Adenovirus Type 5 ◽  
E3 Region ◽  
Adenovirus Type 2

Adenoviruses are nonenveloped icosahedral-shaped particles. The double-stranded viral DNA genome contains four major early transcription units, designated El (a and b), E2 (a and b), E3 and E4, which are expressed in a regulated manner soon after infection. The gene products of the region E3, shown to be nonessential for viral replication in vitro, are believed to be involved in counteracting host immunosurveillance. Human adenovirus type 5 DNA sequences of transcription units L4 and L5 adjacent to E3 were used to localize E3 within the bovine adenovirus type 2. The DNA sequences between 74.8 and 84.4 mu containing E3 and the fiber gene were determined. The E3 region was found to consist of about 2.3 kb pairs and to encode four proteins longer than 60 amino acids. However, these four open reading frames did not show significant homology to any other known adenovirus DNA or protein sequence.

scholarly journals Antiviral Activity of Exopolysaccharides Produced by Lactic Acid Bacteria of the Genera Pediococcus, Leuconostoc and Lactobacillus against Human Adenovirus Type 5

Medicina ◽  
2019 ◽  
Vol 55 (9) ◽  
pp. 519 ◽  
Author(s):  
Biliavska ◽  
Pankivska ◽  
Povnitsa ◽  
Zagorodnya
Keyword(s):  
Cell Cycle ◽  
Lactic Acid ◽  
Lactic Acid Bacteria ◽  
Flow Cytometric Analysis ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Infected Cells ◽  
Adenovirus Type 5 ◽  
Number Of Cells

Background and objectives: The use of antagonistic probiotic microorganisms and their byproducts represents a promising approach for the treatment of viral diseases. In the current work, the effect of exopolysaccharides (EPSs) produced by lactic acid bacteria from different genera on the structural and functional characteristics of cells and the development of adenoviral infection in vitro was studied. Materials and Methods: Cytotoxicity of six EPSs of lactic acid bacteria of the genera Lactobacillus, Leuconostoc and Pediococcus was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. The influence of the EPSs on the infectivity of human adenovirus type 5 (HAdV-5) and on the cell cycle under a condition of adenovirus infection was studied using plaque reduction assay and flow cytometric analysis, respectively. Results: It was shown that exopolysaccharides were non-toxic to Madin-Darby bovine kidney cells (MDBK) as they reduced their viability by 3–17%. A change in the distribution of the cell cycle phases in the non-infected cell population treated with EPSs was observed. The analysis demonstrated an increase in the number of cells in the S phase by 47% when using EPSs 15a and a decrease in the number of cells in the G1 phase by 20–27% when treated with the EPSs 15a, 33a, and 19s. The use of EPSs did not led to the normalization of the life cycle of HAdV-5 infected cells to the level of non-infected cells. The EPSs showed low virucidal activity and reduced the HAdV-5 infectivity to 85%. Among the studied exopolysaccharides, anti-adenovirus activity was found for EPS 26a that is produced by Lactobacillus spp. strain. The treatment of cells with the EPS following virus adsorption completely (100%) suppressed the formation and release of HAdV-5 infectious. Conclusions: EPS 26a possessed distinct anti-HAdV-5 activity and the obtained data demonstrate the potential of using exopolysaccharides as anti-adenoviral agents.

scholarly journals Development and Assessment of Human Adenovirus Type 11 as a Gene Transfer Vector

2005 ◽  
Vol 79 (8) ◽  
pp. 5090-5104 ◽  
Author(s):  
Daniel Stone ◽  
Shaoheng Ni ◽  
Zong-Yi Li ◽  
Anuj Gaggar ◽  
Nelson DiPaolo ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Neutralizing Antibodies ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Cell Types ◽  
Widespread Application ◽  
Human Cd34 ◽  
Immature Dendritic Cells

ABSTRACT Adenovirus vectors based on human serotype 5 (Ad5) have successfully been used as gene transfer vectors in many gene therapy-based approaches to treat disease. Despite their widespread application, many potential therapeutic applications are limited by the widespread prevalence of vector-neutralizing antibodies within the human population and the inability of Ad5-based vectors to transduce important therapeutic target cell types. In an attempt to circumvent these problems, we have developed Ad vectors based on human Ad serotype 11 (Ad11), since the prevalence of neutralizing antibodies to Ad11 in humans is low. E1-deleted Ad11 vector genomes were generated by homologous recombination in 293 cells expressing the Ad11-E1B55K protein or by recombination in Escherichia coli. E1-deleted Ad11 genomes did not display transforming activity in rodent cells. Transduction of primary human CD34+ hematopoietic progenitor cells and immature dendritic cells was more efficient with Ad11 vectors than with Ad5 vectors. Thirty minutes after intravenous injection into mice that express one of the Ad11 receptors (CD46), we found, in a pattern and at a level comparable to what is found in humans, Ad11 vector genomes in all analyzed organs, with the highest amounts in liver, lung, kidney, and spleen. Neither Ad11 genomes nor Ad11 vector-mediated transgene expression were, however, detected at 72 h postinfusion. A large number of Ad11 particles were also found to be associated with circulating blood cells. We also discovered differences in in vitro transduction efficiencies and in vivo biodistributions between Ad11 vectors and chimeric Ad5 vectors possessing Ad11 fibers, indicating that Ad11 capsid proteins other than fibers influence viral infectivity and tropism. Overall, our study provides a basis for the application of Ad11 vectors for in vitro and in vivo gene transfer and for gaining an understanding of the factors that determine Ad tropism.

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