Adenoviridae

About Adenoviruses

Untitled2Adenoviruses are double-stranded DNA (dsDNA) viruses with icosahedral capsids and naked virions. Adenoviruses often cause mild respiratory illnesses akin to the common cold. Among viruses, adenoviruses are approximately medium size, ranging from 90-100nm in length. The prefix “adeno-” is derived from the adenoid tissue, or the tonsils, where the virus was first discovered.

Adenoviruses are transmitted by oral contact and droplet spread, via fomites, and potentially via fecal-oral transmission. The incubation period for an adenovirus infection is usually 1-10 days. Illness usually lasts just 3-5 days, or up to a week. Such sickness is usually mild and patients experience full recovery, but it can occasionally cause complications such as pneumonia, ear infection, or meningitis.


Adenoviruses and Vaccines

Adenovirus vaccines target type 4 and type 7 adenoviruses. The adenovirus vaccine is comes in tablet form and consists of two strains of adenovirus. An important caveat is that the tablet must be swallowed whole, and cannot be crushed or chewed. Adenovirus vaccines are given to military personnel between 17-50 years of age.

Adenoviruses and Kinetic Classes

Kinetic classes are groups of genes subdivided by what stage in the viral cycle they are transcribed. For instance, IE (α) genes (intermediate early genes) are transcribed early and quickly in response to a virus’s entrance into a cell. Delayed early (DE, or β) genes are transcribed relatively later. Late genes (L, or γ) genes are transcribed late (often just before cell lysis).

In Adenoviruses, the MLP, or major late promoter, is the master regulator of late gene expression. Cis-elements and trans-acting factors in turn regulate the transcription of LMP. Cis-regulatory elements are portions of non-transcribed DNA that serve as regulators of surrounding, transcribed nearby genes. Cis-regulatory elements are usually near, or adjacent to, the genes they affect. In contrast, trans-acting elements are control elements embedded within a gene. In adenoviridae, MLP levels are directly correlated to which kinetic class is presently being expressed. A similar control-mechanism protein, MLTU (major late transcription unit), serves a similar function with late genes. Furthermore, several teams of researchers have demonstrated that in adenoviruses, many successive gene products in turn serve as transcription factors for later genes. An important example of this behavior is the E1A/E2A/etc. gene pathway.


The 8 Steps of the Adenovirus Dynamic Phase: 

Ch20-04-Adenoviridae08

  1. Adsorption: The adsorption of an adenovirus onto the surface of a cell is mediated by the interaction of the viral tropogen and the coxsackie and adenovirus receptor (CAR); CAR activation by the virus creates channels that open the cell to the virus.
  1.  Penetration: When surface-exposed loops on the virus interact with CAR, the interaction is extremely strong. This creates a “topology mismatch” between the CAR and the viral tropogen, resulting in the opening of channels that allow the virus to enter the cell.
  1. Uncoating: Adenovirus uncoating is mediated by the viral protease AVP (adenovirus protease) which initiates the protein cascade that leads to the eventual uncoating of the virus. Furthermore, after a virus enters a cell, the endosome acidifies, which dissembles the viral capsid.
  1. Transcription: The MLP, the major late promoter, is the master regulator of late gene expression. Cis-elements and trans-acting factors in turn regulate the transcription of LMP. Cis-regulatory elements are portions of non-transcribed DNA that serve as regulators of surrounding, transcribed nearby genes. Cis-regulatory elements are usually near, or adjacent to, the genes they affect. In contrast, trans-acting elements are control elements embedded within a gene. In adenoviridae, MLP levels are directly correlated to which kinetic class is presently being expressed. A similar control-mechanism protein, MLTU (major late transcription unit), serves a similar function with late genes.
  1. Translation: Initiation of translation in eukaryotic mRNA involves 40S ribosome association with mRNA is mediated by the protein eIF4F.
  1. Replication: Adenovirus DNA is replicated using the proteins TP, Ad DBP, and Ad DNA Pol; the transcription of these genes is temporally separated. Hence, the genes are separated into “early” and “late” genes.
  1. Assembly: The polypeptides VI, VIII, and IX are associated with hexons, and help to assemble the viral particles. Assembly occurs in the nucleus, and occurs when monomers self-assemble into hexon and penton capsomers.
  1. Egress: The transcription of adenovirus death protein (ADP) mediates the initiation of cell lysis, which enables the departure (egress) of viral particles from the cell.

Oncolytic Adenoviruses? 

The proposed mechanism of oncolysis by adenovirus, recapitulated by Chiocca et al in 2008, hinges on the activity of the coxsackie and adenovirus receptor (CAR). Essentially, an adenovirus capsid consists of components including the penton base and the fiber. The fiber binds to the CAR, which is expressed on the membrane of certain cells; most importantly, CAR levels are upregulated on the membrane of cancerous cells


10 Things to Remember about Adenoviruses148172-004-64CF0A9A

  1. Adenoviruses have icosahedral capsids made up of 252 capsomeres.
  2. There are over 47 types of human adenovirus.
  3. Young children and active military members are at the highest risk for adenovirus infection.
  4. Adenoviruses have been used as gene vectors in preliminary research studies.
  5. Some adenoviruses incorporate into the host genome.
  6. Cytotoxic T cells destroy cells infected by adenovirus.
  7. Adenovirus usually causes respiratory illness, and rarely causes more serious complications.
  8. Adenovirus has been linked to tumorigenesis in animal models, and may have oncolytic properties.
  9. Adenoviruses are 90-100 nm in length.
  10. The major late promoter, or MLP, is a master regulator of adenovirus gene expression.

Adeno Timeline

Gene_therapy1953: Wallace P Rowe isolates the first known adenovirus.

1962: JJ Trentin discovers that Adenovirus strains 1 & 2 have oncogenic potential in baby hamsters. This was the first time any oncolytic capacity in any viruses had ever been described!

1977: SM Berget discovers splicing, which thus far had not been seen in viruses OR regular cells before!

1977: Protein primers are discovered in adenovirus.

1997: Adenovirus is used as the first viral vector in gene therapy.


What conditions are caused by adenovirus? 

  • pneumonia
  • gastroenteritis
  • acute respiratory disease
  • pharyngitis

How is adenovirus transmitted? 

  • fecal – oral route
  • via respiratory droplets
  • (less frequently) via sexual transmission

Other fun facts: 

  • the cytopathic effect of many adenoviruses is rounded, swollen cells
  • swimming pools are a common source of eye infections caused by adenovirus

Recent Developments, 2014-2015

  • Adenovirus can be used as a gene therapy vector (see figure below).
  • Adenovirus hexon hypervariable loops enable immune neutralization.
  • T-cells selectively attack adenovirus-infected cells.
  • Sea lions can get adenoviruses.
  • Adenovirus infection can prompts PLCD1 overexpression.
  • from http://transhumanismwr10206.weebly.com/uploads/1/8/3/4/18346115/1365031098.jpg

Recent Citations, 2014-2015

  • Zhao, H et al. “Adenovirus-delivered PDCD5 counteracts adriamycin resistance of osteosarcoma cells through enhancing apoptosis and inhibiting Pgp.” Int J Clin Exp Med. 2014: vol. 7, no. 12. http://www.ncbi.nlm.nih.gov/pubmed/25664052.
  • Wang, Z et al. “Mutation in fiber of adenovirus serotype 5 gene therapy vector decreases liver tropism.” Int J Clin Exp Med. 2014: vol. 7, no. 12. http://www.ncbi.nlm.nih.gov/pubmed/25663991.
  • Qi, JS et al. “Combination of interventional adenovirus-p53 introduction and ultrasonic irradiation in the treatment of liver cancer.” Oncol Lett.2015: vol. 9, no. 3. http://www.ncbi.nlm.nih.gov/pubmed/25663901.
  • Ma, J et al. “Manipulating Adenovirus Hexon Hypervariable Loops Dictates Immune Neutralisation and Coagulation Factor X-dependent Cell Interaction in Vitro and In Vivo.” PLoS Pathog. 2015: vol. 11, no. 2. http://www.ncbi.nlm.nih.gov/pubmed/25658827.
  • Taipale, K et al. “T cell subsets in peripheral blood and tumors of patients treated with oncolytic adenoviruses.” Mol Ther. 2015. http://www.ncbi.nlm.nih.gov/pubmed/25655312.
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