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→Replication
==Replication==
==Replication==
Adenoviruses possess a linear dsDNA genome and are able to replicate in the nucleus of mammalian cells using the host’s replication machinery.
The structure of adenovirus. 1 = penton capsomeres 2 = hexon capsomeres, and 3= viral genome (linear dsDNA)
Entry of adenoviruses into the host cell involves two sets of interactions between the virus and the host cell. Entry into the host cell is initiated by the knob domain of the fiber protein binding to the cell receptor. The two currently established receptors are: CD46 for the group B human adenovirus serotypes and the coxsackievirus adenovirus receptor (CAR) for all other serotypes. There are some reports suggesting MHC molecules and sialic acid residues functioning in this capacity as well. This is followed by a secondary interaction, where a specialized motif in the penton base protein interacts with an integrin molecule. It is the co-receptor interaction that stimulates internalization of the adenovirus. This co-receptor molecule is αv integrin. Binding to αv integrin results in endocytosis of the virus particle via clathrin-coated pits. Attachment to αv integrin stimulates cell signaling and thus induces actin polymerization resulting in entry of the virion into the host cell within an endosome.[2]
Once the virus has successfully gained entry into the host cell, the endosome acidifies, which alters virus topology by causing capsid components to disassociate. These changes as well as the toxic nature of the pentons results in the release of the virion into the cytoplasm. With the help of cellular microtubules the virus is transported to the nuclear pore complex whereby the adenovirus particle disassembles. Viral DNA is subsequently released which can enter the nucleus via the nuclear pore.[3] After this the DNA associates with histone molecules. Thus viral gene expression can occur and new virus particles can be generated.
The adenovirus life cycle is separated, by the DNA replication process, into two phases: an early and a late phase. In both phases a primary transcript is generated which is alternatively spliced to generate monocistronic mRNAs compatible with the host’s ribosome, allowing for the products to be translated.
The early genes are responsible for expressing mainly non-structural, regulatory proteins. The goal of these proteins is threefold: to alter the expression of host proteins that are necessary for DNA synthesis; to activate other virus genes (such as the virus-encoded DNA polymerase); and to avoid premature death of the infected cell by the host-immune defenses (blockage of apoptosis, blockage of interferon activity, and blockage of MHC class I translocation and expression).
Some adenoviruses under specialized conditions can transform cells using their early gene products. E1a (binds Retinoblastoma tumor suppressor protein) has been found to immortalize primary cells in vitro allowing E1b (binds p53 tumor suppressor) to assist and stably transform the cells. Nevertheless, they are reliant upon each other to successfully transform the host cell and form tumors.
DNA replication separates the early and late phases. Once the early genes have liberated adequate virus proteins, replication machinery and replication substrates, replication of the adenovirus genome can occur. A terminal protein that is covalently bound to the 5’ end of the adenovirus genome acts as a primer for replication. The viral DNA polymerase then uses a strand displacement mechanism, as opposed to the conventional Okazaki fragments used in mammalian DNA replication, to replicate the genome.
The late phase of the adenovirus life cycle is focused on producing sufficient quantities of structural protein to pack all the genetic material produced by DNA replication. Once the viral components have successfully been replicated the virus is assembled into its protein shells and released from the cell as a result of virally induced cell lysis.
[[Category:Adenoviridae]][[Category:To Do - Lizzie]]
[[Category:Adenoviridae]][[Category:To Do - Lizzie]]