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Human cytomegalovirus (HCMV) is a member of the Herpesvirus family. A cartoon of the virus particle is pictured below. The virus has a double stranded DNA genome that is covered with an iscodeltahedral shaped protein complex that is known as the capsid. The DNA and the capsid together make up the nucleocapsid which is then coated with a layer of protein known as the tegument. The tegumented nucleocapisd is surrounded by a lipid bilayer called the envelope. Embedded within the evelope are glycoproteins that allow the virus to make contact with a host cell.
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| Figure by Anita K. McElroy. If you like it please take a copy and use it but give the author credit! |
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| The viral life cycle takes approximately seventy two hours (see figure below). After the initial fusion of the viral envelope with the plasma membrane of the cell, the encapisidated virus particle is released into the cytoplasm and within minutes, transits to the nucleus. Via active transport through the nuclear pore, the capsid gains entry and viral DNA is deposited. Viral gene expression then occurs in a temporally regulated manner, first with expression of the immediate early genes, followed by the early genes, then, after viral replication has commenced, the late genes. All of the immediate early proteins have been shown to be transactivators, with IE1-72 and IE2-86 being the most well characterized. The immediate early genes are required for both early and late gene expression. Early genes generally encode for the factors that the virus requires for replication. Late gene expression occurs once the virus has begun replicating its genome and these genes encode for structural components of the virion. Nucleocapsid particles are assembled within the nucleus and then acquire their tegument and envelope via an as yet undefined pathway. Completely assembled virus particles bud off from the cell into the surrounding area and can then go on to infect other permissive cells. |
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| Figure by Anita K. McElroy. If you like it please take a copy and use it but give the author credit! |
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| The figure pictured below summarizes some of the effects of HCMV on the cell cycle. Infection with HCMV leads to specific alterations in the factors that regulate progression through the cell cycle. Activation of cyclins E and B along with inhibition of cyclins D and A set the stage for maximizing viral DNA replication and inhibiting cellular DNA replication. The virus pushes the cell through the G1 phase by activating both cyclin E and inhibiting the repressive pocket protein (PP) component of the E2F complex. The virus is able to halt the cell at that point by inhibiting progression into S phase due, at least in part, to the inhibition of cyclin A. The viral immediate early proteins, IE1-72 (IE72) and IE2-86 (IE86) are partially responsible for activating G1; whether this is due solely to their ability to inhibit the pocket proteins, or to some additional activity is not known. |
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| Figure by Anita K. McElroy and Deborah H. Spector. If you like it please take a copy and use it but give the authors credit! |
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| HCMV evades the immune system through a complicated multifactorial mechanism (see figure below). Several viral gene products are involved in the establishment of immune evasion in the productively infected cell. US2 and US11 bind the major histocompatibility complex (MHC) class 1 heavy chains, trasnporting them in a retrograde fashion from the endoplasmic reticulum (ER) into the cytosol, where they are degraded by the proteasome. US3 prevents the transport of the MHC class 1 complexes from the ER to the golgi. US6 inhibits peptide translocaion into the ER by the transporter associated with antigen processing (TAP). The MHC class 1 homolog, UL18, might asct as a decoy to inhibit natural killer (NK)-cell-mediated killing of HCMV-infected cells. Lastly, US28 functions as a receptor for the regulated on activation, normal T cell expressed and secreted (RANTES) chemokine and moncyte chemoattractant protein 1 (MCP-1), lowering extracellular levels of these proteins via internalization. |
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| Figure by Anita K. McElroy and Christopher S. Morello. If you like it please take a copy and use it but give the authors credit! |
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The figue below summarizes the physiological events that occur upon contact of the virus with the host cell. Heparin sulfate dependent association of virions with the cell results in stimulation of several signaling pathways. Through the action of a G-protein coupled receptor, adenylate cyclase and phospholipase C are activated resulting in the production of several second messengers: cAMP, IP3 (inositol tri-phosphate), and DG (diacylglycerol). These second messengers then go on to activate the MAP kinase pathway, Ca2+ release from the endoplasmic reticulum and protein kinase C respectively. The activation of the MAP kinase pathway leads to the phosphorylation and activation of phospholipase A2 which hydrolyzes membrane phospholipids to create arachidonic acid(AA). AA is then converted into a prostaglandin by PGH2 synthase in a reaction whose by-products include reactive oxygen intermediates (ROI). ROI are then thought to activate the transcription factor NF-KB. It is also believed that binding of the virus can stimulate the production of ROI through another undefined mechanism. |
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| Figure by Anita K. McElroy. If you like it please take a copy and use it but give the author credit! |
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