Replication,+Reproduction,+and+Infection

= Reproductive Cycles of EBV and Replication of Virions  =

Viral Reproductive Cycles
Viruses can exhibit two types of reproductive cycles—lytic cycles, in which the host cell lyses and dies, and lysogenic cycles, in which the host cell survives. In both cycles, the virus enters the host cell, releases its genome, and forces the host cell to produce proteins and nucleic acids to form new viruses. In the lytic cycle, the host cell bursts open (lyses) in order to release these viruses, causing the death of the cell. However, in the lysogenic cycle, the viral genome becomes incorporated into the host chromosome, spreading quietly throughout the organism when the infected cell reproduces through meiosis. A lytic cycle can be triggered if the viral genome passes out of the host chromosome, triggering release of the replicated viruses and lysis of the host cell.

Lytic and Lysogenic Cycles of EBV
The Epstein-Barr virus can reproduce through both cycles, making it a //temperate// virus. However, the majority of the time EBV reproduces through a lysogenic cycle. This explains the behavior of EBV—it exists, dormant, in the vast majority of people, flaring up occasionally. In its lytic cycle, EBV produces certain proteins, including gp350 and gp110, which synthesize virions. These virions can actually bud from the host cell’s membrane, making lysis technically unnecessary.

Virions are not produced in its much more common latent cycle—only a handful of viral proteins. These proteins include Epstein-Barr nuclear antigens, latent membrane proteins that inhibit protein kinases (including tyrosine-kinase signaling), and different types of viral RNA. There are different “programs” of latency in which different combinations of these proteins are produced, as well as a lytic “program.” EBV will “switch on” one program in order to produce as many virions as possible before the virus is attacked by the host’s cell immune system. Thus, whether or not EBV enters a lytic or lysogenic cycle is determined by the capability of the host cell’s immune system.  Only if the host cell cannot inhibit replication of viral DNA will synthesis of viral proteins occur. Once EBV is seriously threatened by the host’s immune response, it will recede into latency, possibly flaring up again as a result of physical or environmental changes to the host. This capability allows EBV to live undetected in its host for, theoretically, its entire lifetime.



//The two reproductive cycles of EBV. Note how the immune response by the host cell causes EBV to go into a lysogenic cycle. Source: University of Wisconsin-Madison. //

Infection
EBV is specific to certain human tissues. While EBV’s host range includes natural killer cells, smooth muscle cells, and T cells, the vast majority of the time it infects B lymphocytes (a type of white blood cell) and epithelial cells in the mouth and throat. (This infection causes the swelling of the throat and lymph nodes seen in EBV-caused infectious mononucleuosis.) EBV usually replicates inside oro-pharyngeal epithelial cells and remains dormant within B lymphocytes.

EBV contains glycoproteins that attach to receptors on the host cell. (There must also be the proper environment—for instance, the proper pH level—to occur, as with all transduction pathways within cells). This causes the capsid to fuse with the cell membrane in a process comparable to endocytosis, causing the virion to be drawn inside the cell. Once inside, the viral genome, which was previously a linear molecule curled into a ring, becomes circular. Then, the viral genome enters the host cell’s nucleus, “taking over” the cell. It uses the cell’s materials to reproduce viral genetic material and proteins to form new virions. Like all herpesviruses, EBV replicate inside the nucleus. This allows EBV to quickly control the host cell’s response to infection, as well as to take full advantage of the host cell’s structure and enzymes relating to DNA transcription. Because of this, EBV has a more complex genome than many other viruses. Inside the nucleus, the capsid and viral genome of EBV is assembled, using the host cell’s own materials. The virions then bud out from the nucleus (herpesviruses, unlike other viruses, contain the //nuclear// membrane of their host cell, rather than the //cellular// membrane) and exit the cell. However, the full process of production of viral proteins will only occur in a lytic cycle, as discussed above.

While the basic process is the same, different mechanisms are used by EBV to infect B cells as opposed to epithelial cells. In the case of B cells, the viral protein gp350 binds to complement receptor 2, while the viral protein gp42 binds to the MHC class II molecule. This process triggers endocytosis—the host cell takes in the virion, which fuses with the cell membrane within the cell with the help of gHgL and gB. When infecting epithelial cells, on the other hand, the virus fuses with the cell membrane on the side //outside// the cell. The protein gp350 still binds to CR2, but the gHgL binds to its receptor as well on the //surface// of the cell. Gp42 is actually an inhibitor to fusion of EBV with epithelial cell membranes. In another complication, because epithelial cells lack MHC class II, EBV replicated within epithelial cells contain many molecules of a certain three-part glycoprotein complex, gHgL42, that is needed for fusion between EBV and the membrane of B cells. Thus, ironically, EBV from epithelial cells infect B cells more effectively than EBV from B cells. The reverse is true - EBV synthesized in B cells is more infectious to epithelial cells than B cells.  //<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif; font-size: 16px;">Proteins of EBV. Note the gp350, gp42, gL, and gH on the upper right side. Source: National Academy of Sciences. //

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif; font-size: 16px;">The discussion of this process can get quite complex; however, the basic process is fairly simple. The EBV virus attaches to the membrane of epithelial or B lymphocyte cells by means of glycoproteins; the virion enters the nucleus; the viral genome either becomes incorporated into the host cell’s membrane (lysogenic cycle) or triggers the replication of new virions, which bud from the cell (lytic cycle).