Pathogenesis And Immunity Of Cytomegalovirus Biology Essay
When a new virus appears within a population the first thought that comes to mind is the need to know more, to do research and to find a cure. This however could not have been the case with Cytomegalovirus. Cytomegalovirus is a latent herpes virus that in normal healthy individual typically goes unnoticed despite affecting a large percentage of the world's population.
Cytomegalovirus abbreviated CMV is a human herpes virus known as HHV-5. Cytomegalovirus is a virus from the subfamily Betaherpesvirinae. It stands as the biggest and most intricate of the herpes viruses listed in the Herpesviridae family. The Baltimore classification system places the cytomegalovirus in class I which consists of double stranded DNA viruses where a plus or minus designation for the viral genome holds no purpose (4). A mature Cytomegalovirus spans a diameter of 200 nm (2).
This virus has an icosahedral capsid that is made of 162 capsomeres. A tegument fills the space between the icosahedral capsid and a lipid envelope (2). Embedded within the tegument are many mRNAs and proteins such as the protein pp71, which aids in activities that increase the infectivity of the viral DNA, and gene transcription (3). Gp55-116 is a major envelope protein of the virus that is expressed on the cell surface of infected cells (1). Cytomegalovirus has two types of capsids respectively called A- and B- that are intranuclear in cytomegalovirus's The B capsid is the noninfectious envelope particle that contains the assembly proteins (5).
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Contained by the Cytomegalovirus's capsid is a genome of linear double stranded DNA. This genome is 240 kilobases in size which is the equivalent of 240,000 base pairs (2). The Cytomegalovirus genome contains inverted repeats that recombine to from four different isomeric forms (2).
The genome of the virus is divided into two parts: a unique long abbreviated (UL), followed by a unique short abbreviated (US). Encoded within the unique short portion of the genome of the linear double stranded DNA Cytomegalovirus is a single gene family designated 2, 6, and 11. These genes produce the MHC Class I viral evasion gene products that are expressed early on to assist the infectivity of the virus (1).
Pathogenesis and Immunity
Cytomegalovirus acquired as a primary infection in a normal healthy person does not usually present with symptoms. A small percentage of individuals may experience mild mononucleosis, hepatitis, or a drawn out fever (6). The virus behaves like most other herpes viruses staying alive, dormant and benign within the cells of the infected individual (1).
Cytomegalovirus in infants when acquired during birth or in the uterus is much more rigorous as is with immune compromised individuals. Nearly 10 percent of infants infected will have severe health problems (1). These health problems could involve anything from the spleen to the lung and if appearing at birth could increase the likelihood of having permanent disabilities or health problems concerning eyesight and hearing within the next few years. Antiviral drugs are sometimes used in infants with a symptomatic cytomegalovirus infection, but these drugs have severe side effects (6).
Human cytomegalovirus encodes for gene products that interfere with the immune response such as disrupting the MHC I ability to present viral proteins to the CD8 t-lymphocytes (3). In healthy individuals the toll like receptors located on the CD8 t- lymphocytes bind to the viral peptide MHC I complex effectively activating the CD-8 cell and gaining control over the infected cells (3). The exact relationship between immune response and human cytomegalovirus is best represented through neutralizing antibody such as anti-gp55-116 which simply targets a single product of one of the envelope glycoprotein genes (3). Cytomegalovirus uses viral mitochondria to inhibit apoptosis. Due to the inhibition of apoptosis the size of the infected cells shrinks, there is a decrease in polymerization of actin and a rounding of the cell occurs (7). In transplant patients that are seronegative for cytomegalovirus receiving seropositive allografts can increase the disposition for rejection of the transplant in recipient patients even with the use of prophylaxis antiviral; cytomegalovirus can still develop as a delayed onset leading to the death of the patient (8).
Cytomegalovirus can attach to the cell using a broad range of receptors. This feature is evident by the cytomegalovirus's ability to infect a number of vertebrate cell types. The cell surface receptor heparin sulfate proteoglycans is used by the cytomegalovirus's gM and gB glycoprotein's to attach to the cellular membrane. However due to the soluble nature of this receptor more stable receptors the integrin heterodimers are then used to induce the pH neutral fusion of the virus to the host plasma membrane(10). The nucleocapsid brings the genome to the nucleus using where it injects the genome through a nuclear pore (11).
Many of the cellular receptors including the epidermal growth factor abbreviated EGFR and the integrin heterodimers β1 and β3 work together in coordination by using signals to aid in the human cytomegalovirus's entry. Certain integrin heterodimers can act alone as receptors of human cytomegalovirus or in combination with other receptors for viral entry (10). Virion glycoprotein's B and H trigger the cellular transcription factors. After initial infection the first proteins transcribed are the immediate early proteins 1 and 2 (13).
The exact mechanism for uncoating of the cytomegalovirus is unknown but it does take place in the cytoplasm of the cell. The nucleocapsid delivers the genome directly to the nucleus. The tegument proteins are divided between the cytoplasm and the nucleus. The vhs for example stays in the cytoplasm and are used to degrade the cellular mRNA in order to make the viral mRNA more likely to be translated for protein synthesis. The VP16 is another tegument protein that binds to DNA and activates transcription (11).
Cytomegalovirus possesses the immediate early genes IE1-72 and IE2-86 that aid in altering the cell cycle by inducing S phase and delaying the exit(9). There are three possible origins of replication that UL9 protein will bind to unwinding the DNA allowing a complex to start synthesizing RNA primers. To begin synthesis of DNA a viral DNA polymerase binds replicating using a rolling circle mechanism. The synthesis of the late genes which encode for the tegument, nucleocapsid and glycoprotein are important components when acquiring the final envelope (11).
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Once the viral DNA is replicated it is put into the preassembled capsid. The partial disruption of the nuclear lamina by the recruitment of protein kinase C initiates viral egress from the nucleus. The inner nuclear membrane envelopes sub viral particles acquiring tegument proteins, and a primary envelope upon first budding, and losing this budding traveling through the outer nuclear membrane. The DNA capsid then moves to Golgi complex vesicles where they mature and exit the cell via budding (12).
Treatment and Prevention
Cytomegalovirus is a latent infection that causes mild to no symptoms in healthy persons. The main individuals at risk are those that are immune-deficient and, or pregnant (6). Pregnant women who are at risk for the cytomegalovirus infection can choose to take a more direct approach through vaccines. These vaccines could to help prevent congenital infections with cytomegalovirus; currently they are still being developed and tested with the hope that eventually they will prove useful in decreasing the risk of congenital cytomegalovirus (16).
A cytomegalovirus vaccine using glycoprotein B was shown to have a fifty percent efficiency rate. One of the target proteins of neutralizing antibodies is the glycoprotein B of the cytomegalovirus. It was shown to increase the number of antibodies against cytomegalovirus in numbers even above those with prior infections. However congenital cytomegalovirus was still found in infants that received the vaccine. A single glycoprotein does not discount the numerous other gene products and proteins that can still go on the cause infections via a different route or a different strain all together (16).
In patients with HIV, cytomegalovirus is an opportunistic pathogen that can lead to blindness and other complications if not properly addressed. The oral treatment Valganciclovir is an antiviral that is absorbed through the gut and becomes active through triphosphorylation which can then go on to inhibit viral DNA synthesis by terminating the growing polypeptide chain. Though the drug is effective when given in proper doses, the virus can become resistant due to mutations, and when interacting with some of the prescribed medications for AIDS patients can cause a suppression of bone marrow function (15).
In order to avoid cytomegalovirus infections all together prevention is the best defense. Washing your hands for at least twenty seconds with soap and water after handling children's toys, dirty diapers or anything else that may have come into contact with contaminated saliva or urine is a good prevention technique. As well as disinfecting contact surfaces and toys after use by infected children (6).
Cytomegalovirus is present in compromised populations. Those with weakened immune systems and women who are expecting are at the most risk within the general population. Cytomegalovirus is also of concern to those individuals that take care of, and handle young children (6). Recipients of transplants, newborns and blood transfusion patients are all considered part of a risk population even if they are not normally viewed as having weakened immune systems when compared the AIDS patients. Due to cytomegalovirus's latent behavior it poses a serious problem whenever the immune system is no longer able to suppress the infection. The specific conditions required to reactivate the virus are due to a combined effort between the virus and the host (17).
In women who are expecting of them 4 percent will experience a primary infection that can be transmitted across the placenta and given to the fetus through the mother's blood to go on and infect the fetus (6). The infection itself effects a large percentage of the population and once infected you are always infected by the virus it just goes latent within your body like other herpes viruses. Cytomegalovirus does not remain latent in just one specific area of the body which leads to an increased concern when it comes to blood transfusions and organ donation (17).
A look at correlations between socioeconomic status and the presence of antibodies gave a mild comparison between developing countries such as Africa and Southeast Asia and developed countries like North America and Europe as having a high versus low count of antibodies respectively. Within the United States however, when looking at the percentage of cytomegalovirus infections that occur in major cities the difference between rates of infection were almost 50 percent with over 79 percent of the population infected in Houston, Texas (17).
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Cytomegalovirus is only as dangerous as your current state of health and environment. Everyone has at some point or another come into contact with cytomegalovirus whether or not you contract the virus is dependent on the conditions of your exposure, and whether or not you suffer symptoms depends on how your body responds to the attack. The immune system is what keeps cytomegalovirus at bay, when the immune system is compromised or not fully developed the virus will reactivate. In at risk populations cytomegalovirus should not be overlooked it is a real cause for concern. Luckily the spread of cytomegalovirus can be controlled through good hygienic practices, antivirals, and hopefully vaccines in the near future.
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