This webpage was produced as
an assignment for an undergraduate course at Davidson College
is Epstein-Barr Virus?
Epstein-Barr virus (EBV) is a gamma-herpesvirus and
is composed of linear DNA about 172 kilobases in length. EBV infects about
95% of the world's adult population between 35 and 40 years of age. Since
EBV is a herpesvirus, EBV is dormant in the host forever after primary
infection. EBV is responsible for mononucleosis other wise known as ìmonoî.
(Baumforth et al., 1999) Mononucleosis is more numerous in countries with
high standards of living than in countries with lower standards of living
because infection at a younger age leads to a symptom less infections.
Thus, in countries where living conditions are crowded and modern methods
of sanitation have not been developed, children are exposed to EBV during
the first few years of their life, and develop a symptom less infection.
Infection often pass unnoticed, and these individuals then have immunity
for the rest of their lives. On the other hand, in countries where the
standard of living is high and modern sanitation has been established,
exposure to EBV is delayed to young adulthood, ages 15 to 30. Then infection
results in symptomatic mononucleosis. (O.R.R. et al., 1981)
is Epstein-Barr Virus Transmitted?
EBV is found in the saliva of the host and is mainly
transmitted through close personal contact involving the exchange of saliva.
EBV has been called ìthe kissing diseaseî since EBV can be transmitted
by the exchange of saliva during kissing. EBV can also be transmitted by
sharing utensils or drinking containers. Transmission in the air or by
blood is very rare. (O.R.R. et al., 1981)
is Epstein-Barr Virus Found?
EBV primarily infects the oropharynx specifically the
salivary glands and oral mucosal membrane as well as the nasopharyngeal
epithelial tissue. Viral replication takes place in these locations and
insures the production of more virus to be passed on to new hosts through
saliva. After infection of the oropharynx and nasopharyngeal tissues, EBV
infects B-Cells where replication of the virus may also occur, but most
importantly EBV can enter a state of latency within the B-Cells allowing
it to remain dormant within the host for the remainder of the individual's
lifetime. (Baumforth et al., 1999)
are the Symptoms of EBV?
An infection by EBV resulting in mononucleosis has no
preference for a particular sex nor is there a particular season for EBV.
If infected as a child the symptoms are very mild and often unnoticeable
but might result in a mild sore throat or a minor case of tonsillitis.
If infected as a adolescent symptoms can be very vague at first. Often
an infected individual will complain of fatigue, malaise, headaches, chills,
puffy eyes, and loss of appetite. As the infection progresses symptoms
like fever, sore throat, swollen lymph nodes, difficulty in swallowing
due to tonsillitis, minor aches and pains, and bleeding gums occur as well
as jaundice or a rash in rare cases. The fever of 101- 105 °F
last for about five days but maybe last intermittently for another week.
In about 50% of cases the spleen becomes swollen as well. Rarely does an
EBV infection result in death. In cases that this has occurred, air
way obstruction due to swollen lymphatic tissue, a ruptured spleen, or
inflammation of the heart or tissue surrounding the heart causing a heart
attack are the causes of death. In some cases EBV infections last for 6
or more months resulting in a condition called Chronic EBV Syndrome in
which the patient's symptoms persist with severity resulting in extreme
fatigue, respiratory infections, a severe sore throat, largely swollen
lymph nodes, persistent fever and headaches, and depression. (O.R.R. et
is Epstein-Barr Virus Diagnosed?
Symptoms of an EBV infection resulting in mononucleosis
can mislead diagnosis. Symptoms may resemble other infections such
as the sore throat of a strep infection, the painful stiff neck of meningitis,
the abdominal pains of an appendicitis, the rash of measles or even rubella,
and even the swollen lymph nodes of certain cancers. The fatigue and loss
of appetite resulting from mono may be misinterpreted as infectious hepatitis.
Sore throat, high fever, and swollen lymph nodes may be misinterpreted
as leukemia. Therefore other methods of detection must be used to detect
infection by EBV. (O.R.R. et al., 1981)
Since EBV can produce certain antigens known as
heterophil antigens, a Paul-Bunnell test or heterophil antibody test is
often used to detect an EBV infection. Since heterophil antibodies have
the ability to clot sheep or horse red blood cells, a small amount of the
patient's blood is added to some sheep or horse blood to see if clotting
occurs. Testing for EBV in this manner and obtaining a titer of 1:10 means
the patient has mono. Often diagnosis using this test is misleading since
younger children do not produce large enough amounts of heterophil antibodies
to obtain the necessary titer, but they still might have the infection.
Therefore other test are used when the Paul-Bunnell test is not positive
in patients suspected of having an EBV infection. Also other infections
can produce heterophil antibodies as well and mislead diagnosis. Thus other
methods such as obtaining a serotype profile are used. (O.R.R. et al.,
Here a measurement of the different antibodies produced
during infection against the different antigens that EBV displays during
its infection is obtained. Other than heterophil antigens, EBV produces
early antigens (EAs) 2-4 weeks into infection and viral capsid antigens
(VCAs) 4-6 weeks into infection both of which are produced during the acute
phase of infection. During the latent phase of infection, Epstein-Barr
virus nuclear antigens (EBNA) are produced. A measurement of antibody response
to these antigens allows for an identification of current infection, recent
infection, or past infection. During acute EBV infection IgG and IgM antibodies
to EAs and VCAs are elevated and no anti-EBNA antibodies are present which
represents a current infection. A recent infection is characterized by
small amounts of IgM antibodies to EAs, large amounts of IgG antibodies
to VCAs, and no anti-EBNA antibodies. For a past infection moderate IgG
and anti-EBNA antibodies are present which continue at moderation for life.
(Baumforth et al., 1999)
Enzyme-linked immunosorbent assay test (ELISA) or
immunofluorescence can be used to detect EBV antibodies and thus an EBV
infection. Also a Southern blot analysis of DNA accompanied with polymerase
chain reaction (PCR) of saliva and throat washings can be used to detect
EBV. (Ikuta et al., 1999)
does Epstein-Barr Virus Do?
After infecting the oropharynx tissues such as the salivary
glands, EBV then infects and transforms B-Cells into B-Cells with unlimited
growth potential. Cytotoxic T-Cells and Natural Killer Cells are then activated
in defense against EBV and regulate the elimination of infected B-Cells.
In extreme cases when long lasting infection results, agammaglobulinemia,
the lack of gamma globulin, occurs due to T-Cells severely suppressing
the B-Cells. In such cases Chronic EBV Syndrome is observed, and symptoms
from EBV last for up to six months due to the severity of B-Cell suppression.
At this time other infections can occur due to the suppression of the immune
system which can complicate recovery. The occurring infections are treated
and eventually the patient recovers. On the other hand, if the T-Cell response
is not strong enough, unrestricted growth of B-Cell lymphocytes occurs
resulting in a lymphoma. Normally an EBV infection occurs, and the patient
observes the usual symptoms such as fever and swollen lymphatic tissue
that result from the immune system fighting the proliferation of infected
B-Cells until full recovery is accomplished. (O.R.R. et al., 1981)
does Epstein-Barr Virus Operate?
EBV suppresses the immune system through several mechanisms
and spreads throughout the host. EBV infects B-Cells by binding to the
CD21 receptor on the B-Cell surface resulting in internalization of the
virus. Either EBV causes the B-Cell to enter a lytic phase or to progress
towards a latent phase depending on which proteins are synthesized during
infection. (Baumforth et al., 1999)
During the lytic phase, new viruses are synthesized
and eventually the B-Cell lyses releasing the viruses which then enter
other non infected B-Cells. Also during the lytic phase, the proteins BZLF1
and BRLF1, viral transactivator proteins, are expressed on the B-Cells,
and BCRF1 and BHRF1, lytic genes, are expressed as well. (Baumforth et
are the Function of the Lytic Genes?
makes a homologue similar to interleukin-10 (IL-10). IL-10 inhibits TH1
T-Cells; Since TH1 T-Cells are inhibited, the secretion of interferon-gamma,
a macrophage activating cytokine, by the TH1 T-Cells does not occur. Thus
EBV suppresses the immune system by inhibiting the activation of macrophages.
(Baumforth et al., 1999)
makes a protein like BCL-2 which can protect the cell during the lytic
phase from apoptosis. (Baumforth et al., 1999)
In the lytic phase, the BARF1 protein is secreted
from EBV infected B-Cells during lytic replication and binds to colony-stimulating
factor-1 (CSF-1), a cytokine that induces macrophage activation. Thus,
by secreting BARF1, EBV suppresses macrophage activation. (Strockbine et
al., 1998). Nonetheless at the end of the lytic phase, a downregulation
of latent genes occurs and the cell undergoes death releasing newly replicated
viruses. (Baumforth et al., 1999)
are the Functions of the Latent Proteins?
EBNA1 is a DNA binding protein that controls the replication of the virus
within infected cells. EBAN1 is required for maintaining latency. (Baumforth
et al., 1999)
During the latent phase, EBV causes B-Cells to become
lymphoblastoid cells, B-Cells with accelerated growth. Replication of the
virus does not occur, and the B-Cell becomes a reservoir for EBV. In the
latent phase, certain genes are expressed resulting in proteins which signify
this phase: six nuclear proteins called Epstein-Barr virus nuclear antigens
EBNA1, EBNA2, EBNA3, EBNA3B, EBNA3C, and EBNA leader protein (EBNA-LP),
the latent proteins: LMP1, LMP2A, LMP2B, and the Epstein-Barr early RNAs:
EBER1 and EBER2. (Baumforth et al., 1999)
this protein results in B-Cell transformation by upregulating the genes
that code for CD23, CD21, LMP1, and LMP2. (Baumforth et al., 1999)
EBNA3B, and EBNA3C: Little is known about these three proteins
except that EBNA3A and EBNA3C are necessary for EBV transformation but
EBNA3B is not. EBNA3C transactivates EBNA2 regulated genes but blocks the
EBNA2 transactivation of LMP1 and LMP2. (Baumforth et al., 1999)
EBAN-LP along with EBNA2 are the first EBV proteins to be expressed after
infection of the B-Cell. They act together to activate cyclin D2 synthesis
which allows the B-Cell to enter the G1 phase of the cell cycle. (Baumforth
et al., 1999)
LMP1 is a protein similar to ion channels and G protein receptors. When
LMP1 genes are expressed in latent cells a dramatic change in the phenotype
of the B-Cell results. LMP1 is involved in processes that ultimately result
in increased expression of cell adhesive molecules resulting in cell clumping,
expression of CD23, CD39, CD40, and CD44, and decreased expression of CD10.
LMP1 can also protect the B-Cell from apoptosis by inducing BCL-2, MCL-1
and A20, anti-apoptotic proteins. LMP1 also induces the production of interleukin-6
and interleukin-10. LMP1 accomplishes its function by signaling through
four different pathways: the nuclear factor kB (NF-kB) pathway, the c-Jun
N terminal kinase ((JNK)-AP-1) pathway, the p38/MAPK (mitogen activated
protein kinase) pathway, and the Janus kinase ((JAK)-STAT (signal transducers
and activators of transcription)) pathway. (Baumforth et al., 1999)
LMP2B: LMP2A obstructs signaling pathways that are trigger by
the binding of the B-Cell antigen to the B-Cell receptor complex. LMP2A
proteins compete with SRC proteins and SYK proteins to block the kinases
that are activated by those proteins. Blockage prevents the transition
of the B-Cell into the lytic phase maintaining EBV latency. Little is known
about LMP2B, but what is suspected is that this protein interacts with
LMP2A and ultimately restores the SRC and SYK kinases allowing B-Cell receptor
signal transduction. (Baumforth et al., 1999)
EBER2: EBER1 and EBER2 are small polyadenylated RNAs and are
the most abundant EBV RNAs in the latency infected cell; thus they are
used as markers for detection of latent EBV infections. But, the main function
of EBER1 and EBER2 is to complex with the interferon inducible protein
kinase, PKR, which causes the inhibition of the antiviral and antiproliferation
effects of interferons, thus counteracting PKRs effects allowing for the
proliferation of the B-Cell. (Baumforth et al., 1999)
However there is a small number of lymphoblastoid
cells that go from that latent stage back into the lytic stage, and this
is mediated by BZLF1 and BRLF1. (Baumforth et al., 1999)
EBV can also infect Natural Killer Cells (NK Cells).
The receptor for EBV on NK Cells is not know, but EBV can enter NK Cells
without being phagocytosed which was determined from a study conducted
in which NK Cells were treated with cytochalasin B, a phagocytosis inhibitor,
and the EBV genome was still found inside the NK Cells. The rest of the
study determined that EBV induced apoptosis of NK cells and that this was
Fas/FasL apoptosis determined from the observation that Fas/FasL expression
increased on NK Cells when treated with EBV. Thus EBV is able to exert
its immunosuppressive effects on NK Cells as well. (Larochelle et al.,
Also when EBV interacts with NK Cells, the production
of interleukin-8 (IL-8) results which is a chemokine that attracts neutrophils.
This interaction also causes neutrophils to secrete Macrophage Inflammatory
Protein-1alpha (MAP-1alpha) which attracts B-Cells to the site of infection.
This result is beneficial to EBV because it ultimately allows more B-Cells
locate at an area of infection giving EBV more B-Cells to infect. This
further allows the spread of infection. (McColl et al., 1997)
Does the Immune System React to EBV?
Cytotoxic CD8 T-Cells specific for a certain EBV antigen
find B-Cells bearing their antigen and kill them; NK Cells can also kill
EBV infected B-Cells. During the lytic stage, CD8 T-Cells specific for
BZLF1 and BRLF1 proteins find EBV infected B-Cells bearing these proteins
and kill them. During the latent stage, CD8 T-Cells for latent proteins
regulate the amount of latent protein expressing EBV infected B-Cells also.
(Steven et al., 1997)
Constant exposure to IL-10, as seen in patients
with chronic EBV infections, results in anti-IL-10 antibodies being made.
These antibodies are hypothesized to be produced by CD5 B-Cells which are
known to be the source of autoantibodies such as ones against IL-10, and
CD5 B-Cells have been shown to increase by three fold during an EBV infection.
Thus the immune system fights back with anti-IL-10 antibodies to unsuppress
macrophage activation. (Tanner et al., 1997)
Infected B-Cells can be caused to undergo CD95-CD95L-mediated
apoptosis (Fas/FasL apoptosis) by CD4 T-Cells. Some TH1 CD4 T-Cells bear
CD95L and can bind to EBV infected B-Cells bearing the CD95 receptor ultimately
resulting in apoptosis. This normal mechanism of regulation of B-Cell
growth is observed during EBV infection. (Wilson et al., 1998)
There Different Strains of EBV?
There are two strains of EBV,
EBV-1 and EBV-2, which differ in the regions that code for the EBNAs and
EBERs. EBV-2 is less effective at causing B-Cell growth and proliferation
than EBV-1. This is mainly a result of differences in the coding regions
of the gene for EBNA2. (Baumforth et al., 1999)
is the Treatment for EBV?
There is no treatment for an EBV infection resulting
in mononucleosis except to treat the symptoms. An infection by EBV can
last from a few days to months. The exact duration is not know. Rest, limited
activity, and plenty of fluids is the usual treatment. Strenuous exercise
is avoided so as not to rupture or damage the swollen spleen. Aspirin or
tylenol is given for headaches. Salt gargles are recommended for sore throats.
The infection seems to go away on its own over time. (O.R.R. et al., 1981)
There are no antibiotics available to treat EBV.
Antibiotics are only given to treat secondary infections during mono. If
a patient comes down with a streptococcal throat infection, the individual
is treated with penicillin or erythromycin. However in some cases when
penicillin is administered to a patient, a rash develops which is misinterpreted
as an allergic response to penicillin. Therefore penicillin is not administered
to patients with mono because the patient may mistakenly be told not to
take penicillin in the future. If the spleen is ruptured surgery should
follow. Lastly, corticosteriods such as prednisone are often given to lesson
symptoms such as a swollen heart or tissues surrounding the heart and breathing
obstruction. (O.R.R. et al., 1981)
There Vaccines for EBV?
There is no current vaccine for EBV but one is being
studied that contains the protein EBNA3 which will hopefully result in
activation of the immune system resulting in antibodies against EBV but
without the symptoms of a usual EBV infection. (O.R.R. et al., 1981)
is EBV Involved in cancers?
EBV has been known to be involved with several cancers.
Burkittís lymphoma is characterized by chromosomal translocations involving
chromosome 8 and chromosome 14, 2, or 22 which results in the deregulation
of MYC protein expression resulting in increased B-Cell proliferation.
The presence of EBV in B-Cells with Burkittís lymphoma has been correlated
with a break in chromosome 8 involving the MYC locus that is different
than the break in chromosome 8 that is found in B-Cells with Burkittís
lymphoma that do not contain EBV. Thus each type of Burkittís lymphoma
results in a different method of deregulation of the MYC protein but with
the same result, increased B-Cell proliferation. (Baumforth et al., 1999)
EBV has also been linked to nasopharyngeal carcinoma
since EBV has been found in undifferentiated nasopharyngeal carcinomas.
PCR has revealed that LMP2A and LMP2B genes are expressed in these carcinomas,
and other latent transcripts have been found running through the BAMHI
A region of the EBV genome in the opposite direction of the conventional
lytic cycle MRNAs transcribed over this region. Thus EBV may be the cause
of nasopharyngeal carcinomas. (Baumforth et al., 1999)
Similar BAMHI A transcripts have also been found
in Hodgkinís lymphoma, and thus EBV has been linked to Hodgkinís as well.
(Baumforth et al., 1999)
1. Baumforth K.R., Young L.S., Flavell K.J., et al. The Epstein-Barr virus
and its association with human cancers. Journal of Molecular Pathology
2. Ikuta K., Satoh Y., Hoshikawa Y., Siarjenji T. Detection of Epstein-Barr
virus in salivas and throat washings in healthy adults and children. Microbes
and Infection 1999; 2:115-120.
3. Larochelle B., Flamand L., Gourde P., et al. Epstein-Barr Virus
Infects and Induces Apoptosis in Human Neutrophils. Blood 1998;
4. McColl S.R., Roberge C.J., Larachelle B., et al. EBV Induces the
Prodution and Release of IL-8 and Macrophage Inflammatory Protein-1alpha
in Human Neutrophils. The Journal of Immunology 1997; 159:6164-6168.
5. Office of Research Reporting (O.R.R.), Public Response National
Institute of Allergy and Infectious Diseases, National Institute of Health.
Mononucleosis. Bethesda: National Institute of Health; 1981. p1-6.
6. Steven N.M., Annels N.E., Kumar A., et al. Immediate Early and Early
Lytic Cycle Proteins Are Frequent Targets of the Epstein-Barr Virus-induced
Cytotoxic T Cell Response. J. Exp. Med. 1997; 185:1605-1618.
7. Strockbine L.D., Cohen J. I., Farrah T., et al. The Epstein-Barr
Virus BARF1 Gene Encodes a Novel, Soluble Colony-Stimulatin Factor-1 Receptor.
of Virology 1998; 72:4015-4021.
8. Tanner J.E., Diaz-Miltoma F., Rooney C.M., et al. Anti-Interleukin-10
Antibodies in Patients with Chronic Active Epstein-Barr Virus Infection.
The Journal of Infectious Disease 1997; 176:1454-14.
9. Wilson A.D., Redchenko I., Williams N.A., Morgan A.J. CD4+ T cells
inhibit growth or Epstein-Barr virus-transformed B Cells through Cd95-CD95
ligand-mediated apoptosis. International Immunology 1998; 10:1149-1157.
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