Download Micro Chapter 42 [4-20

Micro Chapter 42: Beta and Gammaherpesviruses: CMV and Epstein-Barr Virus
Beta and gammaherpesviruses show differences in their viral genomes and the phenotype of infections
they cause
The main betaherpesvirus is human cytomegalovirus (CMV)
The main gammaherpesvirus is Epstein-barr virus (EBV)
On average, over half of people int eh US are infected with CMV, and most are infected with EBV
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This is self-limited and rarely leads to disease in healthy people, but can cause big problems in
immunosuppressed
A hallmark of all herpesvirus infections is persistent infection
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CMV and EBV persist for the lifetime of the infected host
EBV establishes persistent infection of B cells, & can go from latency to a lytic productive
infection
CMV can establish latent infection of hematopoietic cells of myeloid lineage
Intermittent excretion of both viruses on mucosal surfaces with no symptoms is common and
likely responsible for their spread
Acquisition of CMV and EBV infection in the community happens after exposure of mucosal surfaces,
including the oropharynx and genital tract, to the virus
Early in life, CMV is easily transmitted in breast milk, the most common way infants get it
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In developed countries, catching CMV is more common in adolescence, from intimate exposure
to oropharyngeal secretions or sexual contact
CMV is considered an STI
CMV also easily crosses the placenta and infects a developing fetus, causing congenital CMV
infection
o CMV is the most common viral infection of the fetus, and can lead to permanent
neuro damage and hearing loss
EBV is transmitted similar to CMV
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One exception is EBV is found in breast milk, but not transmitted that way
Almost all adults in the developing world have been infected with EBV, while in the developed
world EBV only is seen in populations with risk factors, like being poor
In populations that don’t see EBV much in childhood, infection in adolescence and young
adulthood can cause acute infectious mononucleosis
o Primary infection with CMV or EBV rarely causes symptomatic disease in kids, but
causes symptoms in adolescents
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Mono symptoms are pharyngitis, fever, lymphadenopathy, hepatitis, and lymphocytosis
with reactive lymphocytes
Immunocompromised people in hospitals can also catch EBV or CMV in blood transfusions or
transplants, and this form can often be more severe
CMV and EBV attach to target cells by low-affinity interactions with cell-surface glycosaminoglycans,
followed by high-affinity interactions with specific receptors
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2 ways they enter:
o Interaction with a receptor/coreceptor and fusion at the plasma membrane
o Interaction with a receptor/coreceptor at the plasma membrane, followed by
internalization, acid-dependent fusion, and release of the nucleocapsid and tegument
proteins from endocytic vesicles
EBV infects B cells by attaching its envelope glycoprotein to complement receptor 2 (aka CR2
or CD21)
Both CMV and EBV use glycoproteins B, H, and L to fuse the viral envelope to the endosome
membrane
o EBV does this to infect B cells
o In epithelial cells though, EBV enters at a neutral pH, and doesn’t need endocytosis
CMV and EBV replicate their nucleic acids in the nucleus of infected cells – page 431
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They will sequentially express immediate-early viral proteins, then early, and then late proteins
o These are all needed to make progeny virus
After fusion and penetration, nucleocapsids containing infectious DNA are translocated to the
nucleus
Once the virion DNA is in the nucleus, transcription is initiated by virion tegument proteins and
cell factors that activate expression of viral immediate-early genes
o Tegument proteins also disarm some host cell-intrinsic antiviral responses
Expression of viral immediate-early genes leads to sequential expression of viral genes needed
to make viral nucleic acid, including viral DNA-dependent DNA polymerase, and genes for virion
structural proteins
Assembly of CMV or EBV virions includes nucleocapsid formation, viral DNA packaging, and
envelopment, just like in all herpesviruses
Viral DNA is made as long chains of genome-length DNA copies (concatemers), and then cleaved
into unit-length genomes during packaging and capsid maturation
Newly replicated viral DNA is then encapsidated in the nucleus, and then nucleocapsids exit the
nucleus by budding through the nuclear membrane, acquire the tegument layer of protein in the
cytoplasm, and eventually become enveloped
The virions are then released by exocytosis or by death of the infected cell
The envelope glycoproteins can elicit antiviral antibodies that neutralize it
Latent viral infections – characterized by restricted viral gene expression and no progeny are made
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CMV can persist as a latent infection in CD34+ myeloid progenitor cells, and these
undifferentiated but committed cells spread to organs and differentiate, leading to reactivation
of latent infection
o Latency CMV transcripts are made, but we don’t know what they do
Latent EBV infection shows persistence of the viral genome with no lytic infection, and
expression of specific viral genes
o At first, viral genes like EB nuclear antigen 1 are expressed, to ensure maintenance and
partitioning of the viral genome as a replicating episome during expansion of infected
cells
o Expression of latent membrane proteins LMP1 and LMP2a, provides growth signals to
infected cells that drive cell proliferation
o A small # of viral genes and small RNAs are expressed in long-lived nondividing B cells,
which serve as a reservoir for EBV in the normal host
o By restricting expression of its genome, EBV can maintain its genetic material, while also
limiting its recognition by antigen-specific lymphocytes
o Reactivation of EBV from latency is sporadic
 B cells that reactivate release infectious virus that can infect epithelial cells,
leading to periods of shedding of EBV during the person’s lifetime
 Reactivation of EBV is most often in people with a defect in virus-specific T cell
responses, and those being immunosuppressed
Small noncoding RNAs called microRNAs (miRNAs) work in post-transcription gene regulation, and
serve as a major regulatory mechanism in development, homeostasis, and stress responses, including
viral infections
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Both CMV and EBV encode lots of miRNAs, that are critical in virus replication, including
interference with cell antiviral responses, and establishment and maintenance of latent
infection
Both viruses can also turn on host cell miRNAs
o EBV can turn on host cell ones that can lead to cancer
CMV infects lots of cells, including epithelial and endothelial cells, blood mononuclear cells, neural
progenitor cells, and CNS support cells
EBV infects less cells, just B cells and epithelial cells
NK cells and TC cells are very important in limiting replication of CMV and EBV
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These responses control virus replication during primary infection, and provide surveillance
during viral latency to limit reactivation
Loss of these responses leads to reactivation, virus spread, and disease
So an immunodeficiency that affects TC cells or NK cells, like HIV, put them at risk for
developing severe disease
CMV has proteins that downregulate and degrade MHC1 and MHC2s, and regulate NK cell receptors and
function
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CMV can also encode for cytokines like Il-8 and Il-10, and chemokine receptors, that regulate
inflammatory response to favor virus persistence
Ways CMV and EBV evade the host response – page 433
Most acute CMV and EBV infections are asymptomatic, especially in young kids
Primary infection in young adults causes acute mononucleosis syndrome, which shows fever, fatigue,
pharyngitis, cervical lymphadenopathy, splenomegaly, and peripheral blood monocytosis with atypical
or reactive lymphocytes
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Usually EBV, but CMV causes 1/5 of cases with these symptoms, called heterophile-negative
This is self-limited in otherwise healthy people
Once the symptoms show up, it’s cause the host immune response is already in “full swing”
Atypical lymphocytes seen in the blood are mostly activated CD8+ T cells directed against viral
antigens on infected cells
o Critical to control viral infection, and may be responsible for many of the symptoms of
mono
Newborns infected in utero with CMV can develop significant disease
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It’s acquired from mom infection, which is almost always unrecognized int eh pregnant woman
Congenital CMV infection shows multiorgan disease with unrestricted virus replication and
direct viral toxic effect, due to immature fetal immune response
Congenital CMV can show CNS issues, hepatitis, hematologic problems
o CNS disease includes hydrocephalus, retinitis, encephalomalacia, and hearing loss
o Hearing loss from congenital CMV is the most common nonfamilial cause of hearing loss
o The hearing loss can be delayed till they’re 3-4, due to waiting on virus replication
CMV can be associated with atherosclerosis and coronary artery disease
Chronic CMV and EBV infections are associated with chronic inflammatory diseases and cancers
In immunocompromised people, CMV and EBV infection can cause organ failure and death
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They can start as mono symptoms that progress to life-threatening diseases like hepatitis,
colitis, and pneumonia
For transplants, CMV cause organ rejection
Posttransplant lymphoproliferative disease (PTLD) – EBV reactivates after a transplant
EBV is an oncogenic virus that is associated with Hodgkin lymphoma, Burkitt lymphoma, nasopharyngeal
carcinoma, and gastric carcinoma
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EBV is found in almost half of Hodgkin lymphomas
also if you’ve had mono you’re at a higher risk to Hodkin lymphoma
Burkitt lymphoma is common in Africa, so it’s thought malaria-caused immunosuppression
actives B cells allowing opportunities for reactivation of EBV
To diagnose, one way is to look for large inclusions called owl eye inclusions
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Can also diagnose CMV with an antigenemia assay – uses immunofluorescence to detect CMV
antigen in circulating WBCs
o Finding CMV antigen in blood WBCs means actively replicating CMV
PCR is great for CMV and EBV
Seroconversion – a standard to detect primary infection of CMV and EBV
o Finding IgM anitbodies specific for either CMV or EBV suggests a recently acquired
infection
o Detection of IgG antibodies specific for either CMV or EBV doesn’t give you any info on
the duration of the infection
o These tests are only good for otherwise healthy people, and don’t help any in
immunocompromised people
 There is high incidence of preexisting infection in them
 The underlying immune dysfunction can lead to inconsistent serum finding
Heterophile antibodies - antibodies that aren’t specific for EBV, and instead recognize
antigens on RBCs
o They’re induced by EBV infections, and are what you’re looking for in a heterophile
antibody (aka “monospot”) test
CMV and EBV in immunocompetent people is almost always self limited and usually doesn’t need
treatment
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Immunocompromised people need antiviral meds
The viral polymerases are targeted
Ganciclovir and foscarnet inhibit CMV replication
o Ganciclovir inhibits viral DNA-dependent DNA polymerase