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Herpesviruses
Basic properties
● From the greek word herpein= to creep
● Large enveloped viruses
● Double-stranded, linear DNA genome
● Ubiquitous viruses- in every organism which sought
● All cause lifelong latent infections
● Latent infection can be reactivated
● Make enzymes involved in nucleic acid metabolism
3 subfamilies separated by sequence and biology
● Alphaherpesvirinae- short reproductive cycle
● Betaherpesvirinae- long reproductive cycle
● Gammaherpesvirinae- long reproductive cycle
○ related to Epstein-Barr virus which is in the gamma family
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Eg: pseudorabies virus (pigs); Marek’s disease virus (chickens); channel catfish
virus; pacific pond turtle HV
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It
is shut down by an immune response, but the virus always has a latent infection which
causes reactivation, which causes disease and produces viral particles
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The reactivation can occur
several times or just once, for example cold sores are reoccuring, sometimes monthly,
whereas varicella is only once to cause Shingles, and this tends to be in elderly patients

when their immune systems are weakened
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This means we have co-evolved for millions of years- battle of the virus vs immune
system
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95% for varicella
virus, as most people would've had chickenpox as children
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There is a capsid that encloses the
viral genome, the DNA is linear
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Genome
large genome with 2 unique areas; UL and US
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These are at
the beginning of gene names which tells us which part of the genome they come from
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the
size of the genome can range between 120-230kb depending on which herpes virus it is,
VZV (varicella) is 120, HSV is 150kb, CMV is 230
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They can encode over
80 proteins, HIV only has 9, more proteins are being identified currently
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They express enough
proteins to counteract immune response to viral infection very successfully
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6 for the capsid, and 23 in the tegument- a lot of these proteins
are found to be unessential for the virus, meaning that some of the genes can be deleted
without any effect on replication inside the lab, so that suggests that those proteins are there
for survival inside a host cell, as no proteins are made for no reason
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As soon as infection
occurs- immediate early genes are transcribed to code for proteins that will activate the next
round of transcription
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Then late genes which are structural proteins that make up the capsid and
envelope etc
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transcription of alpha, beta, and
gamma mRNA encode for immediate early, early, and late proteins
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entry by plasma membrane fusion is also
the same in HIV entry
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the first event is where glycoprotein C is an
envelope protein that binds to heparin sulfate on the cell surface- not an essential event, it
just makes attachment more efficient
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Then fusion
occurs between the envelope and the cell membrane, which requires Gb and Gh and GL
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Next, the genome has to get into the
nucleus, so the capsid moves to the nuclear pore but it is too big to get through, so they bind
to the outside of the nuclear pore which causes a conformational change in the capsid and
the DNA is injected into the nucleus
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This is where transcription takes place (in the nucleus) so it can use the host RNA
polymerase 2 to transcribe viral genes
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One of these is VP16 which is very important to initiate gene
expression from that genome that has made it into the nucleus, because VP16 is the
molecule that activates those immediate early genes
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Those sequences are bound by cellular protein called Oct-1
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VP16 is one of the most powerful
known transactivating proteins, far more powerful than any protein in a human cell
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DNA replication involves mainly viral proteins, but there are a few
cellular ones that are recruited to particular areas
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then additional complex encoded by the virus called helicase
primase that unwinds the DNA and allows access for the virus encoded DNA polymerase,
and then you get the new DNA strand growing and replication of the strand
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It is an icosahedral capsid with a diameter of 120nm
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VP19c and
VP23 form triplexes located between capsomeres
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VP26 associates with all of the hexons, but the role of this protein is not clear, and
again the cell can survive and replicate without it
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It has a ring of 12 subunits of UL6, and this
identifies it as the portal
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Virion assembly
the capsid has to acquire the tegement and envelope
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The latter is the most accepted
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the capsid is assembled in the nucleus with its tegument proteins, buds into the nuclear
membrane, and release full viral particle out of the cell membrane
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2
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3
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The glycoproteins go out of the cell, and then are
recruited back into endocytic tubules, which wrap around the capsid, the glycoproteins
attach to the capsid and then it fuses with the cell membrane, and releases a full virion
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Latently infected cells do not produce any viral particles- how they evade the immune
system
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sunlight, stress, colds
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the virus is inapparent
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Many
clinical problems are associated with reactivation
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site of latency establishment
HSV- sensitive ganglia in the neck- trigeminal ganglia (HSV-1)
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Other herpes viruses establish latency in immune cells
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Pathogenesis of herpes
HSV-1 causes cold sores, HSV-2 causes genital lesions, VZV- chicken pox/shingles, EBVglandular fever, CMV- cytomegalovirus affects pregnancy and immunosuppressed
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Chances are you are not aware
of that
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The virus then travels in retrograde fashion and establishes latent
infection in cell body of sensory neuron- that is where it stays for life
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It transmits across from
the neuron to the epithelia to replicate and cause the classic blister of coldsores
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Because neurons
are non-dividing, the HSV genome doesn't have to replicate
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There is however one RNA molecule
made called LAT which is transcribed from the genome, and this repressed IE expression,
which suppresses the rest of expression
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Latency is established which causes the LAT expression,
which continues the latency
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So it is latent in the cell body, and then an external stimulus which
activates the IE genes in particular the ICP0 gene, which upregulates, and then reactivation
occurs, and it goes back to acute infection so it reproduces virions again
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direct pathogenesis- disease that is caused directly by the virus- coldsores are minor,
encephalitis is potentially lethal
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however, this is not confirmed, just speculation
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It is also
the major cause of blindness in western world- herpes keratitis
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herpes gladitorum and scrum pox- skin lesions in wrestlers and rugby
players
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genital herpes- asymptomatic primary infection- virus establishes latency in sacral ganglia,
and reactivation can occur as often as 14-21 days
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especially in immunocompromised individuals eg:
neonates, cancer/transplant/AIDS patients, elderly patients
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generally arises from reactivation of the virus- problematic for elderly patients and
some people have genetic mutations that lead to primary infection leading to encephalitis
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The pathology is so extensive
its detectable in CT scans
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neonatal HSV- infection of newborns occurs if mother is shedding virus from genital herpes
at the time of birth, it picks it up when coming through the birth canal
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infection with HSV2 increases susceptibility to HIV infection
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strategies for immune evasion by HSV
1) latency: during latency, herpesviruses express a very limited gene repertoire, thereby
limiting recognition by the adaptive immune system
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normally, TAP peptide translocator allows foreign antigens to go onto MHC2 and then get
presented to CD8 cells, but the virus has a protein called ICP47 which inhibits the TAP
peptide translocator, so MHC1 does not present anything and the CD8 cells are not
activated
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It
has an Fc receptor made of two proteins gE and Gi, which binds the antibodies, this blocks
the receptors, meaning it cannot be recognised
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4) HSV targets both arms of the interferon pathway- the signalling and the production of
Interferon
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The second arm of the pathway is interferon being
released and binding to uninfected cells
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HSV1 makes US3 which is a kinase that hyperphosphorylates IRF3 which stops
it getting into the nucleus, it is stuck in the cytoplasm so it cannot activate the production of
interferon
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The virus makes ICP34
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The virus also makes US11 which binds directly to protein kinase R which stops
the whole process before it begins
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It digests all the transcripts that have been produced as a
consequence of the interferon response
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ICP0 is an IE protein
which is an E3 ubiquitin ligase which sends molecules to the proteasome for degradation
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Antiviral strategies
Herpes vaccines are not successful
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In the UK it is not
available for children, but is offered for over 70s to prevent the shingles reactivating
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HSV-1/2 anti-viral tablets- acyclovir- effective low risk, but there is a growing issue of
resistance
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It is an acycloguanosine
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The viral kinase
phosphorylates the acyclovir which adds even more phosphates and activates it and it
becomes inserted into the viral DNA so there is immediate chain termination; this is because
there is no 3' OH group to form a phosphodiester bond
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Summary of part 2- latent infection- no virus proteins made or infectious virus produced

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