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170 Cards in this Set
- Front
- Back
Herpes virus is prevalent in ___
|
eyes
|
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Herpes is a large, _____ virus
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enveloped ds DNA
|
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What is the shape of a herpes virus
|
Toroidal (donut shaped?)
|
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True or False
Herpes virus is ubiquitous! |
True - over 120 herpesviruses isolated so far- EVEN YOU could have it.
|
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To date, there are 9 known Human Herpesviruses (HHV). List them
|
HSV-1,
HSV-2, Varicella-zoster (HHV-3), CMV (HHV-5), HHV-6A, HHV-6B, HHV-7, Epstein-Barr virus (HHV-4), HSV-8 (KSHV) |
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True or False- all herpes viruses use the same antigen
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FALSE- they actually share no common antigen
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Herpes simplex virus
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HSV1 and HSV2
|
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Varicella-zoster virus
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(HHV-3, Chicken pox and
shingles |
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Cytomegalovirus
|
HHV-5
|
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Kaposi’s sarcoma herpesvirus
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KSHV or HHV-8)
|
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Epstein-Barr virus
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(HHV-4, Mononucleosis, Burkitt’s
lymphoma |
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_____% of US citizens have HSV1
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50-70
|
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Three subfamilies of Herpes?
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Write it out
|
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The three subfamilies of herpesvirus are based on what 3 biological properties.
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1. host range
2. length of replication cycle 3. establishment of latency |
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The three subfamilies of herpesvirus are based on what 3 biological properties.
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1. host range
2. length of replication cycle 3. establishment of latency |
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Alpha herpes
|
Write it out
|
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Beta herpes virus
|
Beta has a medium host range
|
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Gamma herpes virus
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Gamma has a very specific host range
|
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Alphaherpes are ___ herpes
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human
|
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Characteristics of herpes simplex 1,2
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•Coldsores, lesions at site of infection, reactivation.
• Rare but often fatal encephalitis • Keratitis |
|
Characteristics of HHV-3 (varicella zoster)
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• Transmitted by droplets, replicates initially in the nasopharynx
• Latency is established in dorsal root ganglia • Highly contagious; ~ 95% of adults show serologic evidence of infection |
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HHV-5, Cytomegalovirus are part of which subfamily?
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Betaherpesvirus
|
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Characteristics of HHV-5 Cytomegalovirs
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1) Congenital: hepatosplenomegaly,
retinitis, rash, and CNS involvement. 2) ~10 % of older children and adults: mononucleosis syndrome with fever, malaise, atypical lymphocytosis, and pharyngitis. 3) Immunocompromised hosts: lifethreatening disseminated disease involving the lungs, gastrointestinal tract, liver, retina, and central nervous system. |
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____ is among the most prevalent viral infections worldwide
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HHV-5 or cytomegalovirus
|
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Where does HHV-5 replicate mainly? Where does it shed?
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In the salivary glands and kidneys.
Shedding occurs in the urine and saliva |
|
This virus induces characteristic giant cells with intranuclear inclusions
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HHV-5 or cytomegalovirus
|
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HHV-6,7- is trophic to _____
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CD 4+ cells
|
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True or False
HHV-6,7 is present in nearly everyone by 5 years of age |
True- think roseola
|
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Gamma herpes virus include:
|
HHV-4 (Eppstein barr virus), and HHV-8 (kaposi's sarcoma)
|
|
Details about HHV-4, Epstein-Barr Virus
|
•Transmitted by intimate contact, particularly via the
exchange of saliva •Replicates in epithelial cells of the oropharynx and in B lymphocytes •Widespread in all human populations; causes infectious mononucleosis •Establishes latent growth-transforming infection of B lymphocytes (normally controlled by immune response). •Post-transplant lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma |
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Details about HHV-8 Kaposi's sarcoma
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•Isolated in 1994; new model virus that shows how viruses can cause
tumors •Widespread in sub-Saharan Africa; low levels of infection occur in most Northern European/North American populations •Gay/bi-sexual men are more susceptible to infection: AIDS-associated |
|
True or False
Herpesviruses establish acute and latent infections |
True
Think chicken pox and shingles Think - cold sore breakouts (yuck) |
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Patterns of Infection for herpes virus
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1.Acute infection
2. Virus production 3. symptoms 4. viral clearance 5. persistent infection 6. Virus production over lifetime |
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What is the key to viral latency?
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Immune system evasion and modulation
|
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List some examples of immune system evasion/modulation
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1. Remain non cytopathic
2. Infect tissues with reduce immune surveillance (such as eye, brain, skin, etc) 3. Directly affect immune system 4.Genome integration/episomal persistence. 5. Produce soluble cytokine decoy-receptors. 6. Block antigen presentation by MHC-I. |
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Draw the 4 components of HSV
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1. linear ds DNA
2. Icosahedral capsid 3. Tegument with proteins and mRNA 4. Envelopes with 8 proteins and spike glycoproteins |
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HSV-1: capsid is T=
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16
960 copies of VP5 make up the capsid. |
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HSV 1,2 - Tissue Tropism
|
Viral replication at the site
of entry (mucosal surfaces)Acute/Lytic infection. -Innate defenses limit viral spread. -Progeny virus infects local sensory neurons. -Establish latent infection. |
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HSV-1 axonal is transported by _______.
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the dynein support sytem of microtubules
|
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Replication time of HSV is approximately ___ hours
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8
|
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Describe HSV-1 infection cycle
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1. Virus particle binds to receptors on plasma membrane. Uncoating occurs & DNA enters nucleus.
2.Virion components (±-TIF; VP16)activate immediate early (IE) gene expression. 3. Early (E) gene expression. 4. Viral DNA replication 5. Late (L) gene expression & virus assembly; cell:cell spread. 6. Apoptosis |
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True or False
HSV-1 uses its own RNA polymerase |
False it uses host RNA polymerase
|
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What does immediate early transcript synthesize?
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alpha proteins wheich are used to trigger the synthesis of early gene expression
|
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Beta proteins in HSV-1 of what?
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They provide DNA replication machinery and can trigger DNA replication
|
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What is the role of HSP in HSV-1?
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It tries to degrade host mRNA and stop translation
|
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HSV-1 has greater than how many membrane proteins?
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10
|
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In HSV-1 gc receptor binds to:
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- gC binds heparin sulfate proteoglycans
|
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In HSV-1 gD receptor binds to
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TNF/NGF related receptors, then undergoes conformational change allowing gB, gH, gI, gL to mediate membrane fusion
|
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In HSV-1 entry and uncoating what goes through the nuclear pore?
|
DNA core and ±-TIF, here Genome immediately circularizes upon entry
into nucleus |
|
True or False
HSV-1 entry is achieved by receptor mediated endocytosis |
False- it is by the direct fusion with the PM
|
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HSV gC interacts with _____________.
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cellular heparin sulfate. (HSV-1)
|
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gH/gL & gB mediate _____
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virion penetration.(HSV-1)
|
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Describe the HSV-1 genome
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have ul and us regions flanked by indirect repeats (IR) or direct repeats (dr)
The IR's and multiple ORI allow for different rearrangements 4 ISOMERS! |
|
There are ___ isoforms of HSV-1
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4
|
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Draw the 4 isoforms of HSV-1
Are they all infectious? |
Yes
|
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What are the six important regions of the HSV genome?
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1. linear molecule "a" sequences (circulization and packaging of viral DNA)
2. 9000 long bp repeat (b sequences) that encode a0 (early regulatory protein) and most of the gene for latency associated transcript (LAT) 3. Long unique region (108,000 bp) -replication enzymes and capsid proteins 4. The 6,600 bp short repeats (RS-C sequences) encodes ICP4 5. The origins of replication. 6. The 13,000 bp unique short region (US) encodes 12 ORFs for glycoproteins (host range and response for host defense) |
|
Function of ICP4?
|
a powerful transcriptional
activator that stimulates all early viral gene expression that leads to viral DNA replication. |
|
HSV-1
Ends of linear dsDNA (a sequences) are important for |
packaging
|
|
HSV-1
Long repeat (b sequences) |
encoding IE α0 & LATs.
|
|
HSV-1
Long unique region (UL)– |
encodes DNA replication and capsid proteins.
|
|
HSV-1
Short repeats (c sequences) |
encoding α4 transcription
activator |
|
HSV-1
Replication origins |
OriS and OriL
|
|
HSV-1
Unique short region (US) |
encoding host range &
response to host defense proteins. |
|
How many origins of replication does HSV-1 have?
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3 OriS, OriL, and one other (?)
|
|
In HSV-1 who makes the transcripts?
|
host pol II
|
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True or False
In HSV-1 Protein products of each class regulate expression of proteins in other classes. |
True
(IE->E->L) |
|
In HSV-1 _____enters nucleus enhancing IE viral gene transcription
while_____ specific RNase, attacks host transcripts in cytoplasm |
Tegument protein ±-TIF (VP16)
vhS |
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In HSV-1 IE mRNAs spliced & exported to cytoplasm to ____
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make proteins which have regulatory functions.
|
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In HSV-1 •α 0 and α 4 stimulate and α 47 inhibits ___.
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early mRNA synthesis
MHC1 Ag presentation |
|
Function of α TIF/VP16) in HSV-1
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found in the tegument, it acts immediately upon virus
entry to stimulate transcription. Binding of Hcf (host cell factor) induces conformational change in α TIF, allowing it to bind Oct-1. Oct-1 binds GAXAT, a component of immediate early gene promoters for HSV, and thereby enhances transcription. |
|
Binding of Hcf (host cell factor) induces conformational
change in α TIF, allowing it to bind Oct-1. Oct-1 binds GAXAT, a component of immediate early gene promoters for HSV, and thereby enhances transcription. |
Just review the slide
|
|
What does vhS protein stand for?
What virus releases it? |
Viral host shut down protein
HSV-1 |
|
HcF stands fore what and is found in conjunction with which protein?
|
Host cell factor, VP16
-may have viral latency functions |
|
What is OCT-1 and what does it bind to?
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In HSV-1 Oct-1 binds to garat octomer then to VP16 and HcF complex and is used to enhance early transcription (controls immediate early viral gene expression)
|
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What is GARAT and where is it found?
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It is early gene promotors for HSV
|
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As a monomer, VP16 can stimulate transcription at sites
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distal from the promoter.
|
|
As a heterotrimer, VP16 stimulates transcription
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adjacent to viral promoter.
|
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Early genes (β) reach peak expression ~____ post infection
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5-7 hr
|
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Functions of (β) coded genes in HSV-1
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modulating host cellular activities,promoting DNA replication, viral nucleic acid metabolism, DNA repair.
|
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Appearance of (β) proteins in HSV-1 signals onset of
|
viral dna replication
|
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Early mRNAs are rarely spliced when exported from the nucleus to
generate (β) -proteins. Exported w/ help of |
ICP-27.
|
|
β-proteins shut down:
|
IE mRNA synthesis, host protein synthesis and
stimulate late mRNA synthesis |
|
HSV-1 has what kind of replication?
|
Rolling Circle
|
|
7 proteins necessary for HSV-1 replication?
|
DNA polymerase (UL30)
DNA binding proteins(UL42 and ICP8) ORI binding protein (UL9)and the helicase/primase complex (UL5, 8, and 52). |
|
HSV: Rolling circle DNA replication in the nucleus
|
1. 3'OH nicked in dsDNA at an ORI
2. Intact strand copied, displacing 5’ end of nicked strand. 3.Nicked strand copied by discontinuous DNA synthesis using RNA primers 4. Multiple cycles of copying intact circular template & discontinuous DNA synthesis generates concatamers. |
|
Define concatamer
|
A DNA segment made up of repeated sequences linked end to end.
|
|
Late ___ genes transcribed off of concatemeric
replicated DNA. |
γ
|
|
Functions of γ proteins
|
largely structural and imported into the nucleus or inserted into cellular
membranes γ proteins also shut down early mRNA synthesis. |
|
True or False
in HSV-1 virus DNA replication/L gene expression occurs in discrete “replication compartments” in the nucleus. |
True
|
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HSV-1 capsid assembly takes place where?
|
In the nucleus via a sequential assembly
|
|
Draw the HSV-1 capsid assembly
|
30 HSV-1 gene products
are structural components of the virion. |
|
HSV-1: DNA Packaging
|
Empty capsids recognize “a”
packaging sequences of genomic DNA. ¸ DNA is reeled into capsid until a headful threshold is reached (1 genome equivalent). ¸ When an “a”-sequence of identical orientation to the first is encountered, the genome is cleaved in direct repeat 1 (DR1) region. ¸ The genome may be replicated within 20 minutes, a feat that requires 15,000 nucleotides/ min/strand to be polymerized. |
|
HSV-1
_____ directs budding of through inner nuclear membrane via ______. |
gpUL31
gpUL34 |
|
True or False
During budding of HSV-1 the virus loses its outer envelope |
True
HSV-1 acquires and looses membranes during assembly (enveloped, de-enveloped, enveloped and so on) |
|
Complete cycle of HSV-1 (no details)
|
Immediate Early
Early Late Acute infection cycle Lytic infection |
|
______: viral RNAs
generated during latent infection (40-100,000/neuron). |
Latency associated transcripts
|
|
LAT's in HSV-1 lack what and are found where?
|
lack polyA tails; restricted to nucleus.
|
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LATS may bind ____ to prevent its transcription &
subsequent transactivation of early genes. |
ICP0
|
|
Typical HSV-1 clinical manifestations can occur because
|
sun burn, stress, nerve damage, menstruation, steroids,
|
|
HSV-1: Immune system evasion
|
-HSV shuts off host cell protein synthesis
-HSV can make inactive cytokine homologs that bind cytokine receptors "decoys" -HSV blocks apoptosis |
|
Herpesvirus ICP47 inhibits
|
TAP translocator,
|
|
HSV: Reactivation is
|
acute
|
|
MHC-2 presentation for HSV-1
___activates antiviral response and clears infection |
(DC and M)
|
|
HSV-1: Histopathology
|
Virus-mediated cell death
≤ Nuclear degeneration. ≤ Multi-nucleated cells ≤ Vesicular fluid between epidermis and dermal layer. ≤ Intense inflammatory response in dermal layer ≤ Healing results in pustules. |
|
HSV-1 accounts for 95% of _____ in US.
|
viral encephalitis
|
|
HSV-1 and yer eyes
|
Herpetic keratitis AND Corneal ulcer with hypopyon (collection of pus in the anterior chamber of the eye).
|
|
Acyclovir treats what and how does it work?
|
HSV-1
nucleoside chain terminator ACV phosphorylated 1st by viral thymidine kinase (TK) and then by cellular kinase to produce ACV triphosphate which competes with dGTP for DNA polymerase |
|
____ of all Americans are infected with HSV-1
|
50-80%
|
|
True or False
Most people who transmit HSV-1 are asymptomatic. |
True
|
|
True or False
Co-infection with HSV-1 and HSV-2 is common |
True
|
|
Chicken pox
|
(Varicella)
10 replication at site of infection followed by spread through blood stream (viremia). Complications are rare. |
|
Shingles
|
(Zoster)
After primary infection, virus persists in sensory ganglia of CNS |
|
Varicella-Zoster Virus (VZV) QUICKIES
|
Enveloped icosahedral
capsids. • Linear dsDNA– 112 kb in size with 68 ORFs. • Molecular biology similar to HSV in many respects… |
|
IN VZV every bump =
|
1 infected T-cell
(that eventually undergoes apoptosis |
|
Pathogenesis of VZV
|
respiratory/contact
transmission -systemic infection -Tonsil T-cells - motility -virus delivered to skin through cappillaries |
|
True or False
VZV and HSV can be distinguished from one another by classical histological staining such as hematoxylin & eosin. |
False- it cannot
|
|
Varicella most common in ___, but zoster is common ___
|
winter/spring
all year long |
|
VZV: Therapeutics
|
Acyclovir/Ganciclovir
Foscarnet Vidarabine VZIG |
|
Acyclovir/Ganciclovir
|
Most effective drug against VZV. Reduces duration of
disease, pain and viral shedding. |
|
Foscarnet
|
Used for acyclovir-resistant strains of VZV.
|
|
Vidarabine
|
Inhibits nucleic acid synthesis. (VZV)
|
|
VZIG
|
Varicell-zoster immunoglobulin can prevent or reduce
symptoms. Protection lasts ~ 3 weeks. This passive immunnization is recommended for immunocompromised individuals, pregnant women, newborns and hospital personnel who have been exposed to the virus. |
|
VZV Vaccine: ______% EFFECTIVE
|
85
|
|
VZV Differences from HSV:
|
-Respiratory secretions are infectious
-Systemic disease -The rash itches -Virus is latent in multiple sensory ganglia |
|
Cytomegalovirus (CMV/HHV5) QUICKEE
|
Betaherpesvirinae
≤ One serotype ≤ Structure similar to HSV (envelope, tegument, capsid) ≤ Linear dsDNA genome (230-240 kb in size)… the largest! |
|
CMV: Transmission by
|
Age Group
Fetus ----- Across placenta Infant ----- Contact with maternal body fluids during birth; breast-feeding Youth ----- Contact with urine/saliva from other children Adults ----- Kissing; sexual intercourse; blood transfusion |
|
True or False
CMV goes away eventually |
False - though it is silent, it lasts a lifetime.. however no destruction of human cells
|
|
CMV latent persistance in ____ and_____
|
monocytes and neutrophils
|
|
Immune response ____ against primary infection of CMV,
but not against reactivations. |
(IgM and IgG)
|
|
True or False
Most people are infected with CMV worldwide |
TRUE
|
|
Symptoms of CMV (HHV5)
|
prolonged high fever, chills, severe fatigue
|
|
CMV diagnosis with....
|
Test for IgM or IgG using ELISA.
PCR (the ‘gold-standard’). |
|
Treat CMV with...?
|
Treated with Ganciclovir
(Acyclovir is not effective because CMV does not have thymidine kinase). |
|
Does CMV have a vaccine?
|
No
|
|
____ is the most common virus transmitted to a pregnant
woman's unborn child |
CMV
|
|
Congenital CMV (meaning present at birth) is as common a cause of serious disability such as:
|
Down syndrome, fetal alcohol
syndrome, and neural tube defects |
|
CMV: Histopathology
|
Cytoplasmic Inclusions
CMV nuclear inclusions with perinuclear halo reactive alveolar lining cells |
|
_____ blocks antigen presentatio nby MHC-1 in HSV-1
|
ICP47
|
|
Is there a treatment for CMV
|
No
|
|
HHV6 and HHV7 are what kind of herpesvirus?
|
Beta
|
|
HHV6/7 Tropism
|
CD4+ T- cells predominant
targets– CD4 is not the receptor). • B- cells & macrophages can be infected • Enlargement of lymphocytes followed by lytic degeneration. |
|
What are the two variants for HHV6/HBLV (human B-lymphotropic virus?
|
HHV6-A and HHV6-B
|
|
HHV6 in children cause what?
|
"roseola infantum", a common childhood rash
|
|
HHV6: Transmission & clinical manifestations
|
Virus present in saliva- may spread by
fomites and aerosol. CNS infection - encephalitis Skin infection - rash Liver infection - liver dysfunction |
|
HHV6 Latency and
reactivation (draw it) |
Ugh
|
|
HHV6 Latency and
reactivation (draw it) |
Ugh
|
|
Human herpesvirus 7 (HHV-7)quickee
|
•betaherpesvirus
• First isolated from human CD4+ cells in 1990. • Genome ~170 kbp, organization similar to HHV-6. • The complete genome sequence of HHV-7 determined; shows a high degree of conservation with HHV-6. • However, only limited antigenic cross-reactivity between the two viruses. • At present, there is no clear evidence for the direct involvement of HHV-7 in any human disease. |
|
List two Gammaherrpessvviirrussess
|
EBV (HHV-4) and Kaposi's Sarcoma (HHV8)
|
|
EBV caused by ___ and causes ___.
|
•Transmitted by intimate contact, particularly via the
exchange of saliva infectious mononucleosis ALSO-•Post-transplant lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma |
|
HHV8: Kaposi’s sarcoma herpesvirus QUICKEE
|
Structural genes similar
to other HV. ≤ Genome has numerous homologs to mammalian regulatory genes (incl. VEGF) in an “oncogene cluster”. o Molecular piracy. |
|
How many serotypes does HBV have?
|
Two
|
|
This HV is ...
• Associated with tumors: ✔ Burkitt’s lymphoma ✔ Nasopharyngeal carcinoma |
EBV
|
|
EBV Infects and establishes
latency in _____. |
B-cells
|
|
True or False
EBV is Often asymptomatic children |
True
|
|
EBV: Pathology/Clinical Manifestations
|
Barfing, tonsillar exudate, skin rash, fever, accumulation of atypical lymphocytes
|
|
Burkitt’s Lymphoma Quickee
|
Proliferative B-cell
disease. • Rate of cell division among highest in human tumors. • C-Myc mutation linked to Burkitt’s Lymphoma. • Role of EBV still under study. |
|
“The Commonest Children’s
Cancer in Tropical Africa” |
Burkett's Lymphoma
|
|
True or False
Shingles may provide chronic stimulus of B-cells that carry latent EBV. |
False- It's Malaria that is the constant stimulus
|
|
EBV: Genomic Structure Quickee
|
dsDNA; 172 kb
• Long & short repeat regions differentiate EBV-1 from EBV-2. • Replication occurs in the nucleus |
|
Infection Cycle in B-cells
|
Mimics normal
B-cell differentiation • Virus appears to drive B-cell differentiation into “long-lived memory cells” |
|
Why cause differentiation
into memory cells? (Burkitts lymphoma) |
EBV not recognized by immune system
|
|
Role of EBNA-1 (Epstein-Barr
nuclear antigen) in replication? |
EBNA-1 piggybacks on host cell chromosomes,mediating viral replication
|
|
What does EBV have to do with cancer?
|
Burkitt’s Lymphoma cells have a “germinal centre”
phenotype - microscopically distinguishable regions of lymphoid tissue where B cells expand and undergo selection • It is thought that c-myc (host cell cycle regulation protein) translocation occurs during somatic hypermutation - process during B cell differentiation to mutate variable regions of immunoglobulin genes to recognize foreign elements EBV is a virus that infects B lymphocytes, causing them to grow and divide and extending their lifespan. In most people, it causes infectious mononucleosis, also known as "mono." Mono is usually not a serious disease because the patient’s T cells destroy B cells infected with EBV. But when people have a T-cell deficiency (which may be present at birth, secondary to HIV infection, or caused by drugs that decrease their function such as after a transplant), the EBV-infected B cells grow and accumulate. These growing cells have an increased risk for developing DNA mutations or gene translocations. If these changes affect certain oncogenes or tumor suppressor genes, lymphoma will develop. |
|
_____is a process during B-cell differentiation, during
which mutations are actually part of the process |
somatic hypermutation
|
|
Role of C-Myc (host cell cycle regulation protein)
|
• Oncogene
• Normal cell C-Myc gene functions in regulation of: - Cell cycle and growth • Mutation of C-Myc causes “gain of function” phenotype • BUT- rarely (if ever) is cancer associated with just one mutated gene |
|
EBV Host Cell Entry - whats the receptor?
|
Main receptor is viral gp350, binding to CD21
- MHC Class II co-factor - Important co-receptor is gp42, thought to mediate membrane fusion Much less know about entry in epithelial cells. |
|
EBV Genome & Replication qUICKEE
|
dsDNA linear genome in virion
- DNA circularizes upon entry into nucleus -172 kb, encodes over 100 viral proteins -Replication occurs in the nucleus, associated with viral replication compartments -which may block host cell DNA replication -Compartments dissociate when vDNA is packed into nucleocapsid in nucleus - Virion packaged in cytoplasmic vesicles |
|
Protein of EBV
|
UGH
|
|
EBV can transform resting B-cell to Post-Immortal B-cell in vitro
How? |
Resting B-cell
Pre-Immortal B-cell Post-Immortal B-cell Tumorigenic Cell Strong Telomerase Upregulation Activity Critical -Telomeres cap chromosomes, and serve to regulate how many times a cell can replicate - Telomerase maintains/ increases telomere length * c-Myc translocation causes this too! |
|
Role of EBNA-1
|
Burkitt’s Lymphoma tissue only expresses
one viral protein: EBNA-1 - EBNA-1 is also the only protein expressed in dividing memory B-cells - Expressed in all EBV-related malignancies • EBNA-1 is critical to transcription and replication of the virus - it’s also critical to regulating the push from naïve infected B-cell to long-lived memory cell |