10. Herpes Virus Flashcards
Herpesviruses
• ____ viruses
• Three flavors - ____, beta, ____ herpesviruses
• ____ DNA, approximately 100 genes
• ____ capsid, lipid ____, ds DNA
• ____ with their hosts, well adjusted pathogens
• Ubiquitous, all ____ species and ____ too! (e.g. oysters)
• ____ infections are a hallmark (herpes is forever)
• Everyone's got herpes - fish, chikckens, elephants, oysters (bivalves)
DNA alpha gamma ds icosahedral envelope co-evolve vertebrate invertebrates latent
Three “genera” of herpesviridae
• Alpha herpes viruses ____, ____, ____ – Grow ____-many are ____
– Latency in ____ neurons
• Beta herpes viruses ____
– Cytomegaloviruses (large ____ cells)
– Grow ____
– Latency in ____ glands, kidneys, lymphocytes
• Gamma herpes viruses ____ KS
– Lymphoproliferative diseases – Latency in ____ cells
* Latency > shed among eveeyr herpes virus * VZV > varicella zoster > \_\_\_\_ and \_\_\_\_ * Beta > originally found in salivary glands
HSV1 HSV2 VZV rapidly cytolytic sensory
HCMV
balloon-like
slowly
salivary
EBV
lymphoid
chicken pox
shingles
Eight human herpesviruses
• HSV1 (primary infection, oral cold sores) (____)
• HSV2 (genital herpes, primary and recurrent sores)
(____)
• VZV (chicken pox, shingles) (____)
• CMV ( retardation, deafness, CMV retinitis, organ transplant rejection) (____)
• HHV6 & 7 (____) - developing important clinical diseases-B cell lymphotropic virus and Roseolovirus
• EBV (mononucleosis, cancer) (____)
• HHV8 (Kaposi’s sarcoma) (____)
• Deep sequencing of fecal material > multiple herpes viruses that they haven't figured out what they are yet (not these eight)
alpha alpha alpha beta beta gamma gamma
Latent, Recurrent Infections Typical of Herpes infection
- initial acute infection followed by ____
• Host immune response clears most virus but virus genome persists. Often in immunologically protected cells (____ system)
• Stress, immune suppression reactivates latent virus
• Reactivation may/may not produce ____
• Virus is shed constantly without ____ disease (____-infection)• Types of general infections in human where if you look over time > initial infection (virus production) > symptoms > large amount of virus made
• Virus is not cleared > virus goes latent in some organ
○ Genome persists
• ____ events over time > can be weeks, months, years for th eintetval
• After primary > lesion (cold sore) > contain vrius; but then times where you produce DNA/virus and no lesions
• Look at extended times over humans (for STD, for example) > vaginal swabs > each participiant will have virus at different times > constant shedding of virus with no symptoms
• With simplex > ____ is unusal > unless immunocompromised
quiescence nervous symptoms clinical persistent
cyclic
death
Herpesvirus Architecture: All herpesviruses have the same basic structure-different genomes
* Yellow > lipid \_\_\_\_ containing glycporteins * Surround that > tegument (orange) > two functions: it's a glue to affix \_\_\_\_ to membrane, and bioloigcal activity in infected cell, when transported to nucleus > subvert the cell from making host proteins to making \_\_\_\_; swithcing clock of virus from host to viral * In capsid > \_\_\_\_
envelope
capsid
viral protein
DNA
Herpes simplex virus infections
• Primary infection mouth, skin, eye - type 1
____ type 2
• Latency: neurons type 1: ____ type 2: ____
RECURRENT INFECTION • Reactivation leads to disease or shedding - \_\_\_\_ - whitlow's finger -\_\_\_\_
Virus survives in immune host • Infects many types of cells • \_\_\_\_ entry glycoproteins • \_\_\_\_ protein receptors on cells • \_\_\_\_ pathways of entry
• Summary of next few slides • Type 1 > virus gows in mouth, skin, eye > can be a major or a minor infection > primary major infection would be kid out of action for 10 days (dehyrdate > have chocolate milksahkes) • Virus replicates in local area > migraates up axon of trigeminal nerve ganglion > innervates 3 regions (opth, max, man) > can get recurrence of infection in these areas ○ Virus sits in neruons, and in a state of latency > controls maintence in neuron • And reactivation > stress, etc > virus starts to \_\_\_\_ in neruons > rides down neuron to the site of reactivation (cold sore) > usually in se area where you've always had it • \_\_\_\_ > dentists without gloves, in the oral cavoty virus is shed > can drive virus into cuticle of giner > get primary infection, and thtne recurrences
genital trigeminal sacral cold sore keratitis
4
2
2
replicate
whitlow’s finger
HERPES SIMPLEX - Type 1
PRIMARY INFECTION
- Usually ____ throat, fever, eye infections and, rarely, Encephalitis (major problem for ____).
- Latest evidence: 60% of new genital infections are due to ____
- Occasionally genital > important for genital herpes > 60% of genital infections is due to HSV1 (oral form)
- HSV1 is the major cause of ____ in US bc of recurrences > immune system tries to rid the virus > ab-antigen complex formation in eye > blindness (via ____, and aggregates)
sore neonates HSV1 blindness scarring
HERPES SIMPLEX - Type 1
LATENT INFECTION
1. Asymptomatic - Virus is detected in between episodes of disease-”____ of virus”
2. ____ Viral DNA resides in sensory cells of ____ nerve ganglion.
• Asymptomatic > no \_\_\_\_
shedding
trigeminal
lesion
HERPES SIMPLEX - Type 1
RECURRENT INFECTION
1. Virus replicates and travels down sensory nerve fiber to infect epithelial cells around the nose and mouth
2. Symptoms are usually a ____ form of primary infection
• Symptoms are milder > each recurrence > you're boosting the \_\_\_\_; doesn't clear the virus but it does act to mitigate the ifnection > which is why recurrent is almost always in midlder form of disease
milder
immune system
HERPES SIMPLEX - OCCASIONAL Type 2
PRIMARY INFECTION
NORMAL
1. Usually ____ eruptions on the genitalia
2. Spread by ____ contact
3. Affects both ____
4. Less frequently (30%) found as ____ (cold sores)
* By 50 > \_\_\_\_% of pop infected with type 1; and not 70% infected with type 2; more select [????] * Reduction in number of people who are HSV1 positive > people have become aware of \_\_\_\_ (from stigma of genital infection)
vesicular sexual sexes herpes labialis 70 HSV
HERPES SIMPLEX - Type 2
LATENT INFECTION
• 1. ____ of virus is common
• 2. Viral DNA resides in sensory cells of ____ ganglia -
• RECUURENCE
• ____ outbreak generally in same location in genital area
• Can lump 1 and 2 as same virus, but a little different, but they're really different; look alike, act similarly, but they're really different viruses
shedding
sacral
milder
HSV “VIRUS SHEDDING”
HSV is shed from normal-appearing oral or genital mucosa or tears.
Transmission occurs from contact with an infected partner who does not have visible ____ and who may not know that they are ____.
In persons with asymptomatic HSV-2 infections, genital HSV shedding occurs on ____% of days, compared to ____% of days among those with symptomatic infections.
In genital infections: HSV Type 1 = 3 to 5% HSV Type 2 = 15 to 20% In oral (mouth) infections: HSV Type 1 = 18% HSV Type 2 = 1
• Shedding > major mechanism of \_\_\_\_ of virus • Any vaccine that doesn't affect shedding is undesirable; want to stop shedding from individuals • Asympto HSV2 > 10% of days (within 3 months) virus will shed • Sympto HSV2 > • Iff asympto all the time > you can still be shedding; once sympto > can have lesions, but can have times when you're just shedding ○ Have a lesion > infecitous; no lesion, you may be infectious • Numbers for 1/2 are probably the same?
lesions
infected
10.2
20.1
Neonatal Herpes Simplex (1)
- Incidence 1/4000 live births in U.S.
- Baby is infected perinatally during passage through the ____.
- The risk of perinatal transmission is greatest when there is a ____ (new) infection in the mother.
- Smaller risk from ____ (old) lesions in the mother, probably because of the lower ____ load and the presence of specific ____.
- The baby may be infected from oral lesions from the ____, nurse or a ____.
- This is for Herpes Type 2
- Need good titer of virus in birth canal in order to infect > happens whne mother has a primary infection > produce virus and baby infected on the way out
- Mild skin disease to a dissemianted ifneciton > child has no ab; mother has little protection to contribute
birth canal primary recurrent viral antibodies mother herpetic whitlow
Neonatal Herpes Simplex (2)
• Infection varies from mild skin disease to a fatal disseminated
infection.
• Dissemination: the organ involved are ____, adrenals and the ____.
• For Encephalitis (brain infection)the prognosis is particularly severe.
• Many survivors have residual ____.
• ____ is given in all suspected cases.
• Prevention is to offer ____ to mothers with genital HSV lesions.
• C section > offered to mothers with genital infection > increase in \_\_\_\_ is due to this virus
liver brain disabilities acyclovir caesarean section
c-sections
Herpes Simplex 1 or 2 Disease
* Normal maintenance > primary > mucosal > latent and reactivation * If have difficulty controlling the disease > usually HSV doesn't cause viremia; but if there is > dissmeianted infection > CNS \_\_\_\_
encephalitis
Alpha herpesvirus Latency
- Occurs in neurons of ____ ganglia (non-dividing cells)
- Capsid goes in, DNA genome remains in ____ as an episome
- Only one transcript: ____ (function still not clear)
- With stress, productive infection initiated
- Capsids travel back down axon, then enveloped
- Free virus released with or without ____ symptoms
- HSV-1 ____ downregulate immediate early protein systhesis
- Virus has to travel distance to get from skin to neuron and then travel back and forth > system has been developed by virus and host > virus trciks host into accepting it as a normal event at the cells urface > virus rides in ____ fashion and comes back down > ____ for the reoccurence
- Do not need to know viral replication form this
sensory nucleus LAT clinical miRNAs retrograde anterograde
How to get a Herpes Simplex infection? • \_\_\_\_ and imagination • Any contact with infectious virus-anywhere • Examples: – \_\_\_\_-any contact sport • March 3. 2016 – Sexual contact – Your “old” aunts kiss – \_\_\_\_ rites
contact
herpes gladiatorum
circumcision
How not to spread herpes!
The cause of death of a 2-week-old boy in Brooklyn on Sept. 28, 2011 was oral herpes, caused by
“ritual circumcision with oral suction”.
The ritual is practiced in ultra-Orthodox communities.
The procedure occurs during the circumcision as the Practitioner
Removes the foreskin and sucks the blood from the wound.
17 cases between 2000 and 2015 consistent with transmission of infection during circumcision,
* Practioner sucks blood from wound; if indiviual has herpes > child will get it; to conform, the \_\_\_\_ is used (wtf?) * Interesting epidemiological study
straw
STRATEGY FOR HERPES SIMPLEX VIRUS REPLICATION
How to make a virus?
• Vaccine is \_\_\_\_ or a \_\_\_\_ virus > immunize with attenuated, grows but doesn’t cause disease > stimualtes \_\_\_\_ that's protective when come into contact with WT form of virus • Vaccine for simplex > stop the ifnection (sterilizing immunity) > double-hook in trying to develop vaccines against hepres virus ○ VZV > vaccine against \_\_\_\_ ○ Two vaccines to alter zoster/shingles
viral protein
attenuated
immune system
chicken pox
Envelope Contains 12 Glycoproteins
•5 gp involved in HSV ____
•Virus bind several cell receptors- ____ and ____- most important
•Binding of ____ to cell receptor initiates entry
•____, ____ are essential at
fusion step-fusing two
membranes
* Subunit vaccines > not attenuated/live virus vaccine > make proteins via \_\_\_\_ methods > take H, D, L , B > immuneize with the proteins and follow what happens * Herpovac vaccine > supposed to prveent virus from interacting with its recepotrs ot block entranc eof virus into cell > preventing infection and giving \_\_\_\_
entry HVEM nectin-1 gD gB gH/gL
recombinant
sterilizing immunity
Mechanism of Neutralization-Abs to gD Generated by a Protein Subunit Vaccine
• Want ab to prevent virus from binding receptor; once bound to receptors on cell or virus > ____, also acts to ____ virus and prveent entry into cells
cell lysis
aggregate
HSV2 Prevalence Among Women: Find the sero-negatives
- Screened ____ women for sero-prevalence of HSV-1 or 2.
- 8,000 were sero-negative-
- 4000 were immunized with HSV gD2 3X over 7 months
- 4000 were immunized with HAVaccine “Go out and Play”
- Followed over 20 months to see who was protected-
- Looked at which virus infected the women- ____ or ____?
- Looked at ____ and ____ response to the immunization
- Early experiments > inject/ommunzie with HSV glyco protein D > recpeotr binding protien, and make high tieres of neut ab against virus > protect women but not men agaisnt subsequent infection
- Agenda secfic vaccine > didn’t work in men
- GSK > run with gD > ened women > have to get women who are sero0ngeative (no ifnection of 1/2) > red high incidence of HSV2; looked through 34,000 women > “go out and play” > follow over 20 moths to see who was protected
34,000 HSV1 HSV2 neutralizing antibodies T-cell
OUTCOME OF THE HERPEVAC VACCINE
TRIAL
Overall the scientific community called this trial a failure
Really?
• 183 women were infected with HSV-1 and 56 with HSV-2- Surprise!
Conclusion: ____ is more common than HSV2 as a cause of genital mucosal infections in young women 18-30 years
• No protection in women infected with ____-bummer- but Surprise! there was significant protection against infection
with ____.
Conclusion: Not a clue why-why???
NIDCR should reconsider their future plans since it looks like there is a successful vaccine for HSV1 infections.
Protection was associated with ____ not T-cells Where to go?? WHO? WHAT? WHERE???
* SO many women ifnected with type 1 * Vaccine for HSV2 worked on HSV 1 (not that well) * If make a vaccine > consider both oral and genital form of virus
HSV1
HSV2
HSV1
neutralizing antibodies
VARICELLA ZOSTER
PRIMARY INFECTION
- Infection occurs in seasonal epidemics as ____ (Varicella)
- Contracted from another ____ individual, usually a child
- Systemic infection resulting in a generalized, vesicular ____
- Zoster > ____; varicella > ____; same virus
- Godo vaccine > produce lots of ____ in blood > if infectious virus > enutralized
chicken pox infected rash shingles chicken pox IgG
Chickenpox vaccine-live attenuated virus
Vaccination protects and reduces risk for ____ for persons unable to be vaccinated because of illness or at risk for severe disease.
Vaccine is very effective in preventing disease, : ____ people vaccinated are completely protected
exposure
8/10
“POX” parties to infect children Live virus “vaccine” To avoid immunization 1. \_\_\_\_to infect children 2.Selling measles/chickenpox \_\_\_\_
parties
lollipops
VARICELLA ZOSTER
LATENT INFECTION
1. ____ with little virus or virion proteins produced
2. Viral DNA resides in the cells of ____ ganglia
3. V accine for older folks to prevent ____
4. Two Vaccines: One is live attenuated ____-It works! ____ shots!!! Merck
5. New Vaccine GSK
asymptomatic doral root shingles VZV 2
Varicella Zoster
Recurrent Infection
(Shingles)
- Virus travels down the sensory nerve fiber and infects ____ cells innervated by the fiber
- Infections are ____, painful vesicular eruptions localized to the ____, usually in the head or upper trunk
- Severe systemic infections are observed in immune suppressed individuals
- Recurrence of chikcen pox > ____
- Activation of virus > virus is now dermal and follows senosry nerve fiber and grows along skin of nerve fiber
epithelial
unilateral
dermatome
shingles
SHINGLES- “____”
• Virus is in each one of these \_\_\_\_; still has \_\_\_\_ rom it
devil’s fire
lesion
neuralgia
Shingles Prevention-Vaccination-Live Attenuated VZV
- VZV remains in nerve cells after the chicken pox infection clears and can reoccur years later causing ____. Disease occurs in people ____ plus years, with altered ____, or who receive ____ drugs.
- ____ is recommended to reduce the risk of shingles in people 60 plus years.
- New Vaccine subunit VZV ____ glycoprotein - 90% effective after 4 years-2018 Now available
- Shingles is also called devil’s fire
- 50+ > not always true; if first indications of AIDS were young individuals presenting with shingles > major ____ that keeps the virus in check
- Vaccine is concentrated ____ virus
- GSK > subunit with glycoproteins in ____ of virrus > works well
shingles 60 immune system immunosuppressive vaccine gE
immune response
attenuated
envelope
BETA HERPESVIRUS Cytomegalovirus (CMV)
DISTINCTIVE CHARACTERISTICS
- ____ acute primary infections
- ____ infection or ‘carrier state’
- ____ in carrier state
- Causes ____ infections & abnormal development
- Very important in immunosuppressed humans- HIV and transplant rejection-
a. How does transplant rejection work? - ____ (____ inhibitor) works-____
- 90% of us have CMV; we’re all carriers
- Mother who has child in nursing school > kids get CMV > mother was not immune and she gets infected > virus can cross placenta > grows inf etus > produces abnormalities in hearing (mostly)
- Vir > variations on acylcoovir > drug inhibits DNA ____and DNA ____
harmless persistent asymptomatic fetal ganciclovir polymerase toxic
pol
replication
Congenital Infection
• Defined as the isolation of CMV from ____ urine within 3 weeks of birth.
• Commonest ____ viral infection, affects 0.3 - 1% of all live births. The ____ most common cause of mental handicap after Down’s syndrome and is responsible for more cases of congenital damage than ____ (German Measles).
• Transmission to fetus occurs following ____ or ____ CMV infection. 40% chance of transmission to the fetus following a ____ infection.
• May be transmitted to the fetus during all ____ of pregnancy.
• Damage to fetus results from destruction of target cells once they are formed.
NO ____-SUBUNIT TO gB or gH/gL???
• No vaccines for CMV; but subunit vaccines in progress > \_\_\_\_ and \_\_\_\_
saliva congenital second rubella primary recurrent primary stages vaccine gB gH/gL
CMV in Transplants
CMV is one of the most common infections after solid-organ transplantation, resulting in significant morbidity, graft loss, and adverse outcomes.
50-80% of adults are infected with CMV and reactivation
is common when the immune system is weakened by drugs, transplant or AIDS.
Transplant patients are negative or infected with CMV
If____ recipient may receive a donor organ carrying CMV.
So you can have:
CMV-positive donor, CMV-negative recipient-no Abs-possible ____
CMV-negative donor, CMV-positive recipient-Abs present-____
CMV-positive donor, CMV-positive recipient-Abs present-____
CMV-negative donor, CMV-negative recipient -no problem no ____
* We will see who are immuno-suppressed > kidney transplant > a lot of transplants fail bc of CMV > problem is: if you're recipient of kidney > and you are CMV positive, and the donor's kdiney is CMV-positive > I get the tranpslant but I have ab to CMV > all I have to worry about is whether or not I'm going to reject this tranplant; but if CMV naïve > no ab > get a kidney of someowne with congeintal CMV > put kidney into me > immuno suppress me on top > virus starts \_\_\_\_ bc no protection > reuslts in rejection of the \_\_\_\_ * No ab to CMV (naïve) > immunize me > protected and then the ab would prevent the CMV virus fromr eplicating in transplanted organ > reaso to really want a \_\_\_\_ against CMV
negative reject protected protected virus
replicating
transplant
vaccine
GAMMA HERPESVIRUS Epstein-Barr virus (EBV
DISTINCTIVE CHARACTERISTICS
Benign or malignant lymphoproliferative diseases-latent infections in lympocytes
- ____
- Associated with ____ (Africa)
- Associated with ____ carcinoma (South-eastern China)
- ____ virus
infectious mononucleosis
burkitt’s lymphoma
nasopharyngeal
cancer
Some facts about EBV
EBV infects the majority of adults worldwide. EBV predominantly infects ____ cells and ____ cells.
EBV is transmitted through saliva, enters via the ____ and infects human ____. Primary infection during childhood is relatively benign but during adulthood infectious mononucleosis can result. “Kissing Disease”
EBV is associated with several human B cell lymphomas, endemic Burkitt’s lymphoma, Hodgkin’s and non-hodgkin’s lymphoma and epithelial malignancies such as nasopharyngeal carcinoma, oral hairy leukoplakia and gastric carcinoma.
Immunodeficient patients, AIDS, organ transplant and cancer patients are at great risk.
Vaccine for EBV-____ virion envelope glycoprotein- ____
B
epithelial
oral epithelium
leukocytes
subunit
not yet
Kaposi’s Sarcoma Virus (KS) (Gamma Herpesvirus)
- Associated with ____.
- Vascular tumor that is common in
patients with ____ - Contact oral secretions-____ transmitted
- 5% in US,»_space; 50% in ____
- Treat ____ successfully and KS lesions respond favorably.
- No ____
immunosuppression AIDS sexually africa AIDS vaccine
Some facts about Kaposi Sarcoma
- KS (rare tumor) named for Moritz Kaposi(1872). It has numerous types, the most common of which is associated with ____. All forms are caused ____.
- Most people infected with KSHV do not develop KS unless their immune system is ____. KS increased 20-fold during the AIDS epidemic and KS is still seen in people with HIV/AIDS, as well as in people taking immunosuppressant medications.
- Recovery of immune competence results in disappearance of disease
AIDS
KSHV
suppressed
Nucleoside Analogues
Definition: An artificial copy of a Nucleoside. When incorporated into a virus DNA or RNA during viral replication the nucleoside analog acts to prevent
____ of new virus. Nucleoside anal block the completion of a viral DNA chai new cell by ____.
There are currently ____ nucleoside analogs approved in the United States.
production
HIV
ten
Acyclovir
Acyclovir is used to decrease pain and speed healing of sores in people with ____ infection.
Example:Acyclovir is also used to prevent outbreaks of recurrent ____ herpes. Acyclovir is in a class of antiviral medications called ____. It works by stopping virus ____ in the body.
Acyclovir will not ____ herpes but limits infection.
Herpes DNA replication Inhibition of viral ____
herpes genital synthetic nucleoside analogues spread cure
DNA polymerases
More on KS cancer
KS cancer originates from the lining of ____ and ____ vessels.
KS occurs at numerous sites presenting skin lesions-oral cavity.
KSHV is checked by the immune system, but people with compromised immunity, transplant patients, seniors and people with HIV/AIDS,
are more likely to develop ____ sarcoma.
Diagnosis: ____ biopsy. X-rays, ____.
Treatments; ____ removal of lesions, radiation or ____.
With immune suppression, antiretroviral drugs manage HIV, or cessation of immunosuppressant medications;
Decreased rate to 6 cases/million/year.
blood lymphatic kaposi punch colonoscopy
surgical
chemotherapy
