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Virology Chapter 15 - Herpesviruses
Virology Chapter 15 - Herpesviruses
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Where does the word herpes come from?
Greek word for "creep or crawl" in reference to the spreading of herpetic lesions
Once an individual is infected with herpesvirus, how long does the infection remain in the body?
--Virus establishes a latent state at a specific site
True or false: infection with one member of the Herpesviridae family protects against infection or disease from other members
Where do herpes simplex viruses prefer to establish latency?
mouth, pharynx, and genitals
Where does HSV-1 reactivation occur most frequently?
above the waist
Where does HSV-2 reactivation occur most frequently?
below the waist
What herpetic diseases can be caused by HSV-1 besides cold sores and lesions on the mouth?
--Herpes keratitis of the eye (leading cause of corneal blindness in the US)
--Herpes gladitorium (transmitted through wrestling, frequent contact)
--Herpes rugbeiorum (seen in rugby players)
--10% of genital herpes cases
How can cytotoxic drugs contribute to HSV-1 reactivation?
Cause immune suppression-- triggers reactivation
How can stress contribute to HSV-1 reactivation?
stress causes immune suppression -- leads to reactivation
How can temperature changes and UV light (sunburns) contribute to HSV-1 reactivation?
Too hot or cold body temp and too much UV light triggers activation
What is HSV-1 reactivation triggered by naturally in females?
Menstruation and Lactation
What other factors are associated with HSV-1 reactivation?
How common is HSV-2?
45 million people infected in the US (1 in 5 adolescents and adults)
--New infections occur at a rate of 1 million new cases/year
Why is HSV-2 spread so rapidly?
Majority of infections are unrecognized, undiagnosed, and untreated.
--Infected patients can shed virus even during asymptomatic periods
How can HSV-2 infections be prevented?
Condoms and valacyclovir therapy reduce spread during sex by 75%
--preggos should deliver C section
What can happen if an infant is infected with HSV-2 during birth?
--Skin rash, fevers, mouth sores
--Eye infections (corneal blindness)
--Encephalitis (70% fatal if untreated)
What is caused by Varicella Zoster Virus?
Chicken pox and shingles
--Chicken pox can be severe in infants, adults, and immunocompromised
What is unique about Varicella Zoster transmission?
It is the only herpesvirus that spreads person to person by coughing or sneezing
Chicken pox bitch
How long after infection do chicken pox symptoms develop?
10 - 21 days after contact w/ infected person
Where in the body does Varicella-Zoster virus infect and where does it progress to?
Initially infects the skin or mucosa of the resp. tract
--progresses through the blood/lymphatic system to cells found in reticular connective tissue
What is the first sign of Chicken pox?
Itchy exanthematous (skin eruption) rash
Typical Symptoms of chicken pox?
--300-400 lesions on the body
--Blisters dry and form scabs in 4-5 days
What are adult complications of Chicken pox?
--Bacterial infection of the skin
--Swelling of the brain
When are children vaccinated for chicken pox?
12-18 months prior to their 13th bday
What happens following primary varicella zoster infection?
the virus remains latent in the dorsal root ganglia- neurons of nerve roots
When does the herpes zoster virus get reactivated after the latent period?
After the age of 60, and risk of developing shingles increases with age
What are the symptoms of shingles?
--Vesicular rash on one side of the body formed in a 3-5 day period
How long do shingles symptoms last in healthy individuals? in immunocompromised patients?
10 - 15 days (>30 days for skin to return to normal)
Immune compromised patient
- 3 - 4 weeks of symptoms
- may be chronic
Can shingles be transmitted?
Unexposed individuals can contract chickenpox from a shingles patient, but they cannot get shingles from someone that has shingles
--Only caused by varicella zoster virus that has been dormant
What is postherapetic neuralgia?
- pain that lasts for months or years after a shingles infection
What are the symptoms of postherapetic neuralgia?
mild to severe pain that comes and goes, deep aching, burning, stabbing
--sensitivity to touch and temperature changes
--risk increases with age
What are the treatments for shingles?
--Skin patches with lidocaine
--Pain meds ranging from ibuprofen to oxycodone
How common is Cytomegalovirus? (CMV)
common in all human populations:
40-70% in the US
40-80% in developing countries
Relatively how severe is CMV in the majority of the population?
Usually not serious
Once infected, how long does CMV stay in the body?
For life--virus remains dormant
What does CMV cause in neonates(unborn babies younger than 4 weeks old)?
Opportunistic infection- congenital syndrome
What does CMV cause in young adults?
Infectious mononucleosis with prolonged fever and hepatitis
What can CMV cause in bone marrow/organ recipients?
Pneumonia in bone marrow recipients
Disease syndromes in lung, liver, kidney, and heart transplant recipients
What can be caused by CMV in AIDS patients?
Opportunistic infection- retinitis
How is CMV transmitted?
Close, intimate contact with an infected person's saliva, urine or other bodily fluids
--Sex, breast milk, organ transplants, transfusions
What can be the result of CMV complications in neonates? (unborn babies)
--neonates at highest risk for these complications
1) Hearing loss
2) visual impairment
3) mental retardation
4) motor problems
What has persistent CMV infection been associated with?
1) "Immune Risk Phenotype (IRP)"
2) Low-Grade chronic inflammation in elderly patients (inflammaging)
What has IRP (immune risk phenotype) been linked to in older adults?
--increased susceptibility to disease
--reduced vaccination response
--2 - 4 year decrease in survival
Describe Low grade chronic inflammation in the elderly population (inflammaging)
Overactive innate immunity-- overproduction of inflammatory cytokines
Describe IRP (immune risk phenotype)
--dysfunctional CD8 T cell clones specific for CMV
--high CD8, low CD4 counts
--poor overall t cell responses
Which diseases are associated with Low-grade chronic inflammation (inflammaging)?
1) Alzheimer's disease
2) Autoimmunity (rheumatoid arthritis, diabetes)
3) Cardiovascular disease
What percent of mononucleosis cases are caused by Epstein-Barr virus?
79% of mono cases
(CMV causes other 21%)
The vast majority of EBV infections occur in which age group and what are the symptoms?
Young children, infection is asymptomatic
EBV is infectious in which age group?
Patients in their teens or 20s
What is EBV associated with in developing countries?
How is Espstein-Barr virus (EBV) transmitted?
"The Kissing Disease"
--intimate contact with saliva of an infected person
How long is the incubation period for Epstein-Barr virus?
ranges from 4-6 weeks
What are the symptoms of infectious mono?
--sore throat/ fever
--enlarged spleen/liver (sometimes)
--heart/CNS problems (rare)
--just generally feeling like shit
How long do mono symptoms usually last and where does the virus remain latent in the body?
symptoms resolve within 1 or 2 months
--remains latent in the throat and blood for life
Where was HHV-6 isolated from?
T-cell cultures derived from the blood of AIDS patients
Where was HHV-7 isolated from?
CD4+ T cells of a healthy patient
Which cells are attacked by HHV-6 and HHV-7?
infect and kill CD4+ T cells like HIV does
Are cases of exanthum subitum (sudden rash) and infant fevers/seizures usually caused by HHV-6 or HHV-7?
How prevalent is HHV-6 in the population?
infects nearly all humans by the age of two
What are the two distinct types of HHV-6?
HHV-6B- causes sixth disease
HHV-6 may also play a role in the development of what?
Describe Sixth disease
Also called Roseloa
--high fever, skin rash that starts on torso and spreads to the rest of the body
--rash lasts hours to days
--febrile seizures (rare)
What is Kaposi's Sarcoma caused by?
Describe Kaposi's sarcoma
Aggressive pigmented sarcoma of the skin
--usually appears in elderly men of Mediterranean descent
What are the symptoms of primary HHV-8 (KSHV) infection?
How is HHV-8 (KSHV) transmitted?
largely by saliva
--also blood and maybe organs
How can HHV-8 diagnosis be confirmed?
Can be easily confirmed with a biopsy
What therapies are used to treat Kaposi's sarcoma?
Antiviral drugs effective in the lytic stage of infection
--NOT EFFECTIVE DURING LATENCY and most cells are latent so youre fucked!
Describe Herpes B (Monkey B) virus.
Infects macaques--most carry Herps B infection from being in contact with other monkeys
--virus crossed species barrier to a researcher in 1932
How long is the incubation period for Herpes B infection?
A few days to a month
What are the symptoms of Herpes B infection?
--Numbness/ulcers at exposure site
--nausea, vomiting, stomach pain
--neurological problems when it spreads to CNS (most of these patients die)
Explain the prevalence of Herpes B virus today
only 40 human cases have been reported
--still prevalent in free-ranging macaques in southeast asia (tourist attraction; humans at risk of contact with monkeys)
What is the most definitive test for diagnosis of herpesvirus infections?
Testing the prevalence of viable virus in a clinical specimen (oral/genital lesions for example)
Multinucleated giant cells and inclusion bodies of HSV-1 and Varicella zoster-infected cells
Explain the fragility of the Herpesvirus envelope
--Easily disrupted by heat, dessication, alcohol, soap, detergents
--extremely sensitive to damage (must be transmitted through direct contact for this reason)
--dries out/gets damaged when exposed to air (cannot be transmitted by inanimate objects)
Describe the genome of a typical herpesvirus
--Large genome of linear dsDNA
--over 30 viral proteins
--also has cellular proteins
Describe the capsid that surrounds the dsDNA genome in Herpesviruses
Called an amorphous proteinaceous tegument
--contains atleast 8 viral proteins
What are the three subfamilies of Herpesviruses?
(HSV-1 and 2, VZV, Herps B virus)
(CMV, HSV-6 and 7)
What are the herpesvirus subfamilies based on?
Viral latency and growth characteristics in culture
Where do herpesviruses attach and enter the host?
to cells of the epidermis or dermis of the skin
through multiple cell-surface receptors and proteins located on the surface of the virion
Which integral membrane glycoproteins of the herpesvirus envelope participate in entry?
What are the receptors on host cells that facilitate herpesvirus entry?
Attachment to glycosaminoglycan chains on cells
- preferred binding receptor
Explain what occurs during Herpesvirus uncoating?
1) Nucleocapsid released into cytoplasm
2) Some tegument proteins remain in cytoplasm
3) Other tegument proteins are transported to the nucleus
Which tegument protein remains in the cytoplasm during uncoating?
virion host shuroff (vhs) protein
--functions in degrading cell mRNA and allows viral mRNAs to accumulate in the cytoplasm for translation
Which tegument protein is transported to the nucleus during uncoating?
VP16: binds to viral DNA and activates transcription
What are the two possible pathways for herpesvirus replication after entry into a host cell?
1) Productive, lytic infection
2) Latent infection
Describe what happens after uncoating in a productive, lytic infection of herpesvirus
Viral genome in the nucleus circularizes and is transcribed by cellular DNA dependent RNA polymerase
--Rolling circle replication occurs
What is the purpose of Viral UL9 protein during replication?
Binds to 1 of 3 origins and unwinds DNA
What do viral proteins UL5, UL8, and UL52 do during replication?
Form a helicase/primase complex to synthesize RNA primers
What is the purpose of viral UL30 and UL43 proteins during replication?
act as viral DNA polymerase; starts DNA synthesis
Which enzymes are encoded by Herpesvirus to aid in replication?
1) Thymidine kinase
2) Ribonucleotide reductase
3) Uracil DNA glycosylase
4) Deoxyuridine triphosphatase
(good targets for antiviral therapy)
What is the purpose of regulatory proteins that are encoded by about 50% of HSV-1 and HSV-2 genes?
Involved in latency and evading the host immune system (virokines)
How is transcription similar in Herpesviruses and Poxviruses?
--Temporally and sequentially regulated in both viruses
--Both have early, intermediate, and late gene expression
(named alpha, beta, gamma in herps viruses, respectively)
What does herpesvirus VP16 gene do?
Activates transcription os alpha genes (early genes)
What is the function of beta genes (intermediate genes)?
encode DNA replication and additional viral transcription factors
What is the purpose of gamma (late) genes?
Encode late structural proteins of the virion that are produced after replication of the genome
Where are synthesized gamma proteins transported?
Transported to the nucleus, where capsid assembly begins
What is the first step of the double envelopment process of herpes viruses?
Viral capsid is enveloped by the nuclear membrane as it translocates the nucleocapsid to the cytoplasm of the cell
Where are the two viral envelopes derived from during the double envelopment process?
Nucleocapsid buds through the Golgi-derived vesicles and cellular plasma membrane
How are HSV-1 and HSV-2 able to establish life-long latency in sensory neurons?
Persist as an episome
--less viral genes are expressed (latency associated transcripts; LATS)
--no replication = no detection of virus
When HSV-1, HSV-2, or VZV is reactivated, where does it travel in the body?
travels the nerve pathway to the surface of the skin
What is the most commonly prescribed drug to treat herpesvirus infections? what is the advantage of this drug?
ACYCLOVIR (Guanosine analog)
--used for long term prevention
--administered topically to skin/eye, by IV, or orally
How is acyclovir effective against herpesvirus in the body?
converted to ACG-monophosphate by herpesvirus thymidine kinase, which is 200 x more efficient
--acts as a chain terminator
How can diet effect Herpesvirus infections?
Foods high in L-lysine may help control HSV outbreaks, while foods high in L-arginine may cause outbreaks
--high doses are not recommended
Describe the chicken pox vaccine component
Live, attenuated "Oka" strain isolated from 3 year old Japan boy with an acute case of chicken pox
What is the dosing regimen for the chicken pox vaccine?
One dose between 12 and 18 months of age
--if child is not exposed and is over 13, two doses are given 4 - 8 weeks apart
What is breakthrough varicella?
Wild-type virus that causes a mild form of chicken pox (50 lesions or less)
--occurs in a small percentage of vaccinees
--more common in US than Japan
Describe vaccination against Shingles?
Chicken pox vaccine reduced cases by 51.3%
--Shingles vaccine developed in 2011, reduced risk by nearly 70% in adults 50-59
Why is the development of a CMV vaccine top priority?
Major disease of the immune compromised and infection is the leading cause of inner ear (cochlea) hearing loss and nervous system damage in children
How is genetically engineered HSV used to treat brain tumors?
Patients with malignant gliomas are ideal candidates
--viruses provide a delivery technique that can target the tumor
Why is HSV an attractive vector for future therapies?
HSV can replicate in neurons and glia
--DNA easy to manipulate
Even though EBV has become the leading candidate as a trigger for MS, what is the problem with these studies?
Herpesvirus infections correlate with a whole bunch of shitty things, therefore its hard to say EBV is the causative agent
--Also, uninfected control patients are difficult to find
How has herpesvirus been found to develop symbiosis?
mice latently infected with herps virus were resistant to other bacterial infections because there was chronic stimulation of the immune system and increased cytokine activity
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