Herpes Viruses Flashcards by Liz Messenger

List the 8 herpes viruses of this lecture.

HSV-1
HSV-2
VZV
CMV
EBV
HHV-6
HHV-7
HHV-8

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What type of immunity is required to control herpes?

-cell-mediated immunity

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Describe the structure of herpesviruses

large enveloped icosahedral capsids
large double stranded DNA
encode many proteins to manipulate host and host IS and promote viral replication
limited DNA homology

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2 functions of non-structural genes herpesviruses encode

-modulators of host cell gene expression and host immune responses

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List the subfamilies of herpes viruses, their biological properties, and the official names of the viruses

Alpha-herpesviruses: fast growing, cytolytic; infect mucoepithelial cells; latent in neurons; HSV1, HSV2, VZV
Beta-herpesviruses: slow growing, cytomegalic, infects and latent in epithelial cells, endothelial cells, and leukocytes; CMV, HHV 6, HHV 7
Gamma herpesviruses: lymphoproliferative, infects and latent in lymphocytes and other cells; transformative; EBV, HHV-8

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What is the Herpes B virus? What is unique about this?

alphaherpesvirus transmitted to humans by bite of macaque monkey
only nonhuman primate herpes virus causing severe pathogenicity in humans

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Name and describe the 2 modes of replication of herpesviruses

Productive (lytic) infection: host cell supports virus growth, viral genome replicated and viral proteins made, complete progeny virions produced and released
Latent infection: virus is hidden inside cell, expression of viral genes restricted, no virus particles produced, reservoir for reactivation and recurrent infection

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What can trigger reactivation of latent herpetic infection?

-fever, stress, menses, UV light, trauma, immunesuppression

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4 steps of herpes lytic infection

viral entry via envelope FUSION with cell membrane
Nucleocapsid transport to nucleus
Nuclear events: viral gene transcription, genome replication, progeny nucleocapsid assembly
Nucleocapsids bud from nucleus, viral envelope formed from nuclear membrane, release by exocytosis

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Where do herpes viruses replicate? Where do they get their envelope from?

nucleus

- nuclear membrane

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Describe what occurs in terms of gene expression during the lytic lifecycle

occurs in temporal cascades that are tightly regulated
1. Alpha: immediate early (IE) regulators of viral gene expression
2. Beta: early- proteins required for genome replication
3. gamma (late): virion structural proteins

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Describe gene expression in latency vs. lytic lifestyles

lytic: temporal cascades that are highly regulated

- latent: RESTRICTED, only kept around is used to maintain latency

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Compare the cell types infected in a latent vs. lytic herpes infection

latent: infects few ( 1 or 2) cell types

- lytic: infects many cell types, usually >2

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Spread of herpes viruses and examples of transmission

person to person in close contact
no animal reservoirs
transmission: mouth and respiratory tract, genital tract, across placenta or during birth, blood cells during transfusions, transplants

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Give the spectrum of disease severity: when and who is it better or worse in? Who gets severe infections?

high severity: primary infection and immune impairment
low severity: recurrent infection and immune competent
Severe infection populations: immunodeficient (HIV), immunosuppressed (cancer, transplant), fetus/newborn, malnourished, burn victims

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What immune response is of prime importance in herpes viruses?

cell-mediated and especially T cells
antibodies are somewhat effective, but complement is not
immunity helps control reactivation

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2 ways herpesviruses evade immune system

viral glycoproteins evade antibody and complement

2. encode proteins that interfere with MHC Class I antigen presentation

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Serotypes of herpes simplex virus, where they infect, and where they are latent.

HSV-1 and HSV-2
infect mucosal epithelium
HSV1: latent focus in trigemical ganglion
HSV2: latent in lumbosacral dorsal root ganglion

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How many HSV infections are asymptomatic?

-75%

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Describe gingivostomatitis presentation; what causes it; who gets it?

most common primary symptomatic HSV1 infection
generally seen in children and young adults (10-30%)
prodrome of fever, malaise, irritability, headache, vomiting, lymphadenopathy 1-2 days before lesions
then small, vesicles on inside of cheeks, gums, tongue and mucous membranes of mouth that rapidly ulcerate with time
very painful
perioral lesions also observes
swollen and tender gums
latency in trigeminal ganglion

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Recurrent cold sore (herpes labialis) is usually caused by what HSV?

-oral recurrences more common after HSV-1 than HSV2

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What can cause genital herpes infections? 3 types of genital infections? Risk of other illnesses? How to prevent?

HSV-1 or HSV-2, but HSV-2 is more common
3 infection types: primary, primary first episode, recurrent
acquisition correlates with # of sexual partners; women more susceptible
antivirals and condom use reduce risk
HSV-2 genital ulcers increase risk of acquiring and spreading HIV

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Describe the course of a primary genital herpes lesion

10-21 days of vesiculoulcerative lesions, intense pain, and fever
may be associated with malaise, itching and burning, dysuria, and inguina lymphadenopathy

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Genital herpes recurrences

2/3 have them
reactivation from infected sacral ganglia
more likely after HSV-2 infection and in immunocompromised
symptoms less severe than primary disease
HSV2 recurrence severity is worse than HSV1

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Neonatal herpes: when do they get it? when does it present? 3 syndromes

transmitted through infected birth canal when most women are asymptomatic
1-2 wks after delivery
almost always symptomatic
75% due to HSV2
3 syndromes: skin, eye, mouth (SEM); encephalitis (CNS); disseminated disease (DIS)
*not congenital, acquired during birth**

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How can herpes impact the eyes? Which form causes this? Why is it so serious? What may recurrences eventually form?

Herpes keratoconjunctivitis
HSV-1 infection of eye
# 1 cause of infectious blindness in developed world
severe conjunctivitis and keratitis with damage to cornea
recurrences are common and may cause dendritic ulcers

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What is the most common cause of acute sporadic encephalitis? How will patients present?

HSV-1
result of primary or severe recurrent infection
fever, headache, focal neurologic deficits, temporal lobe involvement
RBCs in CSF, CSF pleocytosis, behavior changes, decreased level of consciousness
*deadly**

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What usually causes HSV meningitis? What do patients present with? Is it life-threatening?

usually due to HSV-2 from genital infections
fever, headache, nausea, vomiting, photophobia, stiff neck
self-limited and not life threatening
can occur in presence or absence of genital flare
no permanent neurologic sequelae

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Eczema herpeticum: what causes it? what is it? who gets is?

locally invasive skin infections due to HSV1- or HSV2
any person with deficient cellular immunity or people with underlying skin disorders or burns
infections may be extensive at usual sites or may appear at unusual sites
lesions progress slowly and cause necrosis with slow/neglible healing

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Herpetic witlow: what is it? what causes it? who gets it?

traumatic herpes
local lesions on fingers and hands
virus enters through abrasions/openings in skin
HSV-1 or HSV-2
seen in hospital personnel, dentists, dental hygientists

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If a wrestler or rugby player comes in with herpes all over one side of their face, what is the diagnosis?

Herpes gladiatorum (mat herpes)

- herpes rugbiaforum or scrum pox

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What does VZV stand for?

-Varicella-Zoster virus

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2 diseases caused by VZV

primary: varicella (chickenpox)

2. recurrence: herpes zoster (shingles)

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Pathogenesis of VZV; where is latency established?

during primary infection, virus infects respiratory mucosa through oral cavity
replicates in oral cavity and regional nodes
primary viremia leads to replication in liver and spleen
secondary viremia results in infection of lymphocytes that carry virus to skin and other areas
latency established within sensory neurons of dorsal root ganglia

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Who is varicella particularly complicated in? What age group was is commonly in (before vaccine)?

-adults and infants <10

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Varicella attach rates among susceptible household contacts in 80-90%. How is it transmitted?

-person to person via respiratory route or direct cutaneous contact

Varicella clinical symptoms

incubation period is 10-21 days
prodrome: fever, malaise, pharyngitis
generalized rash within 24 hours: begins on chest, back and facel spreads rapidly and lasts 3-5 days
all stages of rash present at any given time
contagious 1-2 days before rash and 4-5 days after rash onset

Describe the rash associated with varicella

begins on chest, back, and face and spreads rapidly
starts out maculopapular and then small, fluid-filled vesicles with central dimple (umbilication) on a red base
rash is itchy!!
all stages present at any given time (unlike smallpox)

Varicella complications

chickenpox is usually self-limited
bacterial superinfections of skin (cellulitis)
Encephalitis: spread to cerebellum and cause unsteady gait (ataxia)
pneumonia
hepatitis
congenital and perinatal infections
immunocompromised: pneumonia, encephalitis, progressive-disseminated varicella

What is the common cause of death in adults and teens due to varicella?

-pneumonia

Although anyone with a prior primary VZV infection can have zoster, what is the most important risk factor? What are other risk factors?

age
incidence progressively increases with age with a dramatic increase over 50 y.o
immunocompromised and underlying disorders are other risk factors** zoster recurrences more common in immunocompromised

Zoster clinical features

unilateral vesicular rash that follows a dermatomal distribution
does not cross midline
rash most commonly involves thoracic and lumbar distribution; ophthalmic distribution can lead to serious eye infection
when tip of nose is involved, eye is often infected

What is Ramsay Hunt Syndrome? What are clinical features and complications?

Herpes zoster oticus
affects facial nerve near infected ear
causes facial paralysis and hearing loss on same side as affected ear; vesicular lesions on external ear
difficulty closing 1 eye, ringing in ears, vertigo, change in taste perception or loss of taste
more common in adults over 60, but can be seen in children
complications: permanent hearing loss and facial weakness; postherpetic neuralgia, possible cornea damage is eyelid will not fully close

Post-herpetic neuralgia (PHN)

zoster complications
persistence of pain (>90 days) after healing of rash
occurs in 20% of adults
more common if over 60
risk factors: age, severity of pain before rash heals, number of lesions, ophthalmic distribution, comorbid conditions like cancer

Granulomatous angiitis

a vasculitis of small vessels in CNS

- zoster complication

5 zoster complications

severe pain
Post-herpetic neuralgia
Zoster in immunocompromised
eye infection in 10-25%
granulomatous angiitis

How to prevent VZV? Who is vaccine not given to?

Live attenuated vaccine
Varicella: 2 doses; side effect is rash
Zoster: adults over 60, and 50-59 is recommended; same virus but with 14x potency
avoid giving to immunocompromised (live attenuated!!)

Who is cytomegalovirus problematic in?

-newborns and those with compromised immune systems

What cells does CMV infect and remain latent in? What will these cells look like?

-epithelial cells, endothelial cells, and leukocytes (monocytes and macrophages)

CMV infects humans of all ages, but its prevalence peaks in what age ranges?

2-5 (day care or school)

- young adults (sexual)

What is a major risk factor for CMV and what are 4 common routes of infection?

crowded living is risk factor

- oral, sexual transmission, blood transfusions, organ transplantation

Discuss epidemiology of congenital CMV

leading infectious cause of birth defects
prenatal, natal, and post natal spread
primary maternal infection poses much greater risk to fetus than reactivation
infection in early pregnancy poses highest risk to developing fetus
*infection in mothers, like most CMV infections, are asymptomatic**

What is the leading cause of infectious cause of birth defects?

Congenital CMV, highest risk if infected early in pregnancy and it is the primary infection

1-4% of pregnant women will develop a primary CMV infection, and about 40% of them will transmit the infection to the fetus. Describe what happens to that 40% statistically.

10-15% will show the disease; of these 10% will be normal, but 90% will have sequelae
85-90% of fetuses will be asymptomatic, of which 5-15% will develop sequelae and 85-95% will be normal

What are the clinical manifestations of a fetus that congenitally contracts CMV from a mother’s primary infection? What about from the mother’s reactivation during pregnancy?

Primary: any combination of intrauterine growth retardation, jaundice, hepatosplenomegaly, microcephaly, petechial rash, thrombocytopenia purpura, deafness, myocarditis, pneumonia, cerebral calcifications, chorioretinitis, motor disability; death may occur in first months of life, but more commonly infants survive but are neurologically damaged
Reactivation: late onset hearing loss (15%)

What is the term commonly given to babies born with congenital CMV from their mother’s primary infection?

-blueberry muffin babies

Discuss perinatal and postnatal CMV infection: how is it acquired, who gets it, what are symptoms?

Perinatal: babies can acquire CMV at time of delivery due to maternal cerical excretion (10-15% shed from cervix, 4% shed virus in urine);
highest among young mothers and lower SES
most infants are asymptomatic; may see interstitial pneumonia
post-natal transmission through breast milk is common and low-birth-weight infants are at greatest risk (premies)

A lot of CMV focuses on neonatal transmission, but what can it cause in other ages?

Mononucleosis-like syndrome in normal host
Infection in immunocompromised can be frequent and severe, but symptoms being worse if primary infection; disease in transplant/cancer differs from HIV patients

What is the frequent manifestation of a primary CMV infection in a young adult? Give the symptoms.

CMV mononucleosis
fever (2-4 wks), fatigue, mild hepatitis, lymphocytosis and small % of atypical lymphocytes in blood; exudative pharyngitis is absent and lymphadenopathy is less common
heterophil antibody negative

2 huge causes of Mononucleosis and how you can differentiate the causes.

EBV (79%) and CMV (21%)

- In CMV, exudative pharyngiti is frequently absent, lymphadenopathy is less common, heterophil antibody negative

What is heterophil antibody and what syndrome is this key of?

IgM class antibody that agglutinates RBCs from certain species
seen in EBV mono, but not CMV mono

CMV is particularly common in what 2 groups of immunocompromised patients? Describe their clinical presentations.

HIV: reactivation and diseases when CD4+ <50; retinitis, encephalitis, GI Tract-itis, uncommon in HAART era
Transplants: prolonged fever (2-4 wks), malaise, lethargy, myalgia or arthalgia, leukopenia, thrombocytopenia, mild hepatitis, pneumonia (diffuse, bilateral infiltrate); onset 1-3 months posttransplant

What is retinitis?

-hemorrhages and exudates often around blood vessels

What cells does Epstein-Barr virus infect and transform?

B-lymphocytes

- also infects epithelial cells in oral cavity and monocytes and T cells

Clinical diseases of importance due to EBV

infectious mononucleosis (IM)
PTLD
X-linked LPS
Burkitt Lymphoma
Nasopharyngeal carcinoma
Lymphomas of CNS and others
Hemophagocytic lymphohistiocytosis (HLH)

EBV is often asymptomatic except in what age group? What do these individuals get? How is it spread? What nickname has this acquired due to these facts?

10-30 y.o. get IM
spread via oral secretions
the kissing disease

Clinical symptoms of IM due to EBV; describe their blood cells.

symptoms in over 50% of infections
fever, exudative pharyngitis, lymphadenopathy, and fatigue; petechial rash on palate in 25-60%; facial edema in children
can also have hepato and splenomegaly, and rash
Lymphocytes will be 50-70% of WBVs with atypical lymphocytes comprising >20% of lymphocytes
atypical lymphocytes: reactive CD8+ T cells that contain abundant cytoplasm and lobulated nuclei

EBV IM complications are uncommon in normal hosts, but include what issues?

hepatitis
maculopapular rash with antibiotic treatment!!!
splenic rupture (why athletes should refrain from sports)
autoimmune hemolytic anemia
thrombocytopenia
encephalitis
overwhelming infection and death in X-linked LPS

5 categories of EBV-associated Malignancies

Posttransplant lymphoproliferative disorder (PTLD)
Burkitt Lymphoma
Nasopharyngeal carcinoma
Other lymphomas (Hodgkin, T cell, head and neck, CNS in HIV-infected)
Oral Hairy Leukoplakia

What is Oral Hairy Leukoplakia associated with? (give 2 viruses) and describe it.

excessive wart-like growth of papillae on tongue
occurs in advanced HIV infection and other immunosuppressed patients
one of the most common virally-induced oral diseases in HIV patients

EBV-Associated PTLD

serious complication of organ transplantation and a common malignancy in transplanted children***
usually associated with primary EBV infection, of which the donor organ can be the source
B cell expansion ranging from reactive hyperplasias to aggressive large cell lymphomas
rapidly fatal if not caught

Risk factors for PTLD

type of organ transplanted
primary vs. reactivated infection after transplantation
type and degree of immunosuppression
HLA mismatching
history of symptomatic CMV

Treatment(s) of PTLD and why is it necessary to get it right!!

PTLD necessitates decreased immunosuppression and/or removal of graft
it may look similar to acute cellular rejection, which needs heightened immune suppression. They look alike but required different things!!!

2 ways to diagnose Oral Hairy Leukoplakia

visual diagnosis: tongue lesions consisting of thin white plaques on tongue
incisional biopsy: verrucous hyperplasia with EBV PCR positive and HSV and VZV negative; culture should be normal respiratory flora with no fungal growth

Human Herpesvirus-6 (HHV-6): what is it most closely related to? what does it infect? what are variants?

-closely related to CMV and HHV-7
-lymphotropic virus that infects CD4+ and CD8+ T cells, NK cells, macrophages and neural and epithelial cells
2 variants: A and B with B causing most primary infections in children

HHV-6 clinical manifestations

Most common cause of roseola infantum (exanthum subitum) rose rash of infants aka sudden rash
undifferentiated febrile illness without rash
febrile seizures common with roseola in children up to 2 y.o.
may also see IM, hepatitis, and neurologic syndromes
can contribute to HIV disease progression and exacerbate disease with other viruses

HHV-6 clinical manifestations with transplant

-fever, hepatitis, leukopenia, delayed engraftment, neurologic disease, skin rashes, pneumonia, bone marrow suppression

HHV-6 Exanthum subitum

abrupt onset of high fever (104) that persisted for 2-5 days
fussy and irritable child
rash develops coincidentally with abatement of fever
right as fever comes down, rash will appear on neck, behind ears, and on back where it will then spread to abdomen and trunk with some on face and legs/arms
maculopapular in appearance and not itchy or uncomfortable

HHV-8: tropism, what it causes

Tropism: CD19+ B cells, macrophages, endothelial cells
Identified in all 4 types of Kaposi’s sarcoma: classic KS, endemic, KS in transplantation, AIDS-related KS
primary effusion lymphomas
Multicentric Castleman disease

HHV-8 KS clinical features

painless purplish macules, nodules or plaques
tumors mostly on skin, but can involve any organ
pathology shows spindle shaped tumors with RBCs

5 ways to diagnose herpesviruses

virus isolation in cell culture
nucleic acid amplification (NAAT)
Direct cytology or histology assays
detection of antibodies
genotyping/phenotyping

Cautions of using EBV Heterophil Antibody tests

not specific to EBV, but uncommon in other conditions
replies on polyclonal B cell stimulation
Agglutinates RBCs (most sensitive in horse, least in sheep)
False negatives common early in disease
age specific development
FALSE POSITIVES UNCOMMON

At presentation, EBV may not be detected in the blood, but is usually found in large quantities where?

in oral cavity

- virus cleared from blood much more rapidly than from oral compartment

Antivirals are commonly used to treat what herpesvirus infections? which ones do not have specific antiviral therapies? List the drugs and what they are prescribed for.

Primarily used to HSV, VZV, and CMV
Acyclovir or valacyclovir for HSV or VZV
Famciclovir for HSV or VZV
Ganciclovir or valganciclovir for HIV with CMV retinitis, GI tract infections or transplant with CMV pneumonia, hepatitis
Foscarnet: mucocutaneous acyclovir-resistant HSV infections and CMV retinitis
Cidofovir; Fomivirsen for CMV retinitis

Acyclovir mechanism of action and how resistance arises

must be triphosphorylated to be active
first phosphorylated by viral Thymidine kinase (TK)
then p-lated to di- and tri- phosphate forms by cellular enzymes
P-lated drug can then act as substrate for viral DNA polymerase and drug is incorportated into viral DNA to act as chain terminator and prevents elongation of viral DNA
Resistance results from mutations that inactivate viral TK which prevents activation of drug

Compare common primary HSV oropharyngeal infections between adults and children.

Children: gingivostomatitis

-primary infections in adults commonly cause pharyngitis and tonsillitis

Recurrent disease of oropharyngeal HSV infections is called what?

-herpes labialis (cold sores)

3 types of genital HSV infections and their definition.

primary infection: result of infection in patient who has never been exposed to either HSV-1 or HSV-2 and has no preexisting antibodies
Non-primary first episode: have previous infection with HSV and acquire other strain; fewer lesions due to some protective cross immunity
Recurrent infection: reactivate of genital HSV with HSV type that previously established infection in genital tract

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Herpes Viruses Flashcards

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