herpesviruses Flashcards
what are the human herpesviruses? (list)
1: HSV-1 (HHV-1)
2: HSV-2 (HHV-2)
3: varicella-zoster (HHV-3)
4: epstein-barr virus (HHV-4)
5: cytomegalovirus (HHV-5)
6: human herpesvirus 6 (HHV-6)
7: huma herpesvirus 7 (HHV-7)
8: kaposi’s sarcoma herpesvirus (HHV-8)
what is the one non-human primate herpesvirus of medical importance?
cercopithecine herpesvirus 1 (b-virus)
what is the virion structure of herpes viruses?
icosahedral core surrounded by lipoprotein envelope
what is the herpes virus genome structure?
linear
double-stranded DNA
does the herpes virion contain a polymerase?
no
where in the cell do herpes viruses replicate?
in the nucleus
where do herpes viruses get their envelope?
they’re the only viruses to obtain their envelope by budding from the nuclear membrane, lose it, then get a new membrane from the host’s plasma membrane (Leib said detail wasn’t required)
what is the tegument in herpes viruses and where is it found?
between nucleocapsid and the envelope
contains regulatory proteins s.a. transcription and translation factors, that play a role in viral replication
what are latent infections?
acute disease followed by asymptomatic period during which virus is quiescent
patient exposed to inciting agent or immunosuppressed, reactivation of replication and disease can occur
symptoms can be similar or different
how does HSV maintain its quiescent state?
after HSV infects neurons, set of latency-associated transcripts synthesized
these suppress viral replication
what are latency-associated transcripts and what viruses use them? what do they allow these viruses to do?
noncoding regulatory RNAs that suppress viral replication
used by HSV to allow for latent infection
how does CMV maintain its quiescent state?
produces microRNAs that inhibit translation of mRNA required for viral replication
genome also encodes protein and RNA that inhibits apoptosis in infected cells - allows infected cell to survive
which viruses cause vesicular rash? which infections (primary or secondary) would you expect to see it?
herpes simplex virus types 1 and 2; varicella-zoster virus
occurs both in primary infections and reactivations, though primary infections usually more severe
which herpesviruses can induce the formation of multinucleated giant cells?
herpes simplex virus 1 and 2
varicella-zoster virus
cytomegalovirus
what are the three classes of herpesvirus? how is it determined which class the viruses go into
classified by the type of cells they infect:
alpha herpesviruses: herpes simplex viruses 1 and 2
varicella-zoster
- infect epithelial cells primarily, cause latent infection in neurons
beta herpesviruses:
cytomegaloviruses
human herpesvirus 6
- infect and become latent in variety of tissues
gamma herpesviruses:
epstein barr
human herpesvirus 8 (kaposi’s…)
- infect and become latent primarily in lymphoid cells
give the following details about HSV-1:
- giant cells produced? - fetal or neonatal disease important? - lab diagnostic technique? - antiviral therapy commonly used?
- yes
- no
- culture
- acyclovir
give the following details about HSV-2:
- giant cells produced? - fetal or neonatal disease important? - lab diagnostic technique? - antiviral therapy commonly used?
- yes
- yes
- culture
- acyclovir
give the following details about VZN:
- giant cells produced? - fetal or neonatal disease important? - lab diagnostic technique? - antiviral therapy commonly used?
- yes
- no
- culture
- acyclovir
give the following details about CMV:
- giant cells produced? - fetal or neonatal disease important? - lab diagnostic technique? - antiviral therapy commonly used?
- yes
- yes
- culture
- ganciclovir
give the following details about EBV:
- giant cells produced? - fetal or neonatal disease important? - lab diagnostic technique? - antiviral therapy commonly used?
- no
- no
- heterophil Ab (which is -ve in CMV-induced mono-like symptoms; Leib skipped this in lec)
- none
give the following details about HHV-8:
- giant cells produced? - fetal or neonatal disease important? - lab diagnostic technique? - antiviral therapy commonly used?
- no
- no
- DNA probes
- alpha interferon
what structural factors distinguish HSV-1 from HSV-2?
structural factors: structurally and morphologically indistinguishable but can be differntiated by restriction endonuclease patterns of genome DNA and by type-specific monoclonal antisera
what will HSV-1 cause?
- Oral
- acute gingivostomatitis- recurrent herpes labialis (cold sores)
- Ocular
- keratoconjunctivitis (herpetic stromal keratitis) -> blindness
- Dendritic ulcer
- Retina destruction
- encephalitis (primarily in adults)
- Also genital vesicles (due to, uh, unusual sexual positions)
what will HSV-2 cause?
herpes genitalis
neonatal encephalitis
aseptic meningitis
what symptoms will HSV-1 cause and which ones will HSV-2 cause
1: skin: location of lesions; in HSV-1 lesions are above the waist; HSV-2 lesions below the waste
2: mouth: HSV-1 will cause gingivostomatitis, whereas HSV-2 rarely will
3: eye: HSV-1 will cause conjunctivitis, whereas HSV-2 rarely will
4: CNS: HSV-1 will cause encephaltis, HSV2 will cause meningitis
5: neonate: HSV-1 rarely causes problems, HSV-2 will cause skin lesions, encephalitis, and disseminated infection
describe the replicative cycle of HSV-1:
1: HSV-1 binds to heparan sulfate on cell surface
2: now binds to second receptor = nectin
3: viral envelope fuses with cell membrane
4: nucelocapsid and tegument proteins released into cytoplasm
5: viral nucelocapsid transported to nucleus
6: docks on nuclear pore
7: genome DNA enters nucleus with tegument protein VP16
8: linear genome DNA now becomes circular
9: VP16 protein interacts with cellular transcription factors
10: activates transcription of viral immediate early genes by host cell RNA polymerase
11: immediate early mRNA translated into immediate early proteins
12: these proteins regulate synthesis of early proteins - DNA polymerase and thymidine kinase
13: viral DNA polymerase replicates genome DNA
14: early protein synthesis shut off
15: late protein synthesis begins
16: late structural proteins transported to nucleus
17: virion assembly
18: virion gets envelope by budding through nuclear membrane
19: exits cell via tubules or vacuoles that communicate with exterior
what is acyclovir? when would you use it? what will it do? how does it act? (MECHANISM WAS EMPHASIZED BY LEIB)
- most effective drug against HSV
- used in cases with encephalitis and systemic disease due to HSV-1 and recurrent genital herpes, neonatal infections due to HSV-2
- will shorten duration of lesions and reduce extent of shedding
MECHANISM: CHAIN TERMINATION
- It’s a nucleoside (non-phosphorylated) analogue. Normal cell thymidine kinase won’t monophosphorylate it, but HSV-infected thymidine kinase will; this is followed by di- and tri-phosphorylation, incorporation into DNA and CHAIN TERMINATION
what is different between latently infected cells and non-latent HSV infections?
in latent cells, circular HSV DNA is in the nucleus, but is not integrated into cellular DNA
transcription of HSV DNA is limited to latency-associated transcripts (LATs)
what are immediate early proteins?
first group of proteins synthesized during herpesvirus replication
those whose mRNA synthesis is activated by a protein brought in by incoming parental virion
what are latency associated transcripts (LATs)?
noncoding regulatory RNAs that suppress viral replication
They are also anti-apoptotic, i.e., they keep their host cells alive and well
what are early proteins?
second group of proteins made in herpesvirus replication process
do not require synthesis of new viral regulatory proteins to activate the transcription of their mRNAs
how does reactivation of viral replication occur (in relationship to LATs)?
when the genes encoding LATs are excised, viral replication can be reactivated
how are HSV-1 and HSV-2 primarily transmitted?
HSV-!: saliva
HSV-2: sexual contact
primarily - can get HSV-1 in genital regions and HSV-2 in oral regions - 10-20% of cases
when is transmission of HSV-1 and HSV-2 most likely to occur?
when active lesions are present, but asymptomatic shedding does occur and can transmit the viruses
what percentage of people in the US are infected with HSV? what percentage have recurrent herpes labialis?
80% people infected
40% with recurrent herpes labialis
when do most primary infections of HSV-1 and HSV-2 usually occur?
primary infections of HSV-1 usually occur in early childhood - determined by appearance of antibodies
antibodies to HSV-2 rarely appear until sexual activity
where do HSV viruses replicate?
in skin or mucous membrane at initial site of infection
where do HSV viruses migrate? what happens following migration?
up neuron by retrograde axonal flow
HSV-1 to trigeminal ganglia
HSV-2 to lumbar and sacral ganglia
becomes latent in sensory ganglion cells
where is HSV DNA located in the cell during latency?
most if not all in the cytoplasm
what are some induces that reactivate a virus in latent state?
sunlight, hormonal changes, trauma, stress, fever
what happens when HSV virus is reactivated from a latent state?
migrates down the neuron and replicates in the skin
causes lesions
describe the typical skin lesion due to HSV:
vesicle that contains serous fluid filled with virus particles and debris
ruptures and virus is liberated and can be transmitted
multinucleated giant cells found at base of lesion
can immunity to HSV-1 provide immunity to HSV-2 and visaversa?
not really
immunity is type-specific, but some cross-protection exists
how complete is immunity to HSV?
incomplete
reinfection and reactivation can occur in the presence of circulating IgG
what type of immunity is most important in HSV?
cell-mediated immunity
suppression of cell-mediated immunity often results in reactivation, spread and severe disease
what are the primary and recurrent diseases HSV-1 causes? (list)
1: gingivostomatitis
2: herpes labialis
3: keratoconjunctivitis
4: encephalitis
5: herpetic whitlow
6: herpes gladiatorium
7: disseminated infections
8: erthyema multiforme
what population primarily gets gingivostomatitis? what virus causes it?
children
HSV-1
what are the symptoms of gingivostomatitiis?
fever
irritability
vesicular lesions in the mouth
what is the course of gingivostomatitis?
lesions heal spontaneously in 2 to 3 weeks
primary infection usually worse and lasts longer than recurrences
can have asymptomatic primary infections
what are the symptoms of herpes libialis?
which virus causes it?
fever blisters/cold sores
crops of vesicles, usually at mucocutaneous junction of lips or nose
recurrences frequently appear at the same site
HSV-1
what are the symptoms of keratoconjunctivitis? what are the consequences of recurrent symptoms? which virus causes it?
corneal ulcers
lesions of conjunctival epithelium
recurrences => scarring and blindness
hSV-1
what are the symptoms of encephalitis due to HSV-1?
necrotic lesion, USUALLY in ONE temporal lobe
headache vomiting seizures altered mental status high mortality rate severe neurologic sequelae in those who survive
is encephalitis due to HSV-1 due to primary infection or recurrence? how fast is onset?
can be due to either
onset can be acute or protracted over several days
how would you detect encephalitis due to HSV-1?
MRI can reveal lesion
spinal fluid usually has increase of lymphocytes, elevation in amount of protein, normal amount of glucose
what are the symptoms of herpetic whitlow? where does it occur and in what populations?
pustular lesion of skin of finger or hand
occurs in medical professionals as result of contact with patient’s lesions
in what population does herpes gladiatorum occur? what virus causes it?
in wrestlers and others who have close body contact
HSV-1 primarily
what are the symptoms of herpes gladiatorum?
vesicular lesions on the head and neck and trunk
in what population would disseminated infections due to HSV-1 occur? what sorts of infections would you expect to see?
occur in immunocompromised patients with depressed T-cell function
esophagitis and pneumonia
what diseases does HSV-2 cause? (list)
1: genital herpes
2: neonatal herpes
3: asceptic meningitis
4: erythema multiforme
what are the symptoms of genital herpes? which virus causes it?
painful vesicular lesions of genitals and anal area
due to HSV-2
how would primary case of genital herpes compare with recurrences?
primary disease is more severe and more protracted
primary often has fever and inguinal adenopathy
where would asymptomatic genital herpes infections occur?
in men in the prostate or urethra
in women in the cervix
many infections are asymptomatic, but can be source of infection of others
how is neonatal herpes acquired? which virus causes it?
due to contact with vesicular lesions within the birth canal
due to HSV-2
can be due to asymptomatic shedding
both HSV-1 and HSV-2 can be spread to neonates due to people handling the child
what are the symptoms of neonatal herpes? how does it compare with genital herpes?
milder local lesions on skin, eye, mouth
can also just be asymptomatic infection
no significant congenital abnormalities
how could you prevent neonatal herpes?
C-section
why would a maternal primary infection during labor be more likely to cause serious neonatal infection?
1: amount of virus produced during primary infection greater than secondary/recurrence
2: mothers who have been previously infected can pass IgG across placenta, which can protect neonate
what are the symptoms/clinical presentation of aseptic meningitis due to HSV-2?
usually mild, self-limited disease with few sequelae
what is erythema multiforme? which viruses cause it?
caused by both HSV-1 and HSV-2
rash that appears as a central red area surrounded by ring of normal skin surrounded by red ring = bull’s eye lesion
usually macular or papular
occur symmetrically on trunk, hands, feet
why is the erythema multiforme rash thought to occur?
thought to be an immune-mediated reaction to presence of HSV antigens
what can prevent recurrent episodes of erythema multiforme? how does it do so?
acyclovir
likely reduces amount of HSV antigens
how would you diagnose HSV? (laboratory methods)
1: isolate virus from lesion by growth in cell culture
look for cytopathic effect - usually occurs in 1 to 3 days
virus can then be identified by fluorescent antibody or ELISA
2: rapid diagnosis by Tzanck smear
3: serological tests can be used to diagnose primary infection because will be significant rise in antibody titer
which drugs would be used to treat which symptoms of HSV infections?
acyclovir for:
1: encephalitis and systemic disease due to HSV-1
2: recurrent genital herpes
3: neonatal infections due to HSV-2
foscarnet:
1: mutants of HSV-1 that are resistant to acyclovir
nucleoside analogs (trifluridine)
1: eye infections
penciclovir (derivative of acyclovir) or docosanol:
1: recurrances of orolabial HSV-1
valacyclovir (valtrex) and famciclovir (Famvir):
1: genital herpes
2: suppression of recurrances
how can HSV infections be prevented?
1: avoiding contact with vesicular lesion or ulcer
2: c-section
3: circumcision reduces risk of HSV-2
what are causes of erythema multiforme besides HSV?
many drugs, especially sulfonamides among the antimicrobial drugs
infectious causes such as mycoplasma pneumoniae and Hep B and C
what diseases does the varicella-zoster virus cause?
varicella is the primary infection and causes chickenpox
zoster is the secondary infection and causes shingles
what is stevens-johnson syndrome and what causes it?
erythema multiforme major
characterized by fever, erosive oral lesions, extensive desquamating skin lesions
most commonly caused by Mycoplasma pneumoniae, but can also be caused by viruses such as HSV, hep B and hep C
how is VZV different from other herpesviruses?
despite being structurally and morphologically similar, it’s antigenically different
has single serotype
what are the natural hosts of VZV?
humans
what is a Tzanck smear and what is it used to diagnose?
used to diagnose HSV infections
rapid
cells from base of vesicle stained with Giemsa stain
if multinucleated cells are present, suggests infection by herpesvirus or HZV
how is VZV transmitted?
respiratory droplets and by direct contact with lesions
highly contagious disease of childhood
what is foscarnet? why is it necessary?
treatment for HSV-1
necessary because there are some acyclovir resistant strains of HSV-1, so this is used in those cases
what tissues does VZV infect? how does it reach these tissues?
mucosa of the upper respiratory tract
spreads via blood to skin where rash occurs
infects sensory neurons - carried by retrograde axonal flow into cells of dorsal root ganglia - becomes latent here
where is VZV located in latently-infected cells? what cell types are latently-infected?
infects dorsal root ganglia cells latently
DNA in nucleus but not integrated into cellular DNA
how long is immunity to varicella? can you get zoster if you’re immune to varicella?
immunity is lifelong but zoster can occur despite immunity
how frequently can zoster occur?
usually only occurs once
when is zoster likely to occur?
frequency increases with age, likely due to waning immunity
frequently occurs at times of cell-mediated immunity or local trauma
what are the clinical findings/pathology of varicella?
prodromal symptoms of fever and malaise
then papulovesicular rash in crops on trunk
spreads to head and extremities
rash evolves to vesicles, pustules and finally crusts
itching prominent symptom
describe the replicative cycle of VZV.
similar to that of HSV
what is the incubation period of varicella?
14 to 21 days
what can the complications of varicella be? in what population do they usually occur?
- varicella pneumonia encephalitis
rare but when it does occur usually in adults - reyes symdrome in children
what is reye’s syndrome and what virus causes it?
caused by VZV virus and influenza B
characterized by encephalopathy and liver degeneration
occurs most often in children
what is the clinical presentation of zoster?
occurrence of painful vesicles along course of sensory nerve of head or trunk
pain can last for weeks
can get debilitating postzoster neuralgia
in immunocompromised: can get life-threatening disseminated infections such as pneumonia
shingles will appear along dermatome
how would you diagnose VZV? (laboratory diagnosis)
usually made clinically but can do laboratory test preliminary test using Tzanck smear definitive diagnosis by isolation of virus in cell culture and identification with antiserum can also look for rise in antibody
how would you treat VZV?
no treatment needed for immunocompetent children
adults with moderate or severe cases given acyclovir - can reduce duration and severity of symptoms
immnocompromised get acyclovir
if acyclovir-resistant strain, give foscarnet
for zoster, to accelerate curing of lesions, give famciclovir (famvir) and valacyclovir (valtrex)
how can VZV be prevented?
1: Varivax = vaccine to prevent varicella
2: Zostavax = vaccine to prevent zoster
for whom are the VZV vaccines recommended?
varicella for children between ages of 1 and 12
zoster for people older than 60 and who have had varicella
how could you give immune support against VZV to the immunocompromised?
varicella-zoster immune globulin = high titer of anitbody to the virus
acyclovir
what disease does cytomegalovirus (CMV) cause?
1: cytomegalic inclusion disease in neonates (congenital abnormalities) - most common cause of congenital abnormalities in the US
2: pneumonia and other disease in immunocompromised
3: heterophil-negative mononucleosis in immunocompromised
what are the natural hosts of CMV?
humans
animal strains can’t infect humans
how does CMV relate to other herpesviruses?
structurally and morphologically similar but antigenically different
one serotype
how is CMV transmitted?
1: across placenta
2: within birth canal
3: through breast milk
4: saliva (most common in young children)
5: sexually through semen and cervical secretions
6: blood transfusions and organ transplants
7: urine
how prevalent is CMV worldwide?
more than 80% of adults have antibody
what is the result of fetal infection by CMV?
cytomegalic inclusion disease
what types of vaccines are Varivax and Zostavax? what is a difference between the two?
live, attenuated VZV
zoster vaccine has 14 times more virus than varicella
what is cytomegalic inclusion disease? what virus causes it? what are common features of it (on the cellular level)?
caused by CMV
characterized by multinucleated giant cells and prominent intranuclear inclusions
causes congenital abormalities
are primary or secondary infections with CMV more dangerous to a fetus and why? during which trimester are fetuses most susceptible?
fetus will usually only be infected if primary infection occurs in pregnant woman
usually won’t be infected if mother infected before pregnancy because pregnant woman has antibodies against virus
abnormalities more common following infections during first trimester
who should not receive the VZV vaccines?
contain live virus, so shouldn’t be given to immunocompromised or pregnant women
in which patients would you see symptoms of CMV infection?
they’re usually asymptomatic except in immunocompromised
where would latent CMV infections occur?
primarily in monocytes
can be reactivated when cell-mediated immunity is decreased
can persist in kidneys for years
can be in latent state in cervical cells - can infect newborn during passage through birth canal
what is the mechanism that allows CMV to remain latent? (ie how does it prevent the immune system from eradicating it?)
in infected cells, assembly of MHC-I peptide complex is destabilized by virus => viral antigens not displayed on cell surface so cytotoxic T cell response doesn’t occur. Also encodes RNAs that prevent translation of MHC-1 mRNA transcripts for MHC-1 protein
also inhibits T-cells
what are the clinical symptoms of cytomegalic inclusion disease?
microencephaly seizures deafness jaundice purpura hepatosplenomegaly leading cause of mental retardation in US
what are the clinical symptoms of CMV in adults?
heterophilnegative mononucleosis = fever, lethargy, presence of abnormal lymphocytes in peripheral blood smears
how does the reproductive cycle of CMV compare to that of HSV?
similar except that some of CMV’s immediate early proteins are translated from mRNAs brought into the infected cell by the parental virion rather than being translated from mRNAs synthesized in newly infected cell
how does CMV commonly present in AIDS patients?
commonly infects intestinal tract
causes intractable colitis with diarrhea
retinitis - can lead to blindness
what type of inclusion bodies would you expect to see in cells infected with CMV?
intranuclear
have an oval owl’s eye shape
how is CMV treated?
ganciclovir - only moderately effective - for retinitis and pneumonia in patients with AIDS
valganciclovir - retinitis
resistant strains exist for both drugs
foscarnet (foscavir) effective but causes more side effects
cidofoviir (vistide) for retinitis
fomivirsen (vitravine) for retinitis - antisense DNA approved for intraocular treatment
how would you prevent spread of CMV infections?
no vaccine
isolate infants shedding the disease in their urine from other infants
blood for transfusion to newborns needs to be tested, as should all organs for transplant
what diseases does epstein-barr virus (EBV) cause?
1: infectious mononucleosis
2: associated with Burkitt’s lymphoma and other B-cell lymphomas
3: associated with nasopharyngeal carcinoma
4: hairy leukoplakia
what is the most important antigen of epstein-barr virus? Why this antigen?
viral capsid antigen
most important because used to in diagnostic tests
what type of cells does EBV infect?
mainly lymphoid cells, primarily B lymphocytes
epithelial cells of pharynx => sore throat
latently infects
where is EBV DNA located in latently infected cells?
in the nucleus
not integrated into cellular DNA
some but not all genes are transcribed in latent infection, only subset translated into protein
how is EBV transmitted?
via saliva
saliva with reactivation of latent infection can also spread it
blood transmission rare
what is the occurrence of EBV? in what populations does asymptomatic and symptomatic infection usually occur?
more than 90% of adults have antibody
usually asymptomatic if infected if first few years of life
most clinically apparent in those exposed to virus later in life
describe the course of infection of EBV
first occurs in oropharynx spreads to blood infects B lymphocytes cytotoxic T lymphocytes react against infected B lymphocytes remains latent in B lymphocytes
what are hetrophil antibodies?
Skipped in lec
nonspecific
antibodies detected by tests using antigens different from the antigens that induced them
don’t react with any component of EBV - more likely that EBV modifies component of cell membrane that these antibodies react to
usually disappear within 6 months after recovery
also seen in hep B and serum sickness
how would you diagnose CMV? (laboratory diagnosis)
1: culture in shell vials = special tubes
couple with use of immunofluorescent antibody - makes diagnosis in 72 hours
virus from culture can be used to determine susceptibility to drugs
2: fluorescent antibody
3: histologic staining of inclusion bodies in giant cells in urine and in tissue
4: four-fold or greater rise in antibody titer
5: PCR for DNA or RNA
6: antigenemia by detecting pp65 (protein in nucleocapsid of CMV) in leukocytes with immunofluorescent assay
what are the clinical symptoms of EBV?
enlarged cervical lymph nodes edema erythema of palate and uvula fever sore throat lymphadenopathy splenomegaly anorexia and lethargy common hepatitis frequent encephalitis can occur rarely get splenic rupture - but it can occur if spleen is injured during mononucleosis
how long does it usually take to recover from EBV infection?
2-3 weeks
what is hairy leukoplakia? what virus causes it? in what patient population does it occur?
whitish nonmalignant lesion with irregular, hairy surface on lateral side of tongue
due to EBV
occurs in immunocompromised individuals, especially AIDS patients
in what way is EBV associated with cancers? (ie why is it associated?)
Discussed in tumor lecture
EBV is the initiating event that causes the cells to divide, but that in and of itself doesn’t cause malignancy
> 90% of B-cells will see a reciprocal translocation (between chromosomes 8 and 14) that results in over-expression of the c-myc proto-oncogene.
This is a two-hit process
what is post-transplant lymphoproliferative disorder? when does it occur and what are predisposing factors?
most common is B-cell lymphoma
occurs following bone marrow transplants and solid organ transplants
predisposing factor is immunosuppression required to prevent graft rejection
lymphoma will regress if degree of immunosuppression is reduced
how would you diagnose infectious mononucleosis? (laboratory diagnosis)
1: hematologic approach: look for abnormal lymphocytes in blood smear - atypical lymphs enlarged, have expanded nucleus, and abundant, vacuolated cytoplasm
2: immunologic approach:
a) herterophil antibody test - early diagnosis - only positive by week 2 of illness but not useful after recovery because antibody titer declines - often used to detect heterophil antibody
b) EBV-specific antibody test - in diagnostically difficult cases - look for IgM and IgG
how would you treat infectious mononucleosis?
if uncomplicated, no treatment necessary
acyclovir has little activity but can be used in high doses in life-threatening cases
what does human herpesvirus-8 (HHV-8) cause? in what patient population?
Kaposi’s sarcoma in patients with AIDS
how does EBV enter B-lymphocytes?
at the site of the receptor for the C3 component of complement
what is the mechanism by which HHV-8 causes malignant transformation?
inactivation of tumor suppressor gene
protein called nuclear antigen, which is encoded by HHV-8, inactivates RB
describe the replication cycle of EBV
similar to that of HSV
how is HHV-8 transmitted?
sexually but also in transplanted organs
what is the clinical presentation of kaposi’s sarcoma in AIDS patients?
malignancy of vascular endothelial cells
contains many spindle-shaped cells and erythrocytes
results in dark purple, flat to nodular, lesions at multiple sites such as skin, oral cavity and soles (but not palms)
internal lesions occur in GI tract and lungs
B cells also infected - results in primary effusion lymphoma
how is kaposi’s sarcoma diagnosed? (laboratory diagnosis)
biopsy of skin lesions
HHV-8 DNA and RNA will be present in most spindle cells, but that analysis usually isn’t done
virus does not grow in culture
how is kaposi’s sarcoma treated?
depends on site and number of lesions
can do surgical excision, radiation and systemic drugs, s.a. alpha interferon or vinblastine
describe the immune response to EBV
first IgM antibody to VCA
the IgG antibody to VCA
this antibody persists for life
also heterophil antibodies
what makes all herpesviruses similar?
all enveloped and dependent on envelope
contain tegument that has proteins that can immediately become active in cell upon infection
what are the alphaherpes viruses and what infection pattern defines this group?
ones that infect and go latent inside neurons - neurotrophic (simplexvirus and varicellovirus) wide host range HHV-1 HHV-2 HHV-3 CaHV-1
what are the betaherpes viruses and what infection pattern defines this group?
HHV-5 - cytomegalovirus
have tropism and latency in monocytes and macrophages
narrow host range
what are the gamma herpesviruses and what infection pattern defines this group?
tropism and latency largely in B cells can cause cell transformations so tumor viruses narrow host range EBV HHV-8
what is X-linked lymphoproliferative symdrome? what virus is this relevant to and why?
inherited immunodeficiency
mutated gene encodes for signal transduction protein required for T cell and NK cell function
75% mortality by age 10
EBV can cause severe, often fatal, progressive form of infectious mononucleosis in children with this disorder
how do herpesviruses enter cells?
through cell fusion mechanism
capsid goes straight to nuclear pore and empties DNA material into nucleus
what is the evidence that latent viruses are dynamic rather than static (so doing something while latent rather than just hanging out in the cell inactive)?
1: viruses can produce proteins that prevent apoptosis
2: epidmeological study - have patients with herpes swab genitals daily and record whether they’re having outbreak - were still infectious despite no evidence of outbreak -viral shedding every 3-5 days despite average occurrence of outbreaks every 3 months
what are the occular syndromes associated with herpes infection?
1: dendritic ulcer - people whose herpes reactivates into posterior ciliary nerves into the back of the cornea
2: actue retinal necrosis - extremely rare but causes massive wipe-out of retina
3: herpetic stromal keratitis (HSK) - due to repeated activation - CD14 cell mediated disease - blood vessels grow into cornea - most common cause of viral blindness in USA - can only help by giving new cornea, but can happen again because still latently infected
4: periocular herpes - virus travels back from trigeminal ganglion - crosses over a few branches and comes out into periocular skin
what type of drug is acyclovir and what is its mechanism of action?
nucleoside analogue
structure very similar to building block of DNA
can’t be phosphorylated by human kinase
but must be phosphorylated to be incorporated by DNA
HSV kinase will phosphorylate it (the first phosphorylation - human proteins can do 2nd and 3rd phos)
gets incorporated into DNA in virally infected cell but not in non-infected cell
how would you differentiate smallpox from chickenpox?
smallpox has more rash on extremities (arms legs head)
chickenpox has more rash on torso and head
how do you treat shingles?
NSAI
steroids
substance P suppressors
what could be the effect of chickenpox vaccine on the occurrence of shingles?
our immunity to VZV is likely being maintained by being exposed to children with chickenpox
now that children aren’t getting chickenpox, could see more cases of shingles
where do giant cells form due to CMV?
in kidney section and parotid glands
what are common congenital abnormalities due to CMV?
inflammation of retina jaundice large spleen and liver low birth weight mineral deposits in brain rash seizures small head size sequelae that include psychomotor retardation, deafness
how is CMV most commonly spread?
through urine due to infection in kidney
how long is the incubation period for EBV?
4-6 weeks
what are the symptoms/results of HHV-6?
benign rash with high fever
rarely encephalitis
maybe associated with MS, CFS, epilepsy
what is HHV-6 associated with?
roseola infantum/exanthem subitum - infantile rashes
what is the prevalance of HHV-6?
greater than 90% worldwide
approx 1% have HHV-6 integration into gernline
what is known about HHV-7?
basically nothing. it’s closely related to HHV-6 but no one knows what it does
why is Kaposi’s sarcoma rarely seen in the US now?
because of HAART
in what species does B virus normally occur?
in rhesus macaques
who gets B virus?
zookeepers or people who work in animal facilities
what are the symptoms/results of B virus?
serious encephalitis
death or serious neurological sequelae
how do you treat B virus?
acyclovir
immune serum
Where are the following viruses latent (this can be answered if you know their class)?
- HSV-1 and 2
- Varicella-Zoster (HSV-3)
- EBV (HSV-4)
- CMV (HSV-5)
Alpha: neurons
- Sensory neuron ganglia
- Sensory neuron ganglia
Note that 1 and 2 infect skin first, find a neuron, travel RETROgrade to its ganglia, and remain latent there until they are re-activated. They then migrate ANTEROgrade back to the skin
beta: monocytes and macrophages
3. Leukocytes
delta: B-cells
4. B-cells, driving them to proliferate (and occassionally causing Burkitt’s lymphomas and nasopharyngeal carcinomas)
