Herpes Viruses Flashcards
What is the genome of herpes viruses?
What is the composition of the virus?
double stranded DNA with linear genome
Enclosed in capside surrounded by tegument which is surrounded by lipid envelope
There could be unique isoforms of the UL and Us sections
What is the sequence of transcriptional events?
Burst of RNA synthesis for proteins needed at that time; proteins are transcribed from genomes within the virion
Early proteins synthesized a responsible for DNA synthesis a then DNA rep then all the virion structural proteins produced and assembled into virus particles.
What does the primary infection for HSV1 include (6)
Means of transmission?
Portal Entry?
Target cell?
cold sores, sore throat, fever, rarely encephalitis.
less freq found as a genital infection
Also could cause herpetic keratinitis
Transmission: direct contact
Portal of entry: mucosal membranes, skin
Target: skin
Primary lytic infection of epithelial cells
What is the pathogenesis of herpes?
- Primary lytic infection of epithelial cells
- Virus infects sensory neurons [latency]
Latency associated transcrips (LATs), are the only viral mRNA that will be present in sensory root
Reactivation can occur –> virus travels back to epithelial cells causing lesions and shedding (at same site of primary infection)
HSV1: What is occuring during the latent infection period?
What occurs during recurrence?
Asymptomatic, no virus are being produced (thus NOT chronic)
Viral NDA resides in SENSORY CELLS of TRIGEMINAL NERVE GANGLION!
wait for reactivation (stress, immunosuppression…)
Reccurent infection: virus replicated and travels down sensory nerve fibers to infect epithelial cells around the NOSE AND MOUTH
Symptoms are usually milder for of primary infection
What is the primary infection of HSV2?
Usually vesicular eruptions on the genitalia, less frequently found as herpes labialis (cold sores)
Transmission: (sexual) contact
affects both sexes
Latent infection and
Recurrent infection of HSV2?
During latent infection, no virus are being produced. Viral DNA resides in SENOSRY CELLS of SACRAL GANGLION
Recurrent Infection: milder outbreak generally in same location in genital area
[could occur monthly for some women]
Other HSV lesions:
Herpatic whitlow?
Gladitorium?
Whitlow - associated with herpes on the fingers/abrasion in the fingers; usually seen in dentist, or emergency workers (HSV1/2)
Gladitorium - associated with wrestlers / gyms (HSV1)
Ocular herpes - keratoconjuctivitis (HSV1)
- less common but can occur due to specific contact with infectious agent in different body locations*
- eonatal herpes, encephalitis (primary or reactivation), disseminated herpes*
What is one treatment option?
What are 2 awesome things about this drug?
HSV - acyclovir (nucleoside analog- chain termination by substituting GTP into DNA strand)
Unphosphorylated and becomes phosphorylated in virally infected cells! (via viral thymidine kinase)
Higher affinity for herpes virus DNA polymerase than cellular
Could acyclovir resistance develop?
How do mutations arise?
Resistance is due to mutation in the gene encoding
*viral thymidine kinsae, the drug is not phosphorylated to the active form
* viral polymerase - the polymerase no longer efficiently binds the drug
Doesn’t happen often, usually the viruses are still attenuated, and more likely seen in immunocompromised patients
Pritelivir:
MOA
Directed towards herpesvirus helicase-primase (involved in the unwinding of the DNA)
Stop DNA rep
Specific to herpes virus
–> shown to REDUCE SHEDDING and REDUCE DAYS WITH LESIONS
Varicella Zoster Virus:
Primary infection (3)
- infection occurs in seasonal epidermics as chicken pox (varicella)
- Contracted from another infected individual usually a child, via RESPIRATORY TRANSMISSION
- Systemic infection resulting in a generalized, vesicular rash
Mild prodrome (fever and malaise) for 1-2 days
Successive crops (2-4 days) of pruritic vesicles
Generally appear first on head, most concentrated on trunk
generally mild in healthy children
** you see the vesicles at all different stages!!**
When/how can the virus be transmitted?
Usually infectious stage BEGINS durring the prodrome stage of the virus, BEFORE the vesicular rash appears; infeciton of mucosa of upper respiratory tract
Primary viremia begins around day 5 –> viral replication in liver, spleen and other organs –> secondary viremia = contagious period (around day 11) –> Fever –> infection of skin and appearance of vesicular rash at about day 14, where the individual is still contagious
(contagious from days 11 - 17)
Overall about 20 day cycle
What can scratching a lesion impose?
scratching –> infection with s. aureus
What are the complications of varicella? (5)
What age group are these complications mostly seen?
Bacterial infection of lesions
CNS manifestations (encephalitis)
Pneumonia (rare in children)
Hospitalization ~3 per 1000 cases
Death ~1 per 60,000 cases
Especially seen in infants under 1 or adults over the age of 30 who acquire primary infection
What vaccine is available for vzv?
What is its effectivness
Who shouldn’t receive it and why?
VARIVAX
Live-attenuated vaccine (not to be given to immunocompromised hosts)
95% efficacy [98% effect in protecting from severe dz, 70-85% protective against any form of VZV]
induces seroconversion after 1 dose
duration is probably life long
Now given as: MMRV, thus boosted every so often
VZV latent infection and recurrence?
presentaiton?
Latent: asymptomatic with no virus or virion proteins produced, viral DNA resides in the cells of the DORSAL ROOT GANGLIA
Recurrent: virus travels down the sensory nerve fiber and infe_c_ts epithelial cells inundated by the fiber
Painful, unilateral vesicular eruptions localized to the dermatome, usually in head or upper trunk
Severe systemic infections are observed in immune suppressed individuals
Protection for the elderly?
VZV vaccine - reduces incidence of herpes zoster (postherpetic neuralgina)
What could you do about protecting immunocompromised individuals?
varicella-zoster IMMUNE GLOBIN
provides PASSIVE IMMUNITY
but this cannot induce lifelong immunity; thus should be immunized as soon as person gets out of their immunocompromised state
Can shingles be infectious?
generally not as much - it is not through respiratory but rather the viral particles are in the vesicles themselves. Most of the time they are covered up and not being touched and passed on.
dx:
herpes encephalitis
HSV 1 /2
VZV
EBV
CMV
HHV 6 & 7
HHV 8
herpes encephalitis - PCR
HSV 1/2 – clinical but also PCR
VZV - clinical
EBV - monospot (and/or serology for IgM to VCA)
CMV- PCR, serology, histology
HHV 6&7 - clinical
HHV 8 - clinical, PCR
EBV:
Primary Infection Clinical presentation?
Malignant lyphoproliferative dz?
younger you are, the less symptomatic it will be
kissing disease - teenagers come in with mono
Primary infection: asymptomatic, infectious mononucleosis (mono)
Malignant lymphoproliferative dz:
burkitt’s lymphoma, nasopharyngeal CA
EBV antibodies can be found in about 95% of most of the adult population
EBV can be isoalted from teh thorat washing of acutely ill pt and excretion may continue intermittently for months after all signs of illness have disappeared!
EBV transmission?
Who is at highest risk?
When do we see it most often?
What does this cause?
Saliva!
Teenagers adn adults at highest risk for infectious mono
also, ppl with T-cell deficiencies!
See world-wide with NO SEASONAL incidence
causes life-long infection; asympo shedding of virus
What is the mxn of dz of EBV?
Virus in saliva infects epithelia and spreads to B-CELLS in lymphatics
Infection promotes GROWTH of B-cells [cause them to spew out any antibody B cells are making]
T-cells kill/control B-cell outgrowth –> promote LATENCY IN B-CELLS
Severe disease in T-CELL deficient patients
What is something particular about the B-cell antibodies?
T-cells?
You will see heterophile antibody = lots of different antibodies produced because so many are activated – antibodies produced against weak antigens
You will also see DOWNEY CELLS - atypical lymphocytes
(seen on blood smears)
How do you detect EBV infection?
1. Monopsot test:
detection of heterophile antibodies
false negative 5-15%, esp in children!!
2. Antibody to EBV VCA
IgM/IgG to viral capsid antigen
more specific test than monospot test, less false neg.
What is the serology look like through the course of EBV infection?
Initial - resolution - convalescence ?
Primary - IgG and IgM to viral capsid
down –> antibodies to early antigen
Sign of resolution - antibody + EBV and nuclear antigen (indicative of resoution of disease)
Convalescent serology: IgG+ for VCA but IgM- for VCA
Sx of primary EBV: (5)
Tx?
fever, malaise, lymphadenopathy, hepatosplenomegaly, pharyngitis
During this time, virus is in the saliva!
- no sharing stuff!*
- TX: no treatment*
- (acylovir does not work, no vaccine!)*
What are the most common clinical syndromes of EBV? (6)
Early age - asymptomatic
Infectious mononucleosis
Post-transplant lymphoproliferative disorder (PTLD)
Hairy oral leukoplakia w/AIDS
African Burkitt’s Lymphoma (malaria is a co-factor)
Nasopharyngeal carcinoma (CHINA!)
CMV
Primary infection (6 clinical prez)
VS
Carrier state
Primary infection:
asymptopmatic infection
BUT fetal/neonatal infection CAN BE VERY SERIOUS!!
mono (10%!), AIDS retinitis and pneumonitis, post-transplant pneumo
Persistent Infection/carrier state:
Asymptomatic shedding
serious complications in immuno-compromised pt
what is tricky about CMV ?
Could also cause mononucleosis!
But it with be heterophile Ab negative
VAC negative
How is AIDS/Immunocompromised CMV infection best controlled?
Restoration of T-cells!
Cytomegalic Inclusion Disease/Neonate Infection:
Mother’s CMV state?
Seronegative mother that has a primary infection during pregancy
pneumonia, CNS, calcifications…
How is CMV transmitted? How does it infect? Where does it remain latent?
Who is at highest risk?
Transmissions include: blood, secretions - breast milk, semen
[mostly acquired in childhood, most secretions are via cervical - potential for CMV secretions increase in the third trimester of pregnancy]
–> productive infection of epithelium –> establishes latency in T-cells, macrophages, lymphocytes…
Highest risk: babies and immunosuppressed individuals; suppression of cell-mediated immunity allows for recurrence!
How do we test of CMV?
PCR - detection of CMV DNA
Serology - CMV specific IgM and IgG
Cytology/histology - Owl eye inclusion body
CMV treatment (2)
Ganciclovir: (nucleoside inhibitor)
- Activated CMV-infected cells
- PROBLEM: bone marrow toxicity (est stem cell translplant pt!)
Letermovir: (not yet FDA approved *NEW*)
Prophylaxis in hematopoietic cell transplant
RED incidence of CMV in transplant pt
Targets CMV terminase complex (CMV specific)
Dose-dependent inhibition
What causes Roseola?
SX: (5)
Recurrence/latency?
HHV 6 adn HHV 7
Rapid onset of HIGH FEVER, generalized rash 24-48 hours AFTER fever, T-cells resolve infection –> virus becomes latent T cells
Unknown if there is actual recurrence!
95% of people are seropositive for HHV6/7 by the age of 5
Transmission/pathogenesis
Clinical DX?
Respiratory Transmission – incubation period of 4-7 days
ABRUPT HIGH FEVER (103-105) 2-4 days
AFTER fever –> erythematous lace-like RASH all over body while sparing the face 1-2 days
Receovery withouth complications
NO rapid test! Clinical diagnosis
no therapy, no vaccine
What causes kaposi’s sarcoma?
Who is a higher risk?
What does the typical lesion look like?
HHV 8
YOU MUST BE IMMUNOSUPPRESSED
it is the most common neoplasm in AIDS pt
Seen also at INC in elderly men of mediterranean/eastern european descent (Russian), and endemic in Africa
Iratogenic in post-transplantion
Red/violacious lesion anywhere on the body
Spindle-shaped tumor cells, neovascularization, inflammatory infiltrate
TX?
- Restore T cell function (esp in AIDS pt!) in order to control
* activation of KS during immunosuppression; in HIV pt use antiretroviral durgs reduces/controls KS*
* NO OTHER DIRECT TREATMENT OF KS!*
Transmission?
Sexual transmission (MSM)
