Neurotropic Viruses Flashcards
What do Herpesvirus look like?
- 180-200nm in diameter
- Large genome: 100-250 kbp
- Enveloped viruses are labile in the environment: infectious virions survive up to 2 hours on skin, up to 4 hours on plastic surfaces
What are the α herpesviruses?
What are the ß herpesviruses?
What are the γ herpesviruses?
What are the α herpesviruses?
- Hepes simplex virus (HSV-1, HSV-2)
- Varicella zoster virus
- HHV-1, HHV-2, HHV-3
What are the ß herpesviruses?
- Cytomegalovirus (CMV)
- Roseolovirus (HHV-6)
- HHV-7, HHV-5, HHV-6A, - 6B
What are the γ herpesviruses?
- Epstein-Barr Virus (EBV)
- Kaposi’s Sarcoma Virus (KSHV)
- HHV-4
- HHV-8
Characteristics of α herpesviruses
- Short replication cycle
- Latency primary in sensory ganglia (neurons)
- Broader host range
Defining biological properties of a herpesvirus
- Encode a collection of enzymes involved in nucleotide metabolism, DNA synthesis, protein kinase
- Synthesis of viral DNA and capsid assembly in the nucleus
- Rest of virion put together in cytoplasm
- Two life cycles: lytic replication and latency
Latent infection
- Circular viral DNA is associated with host nucleosomes and is maintained as an episome
- Very little if any viral gene expression - repressed through viral chromatin-associated histone code
- Poorly defined mechanisms trigger reactivation
- Immune system
- UV radiation
- Physical trauma
Herpesvirus last ______
Forever
Maintain latency with occaisonal reactivation for the life of the host
Transmission:
- Person to person
- Intrauterine
- Perinatal
- Skin-skin
- genital-genital
- Oral-Genital
- Oral-Oral
HSV reservoir:
______ is more commonly shed from oral cavity
______ is more commonly shed from genital tract
Humans are the only reservoir
HSV-1; HSV-2
HSV pathogenisis
- VIral transmission to mucosa (epithelium)
- Robust lytic replication (primary infection)
- Virus infects sensory neurons - retrograde transport to the sensory ganglia - latency
- Latency characterized by expression of group of viral mRNAs called Latency Associated Transcripts (LAT’s) - never translated into protein - repress HSV gene expression
- Unknown stimuli trigger viral reactivation - viral capsids subjected to anterograde transport with mature virions
Sites of latency
HSV-1:
HSV-2:
HSV-1: trigeminal ganglia
HSV-2: sacral ganglia
Frequency of reactivation
In untreated HSV-2 positive individuals, the chance of subclinical reactivation at a genital site is approximately 25% on any given day
Exogenous reinfection
Reinfection of a seropositive individual with a different strain of HSV (possible but uncommon)
Treatment of herpesviruses
- Current treatment approaches targeting replicating virus ONLY
- No treatments available that would clear latent herpesvirus infection
- Acyclovir - treatment of choice
- No vaccines for HSV (varicella zoster virus only herpes vaccine)
How does Acyclovir work
Competes with dGTP for viral DNA polymerase
Polymerase binds to ACV-PPP irreversibly
Ties up polymerase
HSV-1 and HSV-2 Primary vs. Recurrent mucocutaneous infections
- Genital disease (both HSV-1 and HSV-2) - treatment reduces shedding by 60-80%)
- Primary oral-facial infection (HSV-1 most common) - Herpes gingivostomatitis or pharyngitis
- Recurrent oral-facial infection - herpes labialis
HSV-1 and 2: Neonatal herpes:
- Inoculation during birth (most common)
- Inoculation during pregnancy results in multiple birth defects
- Disseminated replication
- CNS is commonly affected
- Disease usually manifests within days of life - may not have skin lesions
- Mortality is high, even if treated with acyclovir
- Neurological abnormalities in survivors
Herpes keratitis and conjunctivitis:
Herpes gladiatorium:
Herpes whitlow:
Herpes keratitis and conjunctivitis: leading cause of blindness in the US
Herpes gladiatorium: Dermatitis of athletes in contact sports
Herpes whitlow: Handdermatitis - significant problem in health care workers - gloves do not prevent transmission
HSV-1 and 2 diagnosis
- Vesicles at the site of inoculation
- Clinical virology lab: culture of virus immunofluorescence using antibodies against HSV antigens, PCR assays
- Serology to determine infection status
Varicella Zoster: epidemiology and transmission
- Humans only reservoir
- Cuasative agent of chickenpox
- Spread through person to person contact
- Virus is aerosolized both from lesions and respiratory tract
- Can also be transmitted via direct contact with the skin lesions
Varizella Zoster: Course of Disease
- Virus replication in T cells, epithelial and endothelial cells
- Latency is maintained in sensory nerve ganglia - many ganglia are involved
- Several viral gene products are actively transcribed and translated within latently infected neurons (unlike HSV) - unknown how virus deals with immune recognition
- Primary infection may involve CNS
Chickenpox (characteristics)
- Primary infection with VZV
- Blisters, itching, malaise, fever
- Aspirin counterindicated - Reye’s syndrome
- Serious complications (skin infection, pneumonia) more common in adulthood
- Neonatal VZV is extremely rare
- Can lead to fatality in immunocompromised patients
- Treatment includes antivirals, such as acyclovir, VZV immune globulin
Herpes Zoster
- Reactivation of latent VZV from a single sensory ganglia (most cases)
- 1 million cases/year in US (usually > 50 years old)
- In Trigeminal ganglia can lead to vision impairment
*
Postherpetic neuralgia
A significant complication of zoster: severe pain without vesicular lesion, can mimic appendicitis or a heart attack. Pain can last for many months. Antivirals have no effect
Varicella Zoster: Diagnosis
- Differential diagnosis must exclude bacterial or enterovirus infections
- Most important diferential was smallpox historically
- Clinical lab diagnosis: VZV DNA PCR, detection of VZV antigens in lesions by immunofluorexcence
- Serology to determine immune status of individual
VZV vaccine
Live attenuated virus - Oka strain (1995)
- Up to 15-20% of vaccinated individuals get infected with wild type VZV that goes on to establish latency
- Reduces severity of primary infection
- Establishes lifelong latent infection
- Can be transmitted to immunocompromised
- Immunity in aged not as long lasting; rcommended in population > 60 years of age
