Download The complexities of Varicella Zoster Virus infection: problems for

The complexities of Varicella Zoster
Virus infection: problems for
vaccination and therapy
Infectious Diseases & Immunology
Varicella Zoster Lab
University of Sydney
Associate Professor Allison Abendroth
[email protected]
Human Herpesviruses
Alphaherpesviruses
• Varicella Zoster Virus
• Herpes Simplex Virus 1
• Herpes Simplex Virus 2
Betaherpesviruses
• Cytomegalovirus
• Human Herpesvirus 6
• Human Herpesvirus 7
Gammaherpesviruses
• Epstein-Barr Virus
• Kaposi’s Sarcoma-associated
Herpesvirus
Shared characteristics

Large dsDNA genomes

Virion structure

Lytic and latent life cycles

Extensive immune evasion
strategies
Varicella Zoster Virus (VZV)

Varicella zoster virus (VZV) causes two different
diseases:
(1) chickenpox (varicella)
(2) shingles (herpes zoster)

The same virus causes both diseases
Features of Chickenpox
(Varicella)
•
When you get infected with VZV for the first time, the virus causes a
widespread blistering rash called chickenpox (varicella)
•
It is likely that dendritic cells in the respiratory mucosa become infected
with VZV and transfer to T cell in the draining lymph node
•
T cells then disseminate VZV to distant cutaneous sites, causing the
widespread rash
Initial infection
causes chicken pox
Features of Chickenpox
(Varicella)
•
>90% of chickenpox occurs in children 1-14 yrs of age
•
Chickenpox is a relatively mild disease in healthy children
•
Complications and significant disease can occur in older age groups, the
fetus, new born infants and is life-threatening in immunocompromised
people
Chicken AND Egg Pox
How does VZV spread to others
during chickenpox?
•
Chickenpox is a very contagious disease
•
The virus spreads very easily from people with chickenpox to
others who have never had the disease
•
The virus spreads in the air when an infected person coughs or
sneezes
Features of Chickenpox (Varicella)

Your immune system fights the virus and the chickenpox rash heals
and most of the virus is eliminated

However, the virus is never completely eliminated

Some of this virus travels up sensory nerve fibres (axons) from the
rash at your skin to sensory neurons within ganglia in your spine
Virus
Skin
Nerve fibre
(axon)
Sensory
neuron
Features of Latent Infection

Once the virus gets to your spinal ganglia it becomes dormant
(latent)

This latent infection is life-long

There are no symptoms during latent infection
Initial infection
causes chicken pox
Latent infection
(no symptoms)
Shingles

When VZV reawakens (reactivates) from latent infection, it causes shingles
(herpes zoster)

The virus reactivates in sensory neurons in your spine and travels back to
the skin via nerve axons to cause the shingles rash
Virus
Skin
Nerve fibre
(axon)
Sensory
neuron
Shingles
• Unlike chicken pox (varicella) the shingles (herpes zoster) rash occurs
with a dermatomal distribution
• This is because the virus usually only reactivates from sensory ganglia at
one “level” in your spine
Shingles (herpes zoster)
• Herpes zoster is usually associated with a painful rash
• Sometimes a prodromal pain can precede the appearance of the herpes
zoster rash by several days
Initial infection
causes chicken pox
Latent infection
(no symptoms)
Reactivation causes
shingles
Shingles
• Overall ~20% of people who had chickenpox get shingles
• Chances of shingles increases dramatically with age
• Immunocompromised people are at higher risk for shingles
• The blisters that form typically scab over in 7-10 days and heal
within 2-4 weeks
Day 1
Day 2
Day 5
Day 6
Can VZV be spread from someone
with shingles to someone else?
• The virus is spread through direct contact with fluid from the rash
blisters, not through sneezing or coughing
• Shingles is less contagious than chickenpox
• A person with shingles can spread the virus when the rash is in
the blister-phase
VZV and Neuropathic Pain
• Acute pain can last
throughout herpes zoster
• Burning pain, itching, oversensitivity, "pins and needles”,
tingling, pricking sensation
• Pain may be mild to extreme
• In addition to pain during
herpes zoster, for some
people the problem persists
well beyond rash resolution…
Most common complication of
herpes zoster is post-herpetic neuralgia (PH
•
Herpes zoster is sometimes followed by a severe pain syndrome called post
herpetic neuralgia (PHN)
•
20-60% of people with herpes zoster will experience PHN after the rash resolves
•
PHN also increases with age
•
PHN can last for months or even years
•
Often severe, debilitating nerve pain which has a major negative impact on
quality of life
Treatment strategies for
post-herpetic neuralgia
•
Currently there is no cure for PHN
•
Current treatment options to ease PHN pain include:
• Gabapentin, lidocaine patch, opioid analgesics, pregabalin and tricyclic antidepressants, corticosteriods (anti-inflammatories)
•
Anti-viral approaches (eg. Acyclovir, famciclovir, valacyclovir) are designed to
inhibit viral replication and hasten arrest of viral shedding and increase rash
healing and reduce the duration of acute pain (Chen et al., 2014 Cochrane
Review)
•
For many people these medications are either partially or totally ineffective,
whether administered alone or in combination
•
Pain management of complex and usually inadequate
•
Cochrane reviews have concluded that corticosteriods and acyclovir are
ineffective at reducing the incidence of PHN, and there is insufficient evidence to
determine whether other anti-virals are effective (Han et al., 2013 and Chen et
al., 2014 Cochrane Review)
What causes the pain during shingles
and post-herpetic neuralgia?
•
•
•
•
•
The cause of the nerve pain is unknown
It is thought that when VZV reactivates from neurons, the virus causes damage to these cells
and this may play a role in pain
The paucity of samples of human ganglia from donors during or following documented herpes zoster
have significantly hampered the study of host immune responses to VZV in human ganglia
We have sourced human ganglia from patients who at the time of death had a herpes zoster
rash, but who had not died from VZV related causes
Rather than direct virus induced damage, we showed that the damage to neurons is more
probably due to our own immune system attacking and damaging infected neurons (Hood et al.,
2006, Gowrishankar et al., 2010)
Immune cells
infiltrating the site
of VZV infection
Nerve cells
(neurons)
CD3+ T cells infiltrate into ganglia
during active herpes zoster
Herpes Zoster Ganglia 1
Herpes Zoster Ganglia 1
CD3+ stain
S100 stain
DAPI stain
CD4+ stain
S100 stain
DAPI stain
During active herpes zoster there is a robust infiltration of T cells into the affected
ganglia, with CD4 cells predominating over CD8 cells
Cytolytic nature of T cells during
active herpes zoster
CD8
Granzyme B
A
B
C
CD4
Granzyme B
D
Merge
E
Merge
F
Cytolytic CD8+ T cells are a prominent feature in ganglia during active herpes zoster
CD8+ T cells interact with neurons-satellite
glial cell units during active herpes zoster
CD3
S100
B
A
CD8
D
Merge
C
NCAM
E
Merge
F
Steain et al. Journal of Virology (2014)
Histological examination of PHN-affected
ganglia (>12 months post rash)
Immunohistochemical examination of this tissue for immune cell subsets
revealed CD3+ T cells and B cells are found to persist in PHN affected ganglia
many months following herpes zoster rash resolution
Immune response in human ganglia
during or after herpes zoster
• During active herpes zoster there is a robust infiltration of T cells into the
affected ganglia, with CD4 cells predominating over CD8 cells
• These infiltrating cells express markers of cytolytic potential
• Cytolytic T cells closely associate with neuron-SCG units. This suggests that
the host immune response may be the cause of damage to neuronal cells
during herpes zoster, which then results in persisting pain
• First detection of immune cell subsets within the ganglia of a PHN-affected
patient
• Demonstrates an ongoing immunological process >12 months after rash
resolution in a patient suffering from PHN
A vaccine to prevent chickenpox or
shingles?
• There are vaccines against chickenpox and against shingles
• These vaccines are comprised of live attenuated VZV
Chickenpox vaccine
“Varivax”
Shingles vaccine
‘Zostavax”
14x more
concentrated
• The molecular basis for this attenuation is not understood
• These vaccines are regarded as “first generation” vaccines
• Chickenpox vaccine is regarded as being highly immunogenic,
efficacious and safe in preventing varicella (chickenpox)
A vaccine to prevent chickenpox or
shingles?
• Chickenpox vaccine can still cause mild chickenpox
• The shingles vaccine is only ~50% effective at stopping
shingles (Oxman et al., NEJM)
• Limitations of vaccines include:
• Vaccinees can experience breakthrough infection
• Unsuitable for use in the immunocompromised or pregnant
individuals
• Vaccine virus retains the ability to infect and spread to ganglionic
neuronal and establish latency
• Vaccine virus has been reported to reactivate in some people to
cause to shingles and neuropathic pain
Can we develop a better a “second”
generation vaccine ?
• A better (ie “second generation”) live attenuated vaccine
virus would be incapable of establishing latency in
neurons (ie lack neurotropism)
• There has been at least one VZV neurotropic gene
identified, and there are probably more. These need to
be defined and deleted from the vaccine virus.
Can we develop a better a “second”
generation vaccine ?
• VZV encodes multiple strategies to delaying and/or
modulate the host immune response in a manner that is
likely to confer a survival advantage to the virus
• Examples include:
• Downregulate cell-surface MHC class I expression
• Modulates cell-surface MHC class II expression
• Impairs dendritic cell (DC) functions
• Inhibits interferon (IFN) responses
• Identification of VZV encoded immunomodulatory genes
and their removal from the vaccine virus may enhance
immunogenicity of this vaccine
Summary and Implications
•
Currently:
•
•
•
Large health care cost
Success of anti-viral therapies only partial
Vaccine should be improved
•
Better understanding of VZV pathogenesis
•
Prevention/ treatment/ management
strategies for VZV induced diseases
Acknowledgments
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VZV Lab members
A/Prof Barry Slobedman (University of Sydney)
Prof Tony Cunningham (Westmead Millennium
Institute)
A/Prof Michael Buckland (University of Sydney)
Dr Michael Rodriguez (Dept of Forensic Medicine,
NSW Pathology)
Prof Ann Arvin (Stanford University)
NHMRC Project grant funding