Immune

herpes zoster-origins Resolution

Neurons
Support cells

Replication in Ganglionic
Tonsilar epith

T cell mediated
Viremia to skin
latency
Adult-Child (like HSV-1?
contact
Chickenpox No….)

Herpes Zoster Latent for decades…

“Shingles” Then
A one sided and reactivation
widespread skin
disease
 Risk Factors for zoster
 Age
- most zoster occurs in those over 50

 Cellular immune status

– AIDS
– Radiation Therapy
– Cancer (esp. lymphoma)
– Immunosuppresion from medical therapies
 BMT & Transplants (30-55% in a year!)
 Evidence suggests CD4 >> CD8 are critical to control
of VZV latency
Herpes Zoster -signs
 Pain
– Before, during and after
 Vesicular skin lesions
 Lesions do not cross the midline of
the face -come from ganglia
 Many lesions over wide area-

-viral replication in the ganglia

-many neurons deliver virus to skin
 Fever & Depression.
 Tic (“tic deleroux”)
Ocular Problems of zoster
VZV can potentially infect every
ocular tissue !!

 Punctate epithelial keratitis (PEK)

 Dendritic keratitis
– w/o terminal bulbi
 Stromal inflammation
– Harder to treat than HSV-1!
 Neurotrophic keratitis
– Total loss of sensation
– ulceration
 Rarer Findings
 Uveitis, retinitis,
 Acute retinal necrosis.
 Neurotrophic Keratopathy
The diabetic foot ulcer of the eye
• ~ 8% of HZO patients develop total loss of corneal sensation
~ 3% of HZO patients develop neurotrophic ulceration

Iatrogenic insults are the main reason that neurotrophic corneas

get into trouble.
 Chronic Pain after zoster –Post
Herpetic Neuralgia
“Constant deep burning
or aching”

“Intermittent sharp,stabbing”
Allodynia
-pain invoked by light or innocuous stimulation, (e.g.
clothing, wind gust) -may last long after removal

-is the most distressing component of PHN

-is the most common
-is the most debilitating
Why does shingles cause pain?
Yeow!!
Ouch!!!
Duh…
Dorsal root ganglion To Brain:
Conscious Perception
of Pain
A fibers
C fibers Brain Signals
To supress
Nociception
SENSORY
- interneurons
NERVES
Spinothalamic
Tract

Latent VZV
Reactivated VZV replicates
in DRG…..
-damages DRG, Induces Inflammation … Spinal cord
-damages interneuron that blocks pain
-changes  and C fiber physiology……
Chronic Pain!
Zoster Treatment

1. Treat the eye and active virus in skin

Topical Acyclovir
Oral Valacylcovir
2. 3-5 + fold higher HSV-1 ACV dose
needed for effect on VZV
3. Treat the post-herpetic pain

-Tricyclic antidepressants (gabapentin)

-Amitryptilline -Corticosteroids
_Many PHN treatments don’t work
-PHN is multifactorial syndrome
Vaccination to prevent zoster
– 10 fold higher virus than varicella vaccine
– VZV immune people get it!
– Recommended to those over 60
– only human herpesvirus vaccine

– Protection Results:- not everyone……

– 51% drop in zoster
– 68% fall in burden
of illness ( includes PHN)
 Adenoviral
Infections

• non-enveloped virus,
• 34Kbp DS-DNA, many viral proteins

• At least 51 identified Serotypes

• Two major ocular diseases
• Epidemic Keratoconjunctivitis (8 and 19)

• Pharyngoconjunctival fever (3,4, & 7)

 EKC
 transferred by hands, instruments, solutions.
 Adenovirus can survive >35 days on a
surface
 Epidemics arise from optometrists and
ophthalmologists offices.

 Patients remain infectious

for 14 days after onset
of symptoms
 Clinical Symptoms

 Foreign Body Sensation

 Tearing
 Photophobia
 Sore Throat
 Breathing Problems
 Conjuntivitis
 NO ANTIVIRAL YET

Subeptielial inflitrates
(immune mediated)
may last long time
-require steroids
 Other Viruses causing
Diseases of the Eye
 CMV (Fuchs? with HIV/AIDS
 Epstein Barr virus
– Both common herpesviruses affecting most people

 Entero/coxsacivirus
 HIV (and everything resulting from it)
 Newcastle disease virus
 Vaccinia Mollocsum
 papilloma
 Important Ophthalmic antivirals
Triflourothymidine HSV-1>> VZV

Acyclovir and valacyclovir HSV-1 and VZV

Ganciclovir and valganciclovir CMV retinitis

Foscarnet (phosphonformate) CMV (GCVr) HSV,VZV

Cidofovir CMV (GCVr)

HAART HIV/AIDs
Acyclovir, gancyclovir and
derivatives
ACV Mechanism of Action

–HSV VZV Thymidine (nucleoside) Kinase activates it

–ACV TP binds Viral DNA polymerase >>>>> cell pol
–Incorporated into DNA - acts as DNA chain terminator
 The ‘new’ oral versions - “valtrex”
liver
Liver
Valacyclovir Acyclovir
“Valtrex”

ACV is degraded in stomach and not good orally

“Val” forms are Ester derivatives- higher oro-bioavailability
–e.g. 63-72% stomach absorption vs 15% for ACV
drug is de-esterified by liver to give serum ACV
Allows high oral dosing (esp those needed for VZV)
 ACV - Resistance
 Readily arises in culture
– Defect /loss of TK in culture
– DNA polymerase mutation altering affinity for ACV-
ppp

 Rarely occurs in vivo

– TK needed for reactivation and pathogensis of
HSV,VZV

– Occurs in AIDS due to long term treatments

– Seems HSV VZV must make a ‘little” TK…..
 Ganciclovir (Cytovene)
O
 Used for hCMV only–
– CMV retinitis HN N
– organ transplants
H2N N N
 Now oral version -Val-GCV HO O
– Ester Protects in stomach
 Poor retinal/brain barriers HO
crossing
 Use Ocular implants
GCV Mechanism of action
similar to ACV- requires initial phosphorylation
DNA chain terminator
–CMV has no TK gene!!!
–CMV uses the UL97 viral protein kinase
to phosphorylate GCV!!
–Unlike ACV, GCV-PPP Inhibits both host and
viral polymerase-toxic!

GCV Resistance
Arises frequently (longer treatments)
•10% In Retinitis and organ transplants
•Change in polymerase, viral protein kinase or both
 Foscarnet (phosphonoformate)
 Mechanism of action: O OH
– All polymerases need P-P as a cofactor
– PFA is analog of P-P
– binds to DNA polymerase -blocks P-P binding OH P P OH
– Resistance? - altered DNA polymerase

 Efficacy/toxicity
OH O P-P
– active on ACV GCV resistant viruses
 HSV VZV and CMV

– Toxic - bone, kidney, neuronal deposits O

OH
 Uses:
– CMV retinitis and GCVr CMV in transplants OH P CH
– rarely used on HSV and VZV ARN cases
– Rarely used on systemic HSV and VZV
O
OH
PFA