Transcript Herpes and Other Viral Diseases of the Eye

Viral infections….
and antivirals
Herpes simplex virus
-Primary infection latency  reactivation  Recurrence
-Recurrent stromal disease (immune mediated)
-lead to collagen disorganization and corneal scarring
-
-blindness requires corneal transplant
-partly defined by the genetics of virus
Partly defined by genetics of the host
Infection of
neurons
latency
reactivation
of HSV-1
axonal
transport
Regulating HSV Lytic/ latent
switch
HSV LAT RNA Latency Associated Transcript
Abundantly made at latency -No protein- miRNAs?
Adaptive cellular Immunity plays a role in latency
Varicella zoster virus (VZV)
Only rare eye disease with varicella (primary infection)
Major eye problems with zoster on the head
Varicella zoster virus (VZV)
• Alphaherpesvirus , genetically related to HSV-1
• Smallest Herpesvirus 125 kbp genome,
• Only close cousin is in monkeys
• Simian varicella
• Same targets as HSV-1 (skin and mucous
membranes:- and sensory neurons for latency
• But a very different lifestyle from HSV-1
Virus is endemic; >95% infectedSeasonal- Transmitted with direct contact or airborne droplets
• late winter & spring
Disease:
•Primary infection - chicken pox
•Used to be 5000-9000/year hospitalized, 100/year deaths
Primary and reactivated VZV
disease
Primary VZV infection - Chickenpox
•
Inhale by aerosol droplets
•
Infects resident immune T cells
and mono/dendritic cells in
tonsils/Waldemyers ring
•
Also Transfer to T cells in
regional lymph nodes
•
Reaches skin by T cell viremia systemic spread
Perry and Whyte 1998
•
Infiltration into skin –virus
seeds dermal skin layers-
•
Grows for 10-21 daysregulated by innate immunity
Cleared by adaptive immunity
Problematic in adultsPneumonia- causes death.
Why?
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Lumpkin E A et al. 2010
Varicella Vaccination
Live Attenuated- OKA
• 86-95% effective in children
• Now mandated to 5+ years of age -two shots
• long term protection from disease (not infection)
•Not so effective in adults
•Herd Immunity- reduce spread in those not protected
•Shift the incidence of chicken pox to older ages (adults)
where the complication and death rate rise sharply.
•No varicella-no boosting of immunity throughout life
• Earlier zoster?
Establishment of the VZV latent state
• VZV in skinsensory nerve axons retrograde axon transport neuronal latency
• VZV in T cells directly infiltrate ganglia neuronal latency
• VZV spread over entire neuraxis over body autonomic and sensory ganglia
Then we get old…….
old……(what would Michael Jackson
have looked like?..)
Herpes zoster
-occurs in 1/5 to 1/3 of adults
--1 in 20 get zoster on head
Termed HZO if VZV from 5th cranial nerve
Triggers of zoster?
Is there Subclinical reactivation?
What’s different from
HSV-1 reactivation?
- frequency
- intraganglionic spread
- ganglionitis-ganglionic necrosis
Zoster- Risk Factors
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Age - 84%
– after age 60
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Cellular immune status
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AIDS
Radiation Therapy
Cancer (esp. lymphoma)
medical immunosupression therapies
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BMT & Transplants (30-55% in a year!)
CD4 appear more important than CD8
 Cellular>>>>humoral immunity in control
Harpaz R et al 2008
Herpes Zoster -signs

Pain
-Before, during and after
 Vesicular skin lesions
Rarely cross midline
 Large lesions- wide areaviral replication in the ganglia
mass delivery of virus to skin
HUTCHINSON’S SIGN (lesion on
nose tip)- HZO
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Fever & Depression.
Tic (“tic deleroux”)
Some ocular infections, Pain and CNS disease
occur without clinical zoster (“Sine Herpete”)
DIAGNOSIS? -CSF and PCR
Examples of corneal zoster
VZV Can infect every ocular
tissue to cause:
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Punctate epithelial keratitis (PEK)
Dendritic keratitis
– -w/o terminal bulbi
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Stromal keratitis/inflammation
– -Harder to treat than HSV-1
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Neurotrophic keratitis
– -Total loss of corneal sensation
– -iatrogenic ulceration
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Rarer Findings
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Uveitis, retinitis,
Acute retinal necrosis.
ACT FAST! Loss of retina in days
Neurotrophic Keratopathy
The “diabetic foot” 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.
VZV and Pain
• Zoster affect 300,000 to 1 million
people a year in the US
• 90% will seek prescribed
medication for pain
• 30% will develop debilitating
chronic pain known as Post
Herpetic Neuralgia (PHN)
• Many PHN patients get no
benefits from any form of
treatment
Why is there pain?
Ganglionitis
Ganglionic necrosis
Neuronal connective plasticity and reorganization
Demyelyination
Cell-Neuron Fusion-cytoplasmic mixing
Ocular/ neurological complications of VZV
• Many types of
VZV neurological
disease
• Most are rare and
mis-diagnosed
• Persistent VZV in
CNS vasculature
or CNS/brain
leads to ….
• Cognitive
deficits
• Stroke
• Headaches
• Migraines?
• seizures
Zoster Treatment
First, treat the eye and skin - remove virus
Topical Acyclovir
Oral Valacylcovir
-3+ fold higher ACV HSV dose needed for effect on
VZV- many physicians under-treat
Then:
Treat immune disease under antiviral cover
Treat acute pain- NSAIDS + antivirals
Treat the post-herpetic pain
Things to try to Treat PHN
– Anti-convulsants (affect central pain modulation by GABA
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Gabapentin, lamotrigine, carbamazepine
– Anti-depressants (block serotonin/norepinephine re-uptake

Tricyclics- Amytriptyline, venlafaxine
– Opioids (side effects-use as 2nd line only)
– Capsaicin patch (Quitenza)- depletes substance P
– Lidocaine patch with NSAID
– Antivirals? Debatable- p[robably no active virus growth
– Steroids? Debatable- most PHN is not inflammatory
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Many (1/3rd?) PHN patients receive less than 50%
improvement from any current therapy
Vaccination to prevent zoster
– Zostervax- same as varicella vaccine- 14X more virus
– VZV immune people get it.
– Recommended > 50 yrs, may eventually need two doses
– Is the only human herpesvirus vaccine so far
– Partial efficacy - not everyone is protected
– 51% drop in zoster incidence
– 68% fall in “burden of illness” (including PHN)
Adenovirus follicular conjunctivitis
vs others-differential diagnosis
Adenoviral
Infections
• non-enveloped virus,
• 34Kbp DS-DNA, many viral proteins
• At least 57+ identified Serotypes
• Three major ocular diseases
• Epidemic Keratoconjunctivitis (
8, 19 and 37+ several
new serotypes and interrecombinant strains)
• Pharyngoconjunctival fever (3,4, & 7)
Epidemic Kerato-conjunctivitis
transferred by hands, instruments, solutions.
 Adenoviruses survive >35 days on dry surface
 Many epidemics arise from optometrists
and ophthalmologists offices.
you are the spreaders…
 Patients remain infectious for 14 days after onset
of symptoms
Usually One eye, then other (milder)
Lasts 7 days -2 weeks

Source of new isolates- Japan/Asia
- Japan-EKC is a reportable disease
- Hawaii west coast -mixing ground
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Clinical Symptoms
Foreign Body Sensation
Tearing
Photophobia
Sore Throat
Breathing Problems
Conjuntivitis
NO ANTIVIRAL – YET
– -Correct timely diagnosis an issue
After virus…...
-Subepithelial infiltrates
(immune mediated)
-last weeks to months
- treat with steroids
- requires slow withdrawal
Adenovirus EKC management
CMV and retinitis
• 80% are seropositive
• Virus is endemicearly childhood
• Usually asymptomatic
• Retinitis Rare outside
of HIV/AIDS
-A major factor in “will to live”
Of AIDS patients
Signs
Photophobia
Eye Pain/redness
Floaters
Vision loss
Usually initiates monocular
Other Viruses causing
conjunctivitis or Eye Disease

CM and EBV herpesviruses affecting most people
– may cause conjuntivitis and ,rarely, corneal keratitis

Entero/coxsaccivirus- Hemorrhagic conjunctivitis
-begins as eye pain, then red, watery eyes with swelling,
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light sensitivity, and blurred vision.
HIV (and everything resulting from it)
Newcastle disease virus
Vaccinia Mollocsum contageosum (lid lesions)
Papilloma (lid lesions)
Measles (Conujuntivitis)
Important Ophthalmic antivirals
Triflorothymidine (viroptic)
HSV-1>> VZV
Acyclovir and valacyclovir
HSV-1 and VZV
Ganciclovir and valganciclovir
CMV retinitis, Adeno,
Foscarnet (phosphonoformate)
CMV (GCVr)> HSV,VZV
Cidofovir
CMV (GCVr)
HAART
HIV/AIDs
Trifluridine (viroptic)
Analog of deoxyuridine nucleoside
Incorporated into DNA
CF3 blocks base pairing in DNA
Has higher affinity for viral DNA pol
over cell pol
Used topically only- toxic systemically
Acyclovir, gancyclovir and
derivatives
Acyclovir (FDA licensed in 1981)
Use
Herpes simplex virus
Varicella Zoster virus
human cytomegalovirus
0.1-3 ug/ml
5-20
60-200 (not deemed “clinically effective”)
Safe in Long term Prophylaxis treatments
- Herpes B
and recurrent HSV 2
Prodrug mechanismonly active (and activated) in virus infected cells
Virtually non toxic in uninfected cell
100 x more active in HSV—1 infected cell.
Once activated, has higher affinity (50x) for HSV DNA polymerase over
cellular DNA polymerase.
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
ACV - Resistance

Readily arises in culture
– Defect /loss of viral TK
– Mutation of DNA polymerase- alters ACV affinity

rarely occurs in vivo- why?
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Latency in neurons
TK needed for HSV reactivation
TK- viruses don’t reactivate
ACVR arise In AIDS patients with long treatments
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Have Pol mutations: or
Low persistent viral replication: or
Have minimal TK levels
sufficient to enable reactivation from latency
– Not sufficient to activate/ phoshorylate ACV
Oral forms of Acyclovir
Liver
Acyclovir
ACV
Valacyclovir
“Valtrex”
alone is degraded by the stomach
Valine
Ester derivative has high oral- bioavailability
–e.g. 63-72% absorption vs 15% for ACV
Is
de-esterified by liver on first pass  ACV
Allows
reduced dosing and taking by mouth
GMP
O
Ph
O
N
N
N
Gancyclovir
N
N
O
To 5’
end
N
N
N
O
N
N
O
O
O to 3’ end
Gancyclovir and
Valgancyclovir drugs to combat
HCMV disease
Ganciclovir (Cytovene)

used for hCMV
– also used for adenovirus (for some serotypes, it works)
– also used for stubborn VZV and HSV
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works much better than ACV for CMV disease
– retinitis and systemic disease in transplant patients
BUT
GCV Requires IV dosing but val-GCV (ester form) by mouth
– GCV is More toxic than ACV- Why?
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GCV-PPP also inhibits host cell polymerasemuch less selective
– GCV Does not cross retinal/brain barriers well
Often use ocular implants for retinitis
GCV increases AZT toxicity- bad for HIV patients
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GCV-a
Mechanism of action
GCV
DNA chain terminator
O
–CMV has no TK gene
–CMV uses a protein kinase (UL97) to
phosphorylate GCV (and ACV)
N
N
GCV Resistance
O
• Arises due to long treatment for CMV diseases
(upto 10% In Retinitis and organ transplants)
N
N
O
O
•Rare- mutations in UL97 protein kinase
•( UL97 is needed for hCMV to efficiently assemble)
•Mutations in DNA polymerase that alter affinity
• High GCV-resistant CMV have both genes altered
N
Foscarnet (phosphonoformate, PFA)
• Mechanism of action:
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–
–
–
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All polymerases need P-P as cofactor
PFA analog of pyrophosphate (P-P)
binds to DNA polymerase
PFA blocks P-P binding
resistance – altered DNA polymerase
P-P
O
OH
OH P
P OH
OH O
• Efficacy/toxicity
– active on nucleoside resistant viruses
• Acts at different site to GCV/ACV
– Toxic in bone, kidney, neuronal deposits
• Uses:
– CMV retinitis and GCVr CMV in transplants
– rare use on HSV and VZV ARN
– Rare use on systemic HSV and VZV
O
OH
OH
P
OH
PFA
CH
O
Nucleoside phosphonates
•Cidofovir
•Initially ID as anticancer agent
•Licensed for CMV retinitis
•Analogs of dNMPs – no initial P step needed
• CDV has long intracellular half life
•Has activity to many viral DNA polymerases
•Works against :
many adenoviruses,
poxviruses, -(used if smallpox resurrects?)
herpesviruses , polyomaviruses, HBV?
Could be the universal antiviral drug in not so toxic
Lipid Conjugate Technology
Exploits Natural Phospholipid Pathways
CMX001
Lysolecithin
Polar head
Non-polar tail
Cidofovir
Lipid conjugation
enhances absorption and distribution
CMX001
Cidofovir
 Broadly active against dsDNA
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Orders of magnitude more potent
than CDV; broadly active
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Initially being developed for
adenovirus, CMV and smallpox
 Requires intravenous infusion
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Orally available
 Black box warning for renal
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No evidence of nephrotoxicity or
myelotoxicity
viruses
 Approved for treatment of CMV
retinitis in patients with AIDS
impairment and neutropenia