Transcript Herpes simplex virus type 1 (hsv1) - Alzheimer`s Disease International

HERPES SIMPLEX VIRUS TYPE 1
AND ALZHEIMER’S DISEASE:
THE CASE FOR ANTIVIRAL
TREATMENT
Ruth Itzhaki, Matthew Wozniak
Faculty of Life Sciences, University of Manchester
WHAT CAUSES ALZHEIMER’S
DISEASE?
 Risks: age; Down’s syndrome; family history of dementia;
head injury; the type 4 form of the gene for apolipoprotein
E (APOE).
 ApoE protein transports fats in the blood for usage in
cells. There are three main forms: types 2, 3, & 4.
 However, none of these is either necessary or sufficient
to cause the disease, i.e., another factor(s) must be
needed.
WHY A VIRUS AND WHY HERPES?
 Several viruses that linger in the body (e.g., measles, HIV)
can cause neurological disease.
 Herpes simplex virus type 1 (HSV1) is a likely agent as it is
ubiquitous – infects most people when young.
 It then resides lifelong in latent form in neurons of the
peripheral nervous system – but can reactivate often (in
some people causing cold sores).
 In the very rare acute brain disease that HSV1 causes,
herpes encephalitis, the regions most affected are the
same as those in AD.
VIRUS CHARACTERISTICS
 Their aim is to replicate; they can do so only inside cells.
 They subvert the cell machinery to aid their replication.
 This kills the cells, but herpes viruses can become latent,
i.e., go into sleep mode, causing little or no harm – thus
ensuring their survival.
 They can reactivate from latency – & replicate, then
causing damage.
 Their “life” cycle consists of various stages: binding to
cell surface, entry into cell, uncoating, synthesis of viral
proteins, replication, etc.
HERPES SIMPLEX VIRUS TYPE 1
QUESTIONS
1. Is HSV1 present in “normal” brains?
2. Is the virus active in brain?
3. Is HSV1 in brain associated with AD?
4. Is there a causal link with AD
neuropathology?
DETECTION OF HSV1 DNA IN
BRAIN BY PCR
(J. Med. Virol., 1991, et seq.)
Proportion of human brains containing HSV1 DNA
(N: number of subjects).
%
80
70
60
50
40
30
20
10
0
N = 61
N = 48
N = 28
AD
Elderly normals
Young normals
FIRST TWO DISCOVERIES
Questions:
Is HSV1 present in brain? If so, is it active there?
Answer:
We discovered that HSV1 DNA is present in brains
of many aged people, & that the virus has been
active there – hence capable of causing damage.
APOE-e4 FREQUENCIES OF HSV1+VE &
HSV1–VE AD PATIENTS, & AGEMATCHED NORMALS
(N: number of subjects)
60
HSV1 +ve
(%)
APOE- e 4 frequency
50
N=45
OR: 12.0 (95%CI: 3.44-42.06)
40
30
20
HSV1 -ve
10
N=16
HSV1 -ve
HSV1 +ve
N=30
0
AD
N=18
Normal
THIRD DISCOVERY
Question: Is HSV1 in brain associated with AD?
Answer:
Almost all AD patients with HSV1 in brain have the type 4 form
of the APOE gene. HSV1 and APOE4 together confer a strong
risk of AD, i.e., APOE determines outcome of HSV1 infection.
In other words: some elderly people with HSV1 in brain suffer
from AD; others with HSV1 do not, because they don’t have the
APOE type 4 form.
Many infectious agents infect people but don’t necessarily
affect them; it can depend on a host genetic factor. In fact
APOE determines outcome of infection by diverse microbes.
DIRECT LINKS BETWEEN HSV1 & AD: INFECTION PRODUCES Aβ,
THE MAIN COMPONENT OF PLAQUES
HSV1-infected human cells
HSV1-infected mouse brain
X20
Uninfected human cells
X20
Uninfected mouse brain
X20
X20
DIRECT LINKS BETWEEN HSV1 & AD: INFECTION PRODUCES
AD-LIKE TAU, THE MAIN COMPONENT OF TANGLES.
Infected neuroblastoma cells
Uninfected neuroblastoma cells
Infected glioblastoma cells
Uninfected glioblastoma cells
CO-LOCALISATION OF HSV1 DNA (brown) &
AMYLOID PLAQUES (green) IN AD BRAINS
FOURTH DISCOVERY
HSV1 causes Aβ deposition in infected cells in
culture and in brain of infected mice.
HSV1 causes formation of AD-like tau in infected
cells in culture.
In AD brains, most of the HSV1 DNA is located
specifically within amyloid plaques.
SUMMARY OF ANSWERS
1. Is HSV1 present in “normal” brains?
Yes, in the elderly (J Med Virol. 1991. et seq.).
2. Is the virus active in brain?
Yes, & hence damaging, perhaps recurrently (J Med Virol. 2005).
3. Is HSV1 in brain associated with AD?
Yes, in APOE-ε4 carriers, in ~ 60% of patients (Lancet,
1997; Alz Repts. 1998).
4. Is there a causal link with AD neuropathology?
Yes, HSV1 DNA & plaques co-localise in AD brains (J Pathol. 2009); HSV1
causes Aβ formation in cultured cells & mouse brains (Neurosci. Lett.,
2007); infected cells show AD-like tau (J. Alz. Dis., 2009).
This information suggests the usage of antiviral
treatment for AD.
ACYCLOVIR
 ACV is a nucleoside analogue that stops viral replication.
 ACV targets HSV1-infected cells. Uninfected cells are unharmed
NB. In practice, valacyclovir, the biodrug of ACV, is
used orally as its absorption is very much greater.
ACV INHIBITS HSV1-INDUCED Aβ
ACCUMULATION
ACV INHIBITS HSV1-INDUCED
ABNORMAL TAU PHOSPHORYLATION
ACV INHIBITS HSV1 REPLICATION
SUMMARY RE ANTIVIRALS
(PLoS One, 2011)
 Antiviral agents would be appropriate for treating AD &
would have the great advantage that only the virus, not
the host cells, would be targeted.
 They would prevent most or all viral damage, whether
or not b-amyloid and AD-like tau are involved.
 They are relatively cheap.
PROTECTION OF MICE FROM HSV1 LATENCY IN BRAIN
BY VACCINATION WITH HSV1 GLYCOPROTEINS
(Neurobiol. Aging, 2001)
Proportion of mice with latent infection in brain (%)
45
41 % (N=39)
40
35
30
25
20
15
10
7%
(N=41)
5
0 % (N=9)
0
HSV1 infection + PBS
HSV1 infection + ISCOM vaccine
ISCOM Vaccine
SUMMARY
 HSV1 resides, & has been active, in brain of many elderly
people.
 HSV1 DNA in brain & apoE4 confer a strong risk of AD.
 HSV1 infection of human brain cells, & of mouse brain, causes
AD-like changes.
 HSV1 DNA co-localises with amyloid plaques in AD brains.
 Antiviral treatment reduces greatly Aβ & P-tau production.
 Vaccination of mice prevents HSV1 latency in brain.
 ApoE determines severity of damage (or susceptibility to
infection) by diverse pathogens, including HSV1 in cold sores.
 Results have been confirmed by other groups.
RELEVANT WORK BY OTHERS (1)
 Measles virus causes tangles in brain, & HIV causes amyloid plaques
and tangles. *
 Infections causes cognitive decline in the elderly (Strandberg et al., 2003;
Holmes et al., 2003) - consistent with a viral role in AD.
 Specific serum antibodies (IgM) indicating HSV reactivation correlate
with increased risk of AD (Letenneur et al. 2008; Feart et al., 2011).
 Genetic studies support a viral role in AD (Bullido et al., 2008; Porcellini et al., 2010;
Licastro et al., 2011)
*But HSV1 is the only relevant virus found so far in elderly
brains and so is uniquely placed to cause AD-like damage.
RELEVANT WORK BY OTHERS (2)
 In HSV1-infected APOE-transgenic mice, the potential for viral damage
is greater in APOE-ε4 than APOE-ε3 animals (Burgos et al., 2003, 2006;
Bhattacharjee et al, 2008; Miller & Federoff, 2007).
 Repeated reactivation of latent HSV1 in mouse brains causes
widespread lesions in brain. (Thompson & Sawtell, 2010).
 HSV1 infection of various cell cultures confirms our findings of
increased Aβ, & AD-like tau, & causes functional changes, triggers ADlike caspase-3 activation & tau cleavage (Piacentini et al, 2010; Ill-Raga et al.,
2011;Santana et al., 2011; Zambrano et al., 2008; Lerchundi et al., 2010; Alvarez et al., 2012).
 HSV1 transport in brain is linked with amyloid precursor protein, the
molecule from which amyloid is formed (Satpute-Krishnan et al., 2003; Cheng et al.,
2011).
FUTURE POSSIBILITIES
 Clinical trials of antiviral agents to slow or stop
AD progression.
 In future, immunisation against the virus in
infancy (more feasible now, as the age of
infection is rising with increasing socioeconomic level).
PROOF-OF-CONCEPT TRIAL
 We hope to recruit 100 HSV-seropositive patients with
mild to moderate AD, in four centres.
 Treat half with VCV (2x500mg/day), half with placebo.
 Follow for 12 months, investigating cognitive function
(ADAS-Cog & MMSE), activities of daily living (IDDD),
behavioural and psychological symptoms (NPI), Quality
of life (DEMQOL), & global impression of change (GIC),
assessing pre-randomisation and at 3, 6, 9 & 12 months.
 Check renal function.
POSSIBLE PROBLEMS
 Mutant virus
 Damage caused during latency
 Too much damage before treatment
(Perhaps none apparent until a certain level is reached?
What type? What is the tipping point?)
PAST LAB MEMBERS
Curtis Dobson
Alison Frost
Ann Cookson
Suzanne Shipley
Tom Lloyd
Woan-Ru Lin
Gordon Jamieson
Dazhuang Shang
Acknowledgements
include
Alzheimer’s Society;
Henry Smith Charity.
COLLABORATORS
& ADVISORS
Chris Preston
Andrew Mee
Gordon Wilcock
Stacey Efstathiou
Margaret Esiri
Seth Love
Brian Faragher
Roy Jennings
Marc Combrinck
Bob Cooper
Paul Klapper
Mary Jo Ladu
Raj Kalaria
David Mann
Nigel Hooper