Transcript HSV1 AND COLD SORES (HERPES LABIALIS)

IS A VIRUS A FACTOR IN AD?
1. Several persistent viruses can cause neurological disease.
2. HSV1 is implicated in AD because
a) it has a propensity for latently infecting neuronal cells;
b) it is ubiquitous;
c) it affects, in acute infection, the brain regions which
display the main pathological changes in AD.
NB. Viruses and other infectious agents infect far more people
than they affect.
We searched for HSV1 DNA in brain using PCR.
HSV1 AND COLD SORES (HERPES
LABIALIS)
 Most humans are infected with HSV1 in infancy.
 The virus persists in the peripheral nervous system as a latent (i.e.
dormant) infection throughout life.
 In latency, viral DNA is present, but only one set of transcripts is
made, and no viral proteins.
 Stress, immunosuppression, UV light, menstruation, etc can
reactivate HSV1: i.e., whole viruses are formed, causing an acute
infection.
 20-40% of those infected suffer cold sores.
DETECTION OF HSV1 DNA IN
BRAIN BY PCR
J. Med. Virol., 1991, et seq.
%
80
70
60
50
40
30
20
10
0
Proportion of human brains containing HSV1 DNA
N = 61
N = 48
N = 28
AD
Elderly normals
Young normals
DETECTION OF HSV1 REPLICATION IN
BRAIN
(J. Med. Virol. 2005)
 Anti-HSV1 antibodies in cerebrospinal fluid (CSF) can
persist for several years after herpes simplex encephalitis.
 We found intrathecal antibodies in 14/27 (52%) AD patients
and 9/13 (69%) elderly normals.
 None was due to leakage from blood to CSF (which would
give a false positive). Also, no antibodies were found in the
CSF of 4 children.
Conclusion: HSV1 DNA is present (a whole functional genome)
in many elderly brains, and the virus has replicated perhaps recurrently – causing an acute infection.
INDIRECT EVIDENCE FOR HSV1
REACTIVATION
 Cognitive impairment in elderly cardiovascular patients
correlates with herpes virus burden (Strandberg et al., 2003).
 Cognitive impairment in AD patients declines for at least 2
months after peripheral infection. Microglial cells are activated
(Holmes et al., 2003).
 No such impairment occurs in younger people (Dickerson et al.,
2004), consistent with the absence of HSV1 in their brains.
 Mice with preclinical prion disease show greater than normal
brain inflammation after systemic infection (Combrinck et al.,
2002).
HYPOTHESIS
 Inflammation is a major consequence of HSV1 infection.
 Inflammation is greater in prion-infected (preclinical) than in uninfected mouse
brains.
 Systemic infection can lead to brain damage, therefore CNS infection is even
more likely to be damaging.
NB. Is protective effect of NSAIDs vs. AD due to reduction in inflammation and thus in reactivation events?
APOE-e4 FREQUENCIES OF HSV1 +VE
AND –VE AD PATIENTS AND AGEMATCHED NORMALS (Lancet, 1997, Alz. Repts., 1998)
60
(%)
APOE- e4 frequency
50
HSV1 +ve
N=45
****
40
30
20
HSV1 -ve
10
N=16
HSV1 -ve
HSV1 +ve
N=30
0
AD
N=18
Normal
APOE-e4 FREQUENCY OF COLD SORE
SUFFERERS AND NON-SUFFERERS
(Lancet 1997, Alz. Repts. 1998)
35
APOE-e 4 frequency
(%)
****
30
25
N=69
20
15
NN
10
N=77
5
0
Cold sores sufferers
Non-cold sore sufferers
SUMMARY RE HSV1 & APOE-ε4 IN AD
(& IN COLD SORES)
HSV1 DNA is present in a high proportion of elderly normal and
AD brains (J Med Virol, 1991. et seq.). It has replicated and caused
an acute infection there – perhaps recurrently.
HSV1 in brain of APOE-ε4 carriers confers a strong risk of AD
(Itzhaki et al. Lancet, 1997; Lin et al. Alz Repts. 1998), accounting
for 60% of our patients.
APOE-ε4 is a risk factor for cold sores.
Conclusion: in the nervous system (CNS and PNS), damage
caused by HSV1 is more severe in APOE-ε4 carriers.
APOE: A MAJOR FACTOR IN ONE’S
RESPONSE TO INFECTION
 APOE determines disease severity in 5 disorders known to be
caused by viruses - 3 very different viruses:
HSV1 & cold sores & HSE (Lancet, 1997, et seq; J.N.N.P, 2001)
Hepatitis C virus & liver disease (Hepatology, 2002);
HIV & dementia & peripheral neuropathy (Corder et al. 1998).
Also,
 APOE determines susceptibility to infection by the malaria
protozoon (J. Med. Genetics, 2003).
In each case, the pathogen binds to HSPG and/or apoE receptors
in the cell surface.
RECENT SUPPORTIVE WORK
 Sequence homology between part of an HSV1 glycoprotein and ßamyloid (Cribbs et al. 2000).
 In HSV1-infected APOE-transgenic mice, viral load in brain (in
acute phase) is much greater in APOE-e4 than in APOE-e3
animals* (Burgos et al., 2003).
 APP is transported within HSV1 virions in giant axon of squid.
HSV1 could thus affect APP-processing and synaptic function
(Satpute-Krishnan et al., 2003).
* Such occurrence in humans could account for earlier age of onset and perhaps for the
greater plaque deposition in APOE-e4 carriers.
HSV1 INCREASES b-AMYLOID
LEVEL
 HSV1-infected human neuroblastoma cells show:
a large increase in a C-terminal 55kDa fragment of APP but a
decrease (as expected) in the APP bands
a large intracellular increase in Ab1-42 and in Ab1-40 (this
occurs in human glial cells too).
 Thus, HSV1 affects APP degradation and causes the formation of
Ab.
SUMMARY
HSV1 DNA resides, and the virus has replicated,
in brain of many elderly people and AD patients.
HSV1 DNA in brain and APOE-e4 confer a
strong risk of AD (cf APOE-e4 and cold sores).
Vaccination of mice prevents HSV1 latency in
brain (Neurobiol. Aging, 2001). Feasible for humans?
HSV1 affects APP breakdown in human
neuroblastoma cells; Ab level increases greatly.
APOE determines severity of damage (or
susceptibility to infection) by diverse pathogens.
FUTURE POSSIBILITIES FOR
PREVENTION OR TREATMENT
OF AD
 Immunisation against the virus in infancy (more feasible
now, as the age of primary infection is rising with
increasing socio-economic level).
 Use of anti-viral agents to retard the progression of the
disease
Matthew Wozniak
Curtis Dobson
Ann Cookson
Suzanne Shipley
Woan-Ru Lin
Gordon Jamieson
Dazhuang Shang
Gordon Wilcock
Celia Yates
Margaret Esiri
Paul Klenerman
Bob Cooper
Paul Klapper
Brian Faragher
Roy Jennings
Marc Combrink
Raj Kalaria
Nigel Cairns
David Mann
Nigel Hooper
Will Irving
Eleanor Riley