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From: TSS (
Subject: Prion Dormancy and Disease (FULL TEXT) ''Progress will require political will. Meanwhile prion researchers watch the inaction with dismay.''
Date: December 3, 2004 at 2:46 pm PST

-------- Original Message --------
Subject: Prion Dormancy and Disease (FULL TEXT)
Date: Fri, 3 Dec 2004 16:55:36 -0600
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy

##################### Bovine Spongiform Encephalopathy #####################


Prion Dormancy and Disease

Robin W.Carrell

There has been concern that the outbreak
of mad cow disease (bovine spongiform
encephalopathy, or BSE) in the United
Kingdom would result in a large-scale spread
of the infection to humans. Public worries,
however, appear to have been allayed by the
fading of the current epidemic (1) of the hu-
man form of mad cow disease, variant
Creutzfeldt-Jacob disease (vCJD). Yet recent
survey findings (2) and blood transfusion
studies (3, 4) raise deep concerns among pri-
on researchers that many more cases of unde-
tected prion protein infection may underlie the
overt epidemic. It is crucial to know whether
such apparently dormant carriers are them-
selves infective and whether they are at risk of
eventually developing clinical disease. The
need for more extensive clinical surveys in the
UK is a priority, but the urgency for these and
other follow-up studies has been dampened by
the disparate nature of recent findings, which
are readily dismissed by some as "atypical" or
of "uncertain significance." These reasons for
inaction are rebutted by the experimental stud-
ies of Wadsworth et al. (5) reported on page

The author is at the Cambridge Institute for Medical
Research, University of Cambridge, Cambridge CB2
2XY, UK. E-mail:

XXXX of this issue. Using transgenic mice ex-
pressing the normal human prion protein, they
show that an amino acid sequence variation
(polymorphism) at position 129 of this protein
drastically affects the infectivity and clinical
consequences of BSE and vCJD infection.

The normal human prion protein ex-
pressed by brain neurons can undergo an
aberrant change in conformation, resulting
in misfolded forms that self-propagate.
these aberrant prion proteins produce char-
acteristic neurodegenera-
tive changes in brain tissue
resulting in a progressive

and fatal encephalopathy (6, 7). This disease
process occurs sporadically in humans: Each
year one in a million deaths worldwide is at-
tributed to the spontaneous development of
Creutzfeldt-Jakob disease (CJD). Conse-
quently, based on a life expectancy of 70
years, one in 15,000 people will die from
CJD, with the likelihood that rather more
than that number are infected but die from
other causes. Thus, humans have always been
exposed to CJD, but because the spread of
the disease requires either the direct inges-
tion or injection of infected tissues, CJD has
remained a sporadic disease confined to a
few individuals. Historically, the great risk to
our species from prion protein infection has
come from cannibalism, as evidenced by the
devastating kuru epidemic
among the Fore tribe of
Papua New Guinea. Evo-
lution has provided some
protection against this
threat: Variations at critical
amino acids in the normal
human prion protein se-
quence limit susceptibility to infective propa-
gation of aberrant forms of the prion protein
(8). Notably, a polymorphism at position 129
of the normal human prion protein—either a
valine (V) or methionine (M)—provides
some protection against kuru among 129MV
heterozygous individuals. In contrast,
129MM homozygotes are particularly sus-
ceptible to prion infection (9).

The protective effect of a valine rather
than a methionine at position 129 is evident
in the current vCJD epidemic in the UK.
This epidemic is a consequence of wide-
spread infection of cattle with BSE from the
early 1980s to 1996. During this period, hun-
dreds of thousands of infected cattle entered
the food chain (10). The consequent cross-
species infection of humans with BSE re-
sulted in the new variant form of prion en-
cephalopathy called vCJD. This disease dif-
fers from sporadic human CJD in both brain
tissue pathology and in the electrophoretic
pattern that classifies each of the aberrant
forms of prion protein. The UK vCJD epi-
demic, which now appears to be fading at
150 cases (1), has two striking features (see
the figure). All of the affected individuals
are 129MM homozygotes, and most are
young, less than 30 years old. The tailing-off
of this epidemic has been assumed by many
to be the end of the vCJD threat, but to those
involved in prion research it seems unlikely
that infection would be confined to just one
age group or to a single genotype. These
fears are supported by recent findings.

In a UK survey of 12,700 surgically re-
moved appendices, three stained positively
for prion protein accumulation, indicating an
unexpectedly high rate of infection, equiva-
lent at a national level to thousands of infect-
ed individuals (2). Doubts as to the signifi-
cance of the appendix survey findings have
been answered by later studies of two recipi-
ents of blood transfusions from a donor who
subsequently developed vCJD. The first re-
cipient, who had a 129MM genotype, devel-
oped vCJD with typical clinical and histo-
logical changes 6 years after transfusion (3).
But the critical findings came from autopsy
of the second recipient, of genotype 129MV,
who remained in good neurological health
but died 5 years after the transfusion from a
ruptured aortic aneurysm (4). Autopsy
showed no evidence of brain involvement,
but a pattern of prion protein accumulation
was observed in lymphoid tissue similar to
the diffuse deposition seen in the positive
specimens in the appendix survey. The over-
all conclusion from these studies is that there
are two levels of infection: one that results in
overt vCJD, as in the genotype 129MM
transfusion recipient, and another that results
in a subclinical or dormant carrier state, as in
the 129MV recipient.

These conclusions are strongly supported
by the new study of Wadsworth et at. (5).
These investigators analyzed transgenic mice
expressing the 129MM or 129VV variant of
the normal human prion protein for suscepti-
bility to infection with BSE or vCJD.
Exposure of 129MM mice to vCJD resulted
in the consistent development of clinical dis-
ease, whereas 129VV mice were relatively re-
sistant to infection. The infection that did oc-
cur in 129VV mice resulted in the atypical
diffuse deposition of prion protein that was al-
so observed in the human appendix and trans-
fusion studies. Moreover, subpassage of brain
tissue from infected 129VV mice resulted in
typical vCJD infection among 129MM
mouse recipients, but only in subclinical and
atypical infection among 129VV mice.

These findings underscore the quandary
faced by public health officials in the UK.
Are the thousands of dormant carriers of
vCJD indicated by the appendix survey at
risk of developing clinical disease? Are they
infective to others, or only to 129MM indi-
viduals, or not at all? Or are the survey find-
ings just a manifestation of dormant spo-
radic CJD present in all populations? These
questions need to be addressed with priority
and urgency. The answers are vital to the fu-
ture practice of blood transfusion, surgery
and dentistry in the UK and for health serv-
ices in other countries. Progress is frustrat-
ingly slow. Essential follow-up studies and
access to data are being hindered or even
prevented by demands for patient anonymi-
ty (2) or by medico-legal concerns {4}. Such
reservations are out of proportion to the po-
tential threats posed by a resurgence of
vCJD infection in the UK. Progress will re-
quire political will. Meanwhile, prion re-
searchers watch the inaction with dismay.


1 N J. Andrews, The UK Creutzfeldt-Jakob Disease
Surveillance Unit,
(accessed 6 November 2004).

2. D.A. Hilton et al. J. Pathol. 203 733 (2004).

3. C. A. Llewelyn et al. Lancet 363 417 (2004).

4. A. H. Peden et al.. Lancet 364, 527 (2004)

5. J. D. f. Wadsworth et al. Science 306, xxx (2004), pub-
lished online 11 November 2004 (10.1126/sci-

6. S. B. Prusiner, Science 278, 245 (1997).

7. S. J. Collins, V. A. Lawson, C. L. Masters, Lancet 363, 51(2004).

8 S. Mead et al. Science 300. 640 (2003)

9. H. S. Lee et al. Infect. Dis. 183, 192 (2001).

10. R. M. Anderson et al. Nature 382. 779 (1996). Science VOL 306 3 DECEMBER 2004


>Progress will re-
>quire political will.

>Meanwhile, prion re-
>searchers watch the inaction with dismay.

THAT would be an understatement.

FAMILY members of victims of all Human TSEs have watched
the inaction by Gov. officials with great disgust and
bitterness for decades, from what i call nothing more than corporate homicide. they knew years ago, but continued to poison and kill, continued to import and export all in
the name of corporate interest, save the industry at
all cost mentality. THIS is still going on in 2004///


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