Download REVIEW ARTICLE Slow Virus Infections of the Nervous System

J. gem Virol. 0978), 4I, 1-25
Printed in Great Brim&
REVIEW ARTICLE
Slow Virus Infections of the Nervous System: Virological,
Immunological and Pathogenetic Considerations
By V. TER M E U L E N AND W. W. H A L L *
Institute for Virology and Immunobiology, University of Wiirzburg, Versbacher Str. 7
87oo Wiirzburg, W. Germany
INTRODUCTION
During the last two decades, after Sigurdsson's introduction of a new concept of an
infectious process, slow virus infections of the central nervous system have developed into
novel and attractive disease models (Sigurdsson, 1954). Through his studies of naturally
occurring diseases in sheep, including Maedi, Visna and scrapie, Sigurdsson observed that
these infections were characterized by an incubation period lasting for many months to
years and a predictable protracted clinical course usually leading to death. Subsequent
studies carried out by many research groups have basically confirmed Sigurdsson's concept.
It was found that slow virus infections are related to unconventional and conventional
agents, both of which have been associated with naturally occurring diseases in animals and
man (Table I).
The unconventional agents which have not been visualized, isolated or characterized
reveal unusual biological and physico-chemical properties, exceptional for any known
infectious agent. The conventional viruses, isolated from diseased brain material, resemble
classical viruses with typical structural, physico-chemical and biological characteristics. For
the latter group of viruses, progress has been made in the understanding of the infectious
process since the isolates provided an experimental basis for virological and immunological
studies in these diseases. Numerous comprehensive reviews have been published dealing with
many different aspects of slow virus infections (see reference Slow Virus Infections). This
review, which will be restricted to the slow virus diseases of the central nervous system
associated with conventional agents, summarizes the findings from recent investigations in
an attempt to discuss and interpret the mechanisms which may be responsible for these
disorders
Visna
The appearance of a subacute encephalomyelitis in Icelandic sheep was first observed in
1935 (Sigurdsson et aL 1957). The disease was named Visna which refers to the clinical picture o f ' shrinkage or wasting'. Apparently, this disease was brought to Iceland by Karakull
sheep imported from Germany. Sigurdsson and co-workers were the first to investigate this
affliction of the central nervous system (CNS) and demonstrated that the disorder was associated with a virus infection (Sigurdsson et al. I957). Visna was readily transmissible by intracerebral inoculation of brain material obtained from diseased sheep and an R N A virus
could be isolated from brain material (Sigurdsson et aL 196o). These important observations
led to intensive studies of this disease.
* Present address: The Rockefeller University, New York, N.Y., U.S.A.
I-o_
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
V. TER MEULEN AND W. W. HALL
Table I. Slow virus diseases of the central nervous system in animals and man
Host
Animals
Men
Infectious agents
Unconventional agents
Scrapie
Transmissible mink encephalopathy
Kuru
Creutzfeldt-Jakob disease
Conventional viruses
Visna
Canine distemper demyelinating encephalomyelitis
Subacute sclerosing panencephalitis (SSPE)
Progressive rubella panencephalitis (PRP)
Progressivemultifocal leukoencephalopathy (P1V[L)
Clinical and neuropathological characteristics
After an incubation period of several months or years the disease, insidious in its onset,
usually starts with slight aberration in gait, developing into paraplegia or even total paralysis
(Gudnadottir, I974). Typical signs present in acute virus infections are missing. The clinical
course is variable ranging from a slowly progressive to a rapidly deteriorating condition. In
early experimental infection, in the absence of any clinical signs, a short lasting pleocytosis
in the cerebrospinal fluid (CSF) is noticed. With the appearance of neurological symptoms,
an elevation of CSF protein and cells often occurs in up to Ioo to 3oo cells/ml. A slight
increase in white blood cells is sometimes found.
The neuropathological changes observed in Visna diseased sheep are of an inflammatory
nature and are located in the white and grey matter of the brain and spinal cord. Severe
meningitis, choroiditis and intense infiltration, and proliferation of mononuclear cells are
found in the perivascular areas. The subventricular areas of the brain and white matter of the
spinal cord are the main regions which are most severely affected (Sigurdsson et al. I962).
Moreover, a diffused destruction and demyelination occurs especially in the ponse, medulla
oblongata and spinal cord. Lesions are frequently located near the ventricles and aqueduct.
These changes do not parallel the onset of clinical symptoms as was recently demonstrated
in sheep experimentally infected with Visna virus (Petursson et al. I976). Two weeks after
intracerebral inoculation, a generalized encephalitis with small areas of demyelination is
found in animals which do not exhibit any signs of a CNS disease.
The virus
Visna virus belongs to the family of retroviruses (Haase, I975). Its size, morphology and
physico-chemical properties are similar to oncornaviruses. The virus matures from infected
cells by budding and contains a polyploid genome composed of z to 4 R N A subunits. The
structural proteins are comprised of at least 15 polypeptides, one of which is phosphorylated
and 2 or 3 glycosylated (Mountcastle et al. I972; Haase & Baringer, I974). The glycoproteins are located on the surface of the virion. As in oncornaviruses, most of the total Visna
virion protein is in the form of small polypeptides. The major polypeptide, with a mol. wt.
of approx. 3oooo, carries the antigenic determinants which characterize the group of lentiviruses consisting of Visna, Maedi and progressive pneumonia virus. The lentiviruses, as
well as the oncornaviruses, contain an RNA-dependent D N A polymerase. However, besides
comparable features, the lentiviruses also reveal distinct differences from oncornaviruses.
Lentiviruses induce a chronic inflammatory disease, which leads to a pronounced cytolytic
effect in cell cultures, and contain a prominent cell fusion activity. Moreover, no antigenic
relationship or nucleic acid sequence homology to oncornaviruses has been demonstrated
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
Review: slow virus infections o f the C N S
3
(Harter, I977). The possibility that lentiviruses possess oncogenic properties has been suggested but not unequivocally demonstrated (Takemoto & Stone, 1971).
Pathogenetic aspects
The isolation of Visna virus from infected animals, its propagation in tissue cultures and
the induction of Visna in sheep with tissue culture grown virus made it possible to study the
pathogenesis of this disease. Intracerebral inoculation of ¥isna virus in sheep leads to an
infection of brain cells mainly along the needle track, the choroid plexus and ependymal cells
lining the ventricular system. As a consequence of this initial inoculation and local infection
of the brain, a viraemia occurs which also infects other organs, especially the lungs, lymph
nodes, spleen, bone marrow, liver and kidney without the specific pathological changes
attributable to Visna infection (Petursson et al. 1976). From all of these organs, virus at low
titres can be consistently isolated during the long incubation period and in the course of
clinical disease (Gudnadottir, 1974) mainly by explant cultivation methods. Moreover, virus
can be recovered throughout the period of infection by co-cultivation of peripheral blood
leukocytes with sheep choroid plexus cells. Preliminary data suggest that lymphocytes might
be the site of virus replication (Petursson et al. 1976).
However, only the sheep brain seems to be the target organ for Visna virus. In response to
the experimental infection, infiltration of immune and inflammatory cells occurs in the CNS
leading morphologically to an acute meningo encephalitis. Despite these neuropathological
changes, the animals do not develop a clinically recognizable disease at this stage. The
infection of the brain does not spread as in any other known acute CNS infection because
Visna virus replication is limited or restricted resulting in a persistent infection (Haase et al.
I978 ). This limitation of virus replication in vivo, which is not observed in vitro in infected
sheep cell cultures, yielding high virus titres and a pronounced cytopathic effect, has been
attributed to host factors and/or special events of virus replication. It is known from acute
infection with other viral agents that the age of a host and its immune system are important
factors for susceptibility and control of an infection. Experiments have been carried out by
different groups to analyse the influence of age and immune status on replication and persistence of Visna virus in sheep as well as the induction of neuropathological changes.
Development of pathological lesions
Icelandic sheep between the ages of 7 and 15 months were intracerebrally infected with
Visna virus and sequentially analysed for virus yield and pathological lesions in brain and
other organs over a period of I2 months (Petursson et al. 1976). Low titres of free virus were
often detectable in most of the tissues and fluids, but the best yield was obtained by applying
tissue culture explant techniques. Virus was detectable in many organs during the whole
period of observation despite a specific humoral immune response. Pathological lesions
attributed to the virus infection were only detectable in the central nervous system and were
relatively independent of the incubation period and age of the animals at the time of infection. However, it was particularly striking that a correlation between severity of CNS
lesions and frequency of virus isolations could be established, suggesting that a certain
threshold of virus replication is required for the induction of pathological lesions. Some of
these animals were additionally immunosuppressed by anti-lymphocyte serum and cyclophosphamide (Nathanson et al. 1976). This regimen did not enhance virus replication in vivo
but led to a prevention of histopathological lesions in some animals, suggesting that
immune pathological mechanisms may play a role in the development of the ' early' lesions
in this disease.
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
4
V° TER MEULEN AND W. W. HALL
Different results were obtained in American sheep (Narayan et al. 1974, t977 a). Virusinfected foetal American lambs with and without immunosuppression by thymectomy or
antilymphocyte serum failed to develop histological lesions but also revealed a depressed state
of virus replication. No increase of virus was detectable in animal organs during the period
of testing, indicating that the poor replicating efficiency of Visna virus in vivo is dependent on
factors other than the immune status or factors associated with maturation. However, despite the lack of substantial virus growth in infected sheep, virus was present in many
organs at all times during infection, The answer to the underlying mechanism of this
particular virus-host relationship in Visna has come from biochemical studies of Visna virus
infection in brain material and the analysis of the immune response in these animals.
Mechanism o f persistency
In sheep choroid plexus (SCP) tissue from an infected sheep, Visna D N A was demonstrated by in situ hybridization in toci of many cells in the absence of detectable virus
particles, seen by electron microscopy, and infectious virus recoverable from cell-free homogenates (Haase et al. I977). Only in culture explants from SCP tissue could infectious virus
be isolated. In contrast to the relatively high proportion of cells containing Visna DNA,
Visna virus protein was demonstrable by immunofluorescence in only a small fraction of
cells. This block in virus gene expression probably occurs at the transcriptional level, as
suggested in preliminary studies of these tissues, since only few cells contained Visna R N A
(Haase et al. I978). Estimates ofVisna R N A copies in these cells indicate comparable levels
to those found in infected tissue cultures. Haase and co-workers (I978) and Brahic et al.
0977) showed that permissively infected cells contain approx, iooo to 2000 Visna RNA
copies per cell a few hours after infection. It can be assumed that these cells which contain
Visna R N A are probably producing the minimal amount of free virus found in organ
tissues. These investigations provided the first evidence that, after the initial infection in
animals, a stable association between virus genetic information and the host cell is established by the formation of virus D N A copies.
Host immunity and antigenic shift
This mechanism does not, however, account for the finding that free Visna virus can be
isolated in the presence of an antiviral immune response in an infected animal. Experimentally infected animals reveal measurable anti-Visna complement fixing and neutralizing
antibodies after I to 2 months which are maintained during the course of infection (Petursson et al. I976; Narayan et al. I977a). At the level of cell-mediated immunity a Visna virusspecific reaction, measurable by the incorporation of tritiated thymidine into lymphocytes
stimulated by Visna antigen, can be detected during the first weeks after infection (Griffin
et al. I978). Lymphocytes from peripheral blood, as well as from CSF, revealed such a
specific response, which had its peak at z weeks and fell to normal 6 weeks after inoculation.
The available immunological data from the initial phase of the long incubation period of
Visna virus infection suggest that the immune responses at this period of infection might be
similar to those observed in acute virus infections; however, they fail to control the infectious process (Griffin et al. ~978).
The possibility of isolating infectious Visna virus from peripheral blood leukocytes (PBL)
by co-cultivation methods during the long incubation period and the course of the disease
has provided the experimental conditions for analysing the immune responses not only to the
original virus inoculum but also to the numerous isolates from PBL. In studies carried out
with Icelandic sheep, Gudnadottir 0974) compared the antigenicity of re-isolated Visna
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
R e v i e w : slow virus infections o f the C N S
5
strains from different animals with the originally inoculated strain in a neutralization assay
and found distinct differences which she interpreted as an antigenic drift of Visna virus in the
presence of antiviral antibodies. This observation was confirmed by Narayan and coworkers (I977a) and extended by a detailed investigation on the development and characterization of mutants occurring in Visna infections (Narayan et al. i977 b, 1978). This group
found that, in the course of infection in an animal, many mutants can appear months after
inoculation when neutralizing antibodies to the parental virus have already developed. No
mutant could be isolated in the early phase of infection. Both virus with a parental genotype
and mutants persist in the presence of a humoral immune reaction and can be recovered later.
Moreover, preliminary data suggest that mutants probably evolve sequentially followed by a
specific antibody response (Narayan et al. I978 ). In vitro studies of these mutants revealed a
stable antigenicity after plaque purification and showed that the mutants differ not only
antigenically from the parental strain but also from each other. The phenomenon of mutation in the presence of antiviral antibodies could also be demonstrated in tissue cultures
within several passages (Narayan et al. i977b). Mutants were derived which showed significant antigenic differences from the strain inoculated. Narayan and co-workers also infected
susceptible sheep with Visna mutants. These animals developed pathological CNS lesions
and an immune response to the mutant revealing a one-way cross-reaction to the parental
strain from which the mutant was derived (Narayan et al. I978 ).
These important observations on the occurrence of Visna mutants in the event of an infection have been interpreted as an important factor in the pathogenesis of this chronic disease.
It is conceivable that each rise of progeny virus which cannot be neutralized leads to a new
infection of brain cells which is accompanied by an inflammatory and an immune response
resulting in CNS damage and finally in a clinically recognizable disease.
Subacute sclerosing panencephalitis
Subacute sclerosing panencephalitis (SSPE) is a rare, slowly progressing disease of the
central nervous system which occurs primarily in children and young adults (Payne &
13aublis, t97r ; ter Meulen et al. I972; Agnarsdottir, I977). This disorder was described under
different headings (Schilder, 1924; Bodechtel & Guttmann, x929; Dawson, I933; Pette &
D6ring, I939; van Bogaert, I945) based on neuropathological grounds but Greenfield
(I95O) unified the different entities under the term SSPE which is now generally accepted. In
I933 Dawson incriminated a filterable virus as the aetiological agent but the first evidence of
virus involvement was reported by Bouteille et al. 0965) and Tellez-Nagel & Harter (I966)
who observed tubular structures resembling paramyxovirus nucleocapsids in brain tissue
from SSPE patients. The paramyxovirus was soon identified as measles virus by Connolly
et al. (1967) who showed that SSPE patients had extremely high measles antibody titres in
their serum and cerebrospinal fluid (CSF). Further studies (Freeman et al. I967; Connolly
et al. I968 ; ter Meulen et al. 1967, I969) using immunofluorescence methods demonstrated
that measles virus antigen was present in neurons and glial cells. In spite of the detection of
measles virus antigen in the brain, attempts to isolate virus by conventional methods were
unsuccessful. It was not until brain cells were co-cultivated or fused with continuous cell lines
that infectious measles-like virus (referred to as SSPE virus) was obtained (Horta-Barbosa
et al. i969; Payne et al. I969; Barbanti-I3rodano et al. I97o). This agent has now been
repeatedly isolated from both biopsy and autopsy material and also from lymph nodes of
SSPE patients (Agnarsdottir, I977).
Although these findings incriminated measles virus as the aetiological agent in this
disease, the pathogenesis still remained unexplained. If measles virus is involved, then
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
6
v. TER MEULEN AND W. W. HALL
additional factors, either host or virus derived, must play a pathogenetic role since rarity and
rural prevalence (Detels et al. I973) of this disease cannot be correlated to the ubiquitous
measles infection. Moreover, the mechanisms have to be explained whereby measles virus
infection persists in the CNS. The availability of isolates from SSPE patients has initiated
numerous studies to find an answer to these questions.
Clinical and neuropathological characteristics
SSPE has been observed in many ethnic groups with an incidence of approximately one
case per million in children. A history of acute measles is quite often found before the age of
two. The mean age of onset of SSPE is 7 to 8 years of age with an average interval of 5 to 6
years after acute measles infection. However, cases of SSPE have also been reported at below
2 and over 2o years of age.
The clinical course usually follows a stereotypic pattern beginning with insidious behavioural changes which, after a period of weeks or months, are superseded by characteristic
neurological symptoms. This clinical picture is characterized by various disturbances of
motor function, myoclonic jerks and epileptic seizures. At a later stage of disease, a progressive cerebral degeneration with symptoms and signs of decortication occurs. Although there
have been reports of remission, the disease usually follows an ingravescent course over a
period of months to years, always ending in death.
Besides this clinical picture, the patients reveal typical electroencephalogram and pathognomonic laboratory findings. Each SSPE case tested showed a marked increase in CSF IgG
and extremely high measles virus antibody titres in serum and CSF specimens. Measlesspecific IgG antibodies represent nearly Io to 200/o of total serum IgG and about 75 % of
total CSF IgG (Mehta et al. I977). Moreover, there is always a reduced serum-CSF ratio of
measles virus antibodies and the finding of oligoclonal CSF IgG, which in large part is measles
virus specific, indicating a local production of measles virus antibodies within the CNS
(Vandvik & Norrby, i973).
The encephalitic process is characterized by perivascular cuffing consisting of lymphocytes and plasma cells with diffuse mononuclear infiltration of the grey and white matter.
The most striking histological features of SSPE are the enormous increase in hypertrophic
astrocytes and proliferation of microglia cells as well as demyelination and the presence of
intranuclear Cowdry type A and B inclusion bodies (Cowdry, I934). The inclusion bodies
containing measles virus nucleocapsid are most frequently seen in oligodendroglia cells.
Measles virus antigen is, however, not only detectable in cells revealing intranuclear inclusion bodies but also in the cytoplasm of many neurons and oligodendroglia cells which do
not show morphological changes (ter Meulen et al. I969). Moreover, measles antigen has
been demonstrated in mononuclear cells from the CSF, in lymph nodes, spleen and liver as
well as in renal glomeruli (Dayan & Stokes, 197 r, I972 ). However, no convincing evidence
has been found for complete measles virus replication cycles in the CNS. Infectious virus
could not be isolated directly from brain material by conventional methods, nor have virus
particles, the process of budding, or giant cells - a characteristic cytopathic effect o f measles
been seen by ultrastructural and histological investigations of brain sections.
-
Measles and S S P E viruses
The isolation of SSPE virus from diseased brain material has led to thorough, comparative virological investigations of measles and SSPE viruses. Biological differences between
these viruses were observed regarding cell susceptibility, growth kinetics in different cell lines,
including organ cultures, and neurotropism in inducing an acute or subacute encephalitis in
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
Review: slow virus infections o f the C N S
7
a variety of laboratory animals (reviewed by Agnarsdottir, I977). However, none of these
studies has convincingly ruled out that these findings are not within the range of the variability also found among different measles virus isolates. Standard serological techniques
such as haemagglutination inhibition (HI), haemolysin inhibition (HLI) or complement
fixing tests failed to reveal antigenic differences. However, other immunological tests indicated the existence of minor antigenic variations between measles and SSPE viruses. In
neutralization tests, it appeared that SSPE viruses were less sensitive to neutralizing measles
antibodies than measles virus (Payne & 13aublis, I973). By a binding inhibition test based on
an indirect radioimmunoassay, it was possible to detect differences between SSPE and
measles virus strains (Hall et al. ~977a). Moreover, results of this binding inhibition test suggested that SSPE viruses might be more closely related antigenically to canine distemper
virus than to measles virus. While the immunological data suggest minor differences in the
immunological reactivity between these viruses they are not sufficient to distinguish clearly
between these virus strains. Some of the most interesting information concerning SSPE has
recently come from comparisons of the biochemical properties of wild type and vaccine
measles virus strains with different SSPE viruses.
Initial studies on the genetic relatedness using R N A hybridization have shown that small
but distinct differences exist (Hall & ter Meulen, I976). These findings were extended in an
analysis of the mRNAs synthesized in infected cells and it was shown that the smallest
m R N A was larger in SSPE virus infected cells than in measles virus infected cells (Hall et al.
I978). This R N A is thought to code for the membrane protein of the virus which would
support the findings of Schluederberg et al. (I974) and more recently of Wechsler & Fields
0978) who reported that the M-proteins of SSPE strains were larger than those of measles
strains. Definitive evidence that the M-proteins were different came from an immunological
study of purified M-proteins of one measles and one SSPE virus strain (Hall et al. i977 b,
~978; ter Meulen et al. I978). Antisera against M-proteins were prepared in rabbits and
specific antibodies detected in a solid phase radio immunoassay which did not react with
measles or SSPE virus haemagglutinin, haemolysin or complement fixing antigens in the
appropriate test system. The antigenic relatedness of the M-proteins was assayed by immunodiffusion and immunoelectrophoresis and it was shown that the two M-proteins were immunologically distinct since an immune reaction occurred only in the homologous system.
These results provided a firm basis for an antigenic differentiation of measles and SSPE
virus and demonstrated that SSPE virus is, in fact, closely related but not identical to measles
virus.
Pathogenetic aspects
The association of the measles-like virus with a chronic CNS infection which does not in
any way resemble known measles virus complications and the epidemiological observation
that SSPE is preceded by an acute measles virus infection has led to many hypotheses to
explain the aetiology and pathogenesis of this disease (ter Meulen et al. I978). Measles virus
infection of a sere-negative immunocompetent host results in an acute disease. During this
acute illness the virus infection has a direct effect on the immune system and a typical measles
virus c.p.e, consisting of giant cell formations can be found in lymph nodes and thymus
(White & Boyd, I973). Moreover, a partial or total tuberculin skin test anergy develops in
tuberculous children, indicating a reduction of sensitized T lymphocytes (yon Pirquet, ~9o8).
Normally, the organism controls this infection and obtains a lifelong immunity. In contrast,
however, individuals suffering from congenital or acquired T cell deficiencies often develop
abnormal rash, fatal lung or CNS complications (Gatti & Good, I97o) in the course of
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
8
V. T E R M E U L E N A N D W. W. H A L L
measles infection. These observations indicate that an intact cell-mediated immune system is
vital for the host in order to overcome an infection with measles virus. Therefore, the
demonstration of measles virus in SSPE brain has led to the interpretation that this CNS
infection might be a late complication of measles infection in an immunocompromised host.
Host-immunity
So far, no immunological deficiencies in the humoral immunity, including the complement
system, have been detected in SSPE. All standard tests employed to assess humoral immune
responses are within normal limits. A single exception is a hyperimmune reaction against all
demonstrable measles antigens. These antibodies neutralize infectious measles and SSPE
virus and are capable of lysing measles infected target cells in the presence of complement
(Kibler & ter Meulen, I975). In addition, measles specific IgM has been demonstrated to be
present in CSF and serum of some patients underlining the fact of a measles virus persistency
in this disease (Kiessling et al. I977). However, in view of the antibody responses, the normal
immunoglobulin level and the normal number of B and T cells of SSPE patients, the lymph
node histology in some patients with SSPE has been an unexpected finding. Lymph node
biopsy material from SSPE patients, obtained after intensive immunological stimulation,
showed a paucity of primary follicles and almost a complete absence of germinal centre formations (Gerson & Haslam, ~97I).
In terms of cell-mediated immunity, no generalized defect has been found in patients with
SSPE (reviewed by Agnarsdottir, 1977). The blastogenic and lymphokine responses are
unimpaired after stimulation with mitogens or antigens unrelated to measles virus. However,
anamnestic skin tests with measles antigen are often negative whereas primary sensitization
with dinitrochlorobenzene, a potent skin test antigen, has always been positive. A disparity
of results was obtained by using measles virus or SSPE virus antigens in assays for cellmediated immunity (CMI). Depending on the test system employed and on the potency and
purity of the virus antigens used, a minor inhibition of CMI or normal reactions in comparison to controls was observed in SSPE patients (Agnarsdottir, 1977). Moreover, a blocking
factor present in serum and CSF from some SSPE patients was found to inhibit production of MIF (Sell et al, ~973) and lymphotoxin (Ahmed et al. x974) as well as lymphocyte
transformation (Allen et al. 1973) and lymphocyte cytotoxicity (Valdimarsson et al. I974).
This factor is believed to be an immune complex consisting of measles antigen, antibody and
complement. However, other investigators have not been able to confirm the existence of this
blocking factor in lymphocyte-mediated cytotoxicity assays (Kreth et aL I975; Perrin et aL
~977)An open question is the functional state of T cell dependent cytotoxicity in relation to
measles-virus-infected cells in SSPE patients. Several groups have shown the presence of
antibody-dependent lymphocyte cytotoxicity, but failed to detect specific T cell killing of
measles virus-infected target cells (Kreth & Wiegand, I977; Perrin et al. I977). The failure
has been attributed to the lack of matched histocompatibility antigens (HLA) between target
and effector cells in the assay system. However, recently Kreth et aL (I978) provided some
evidence that in spite of HLA identity within the test system no T cell killing occurred with
SSPE lymphocytes, whereas in acute measles a specific cytotoxic T cell effect was observed.
However, before one can accept a T cell-specific defect in SSPE, which was initially postulated by Burnet 0968) as an important pathogenetic mechanism for this disease, it has to be
shown that no secondary population of effector T cells in SSPE are detectable after specific
re-stimulation of memory T cells in vitro.
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
Review: slow virus infections o f the C N S
9
Virus-cell interaction
The virus-host relationship in SSPE obviously plays a major role in this disease. From a
virological point of view, the impairment of virus replication in SSPE brain cells, as well as
the biochemical and immunological differences between SSPE and measles viruses, have to
be explained. Biological and biochemical characterization of tissue cultures derived from
SSPE brain material and latently infected with SSPE viruses revealed a state of virus defectiveness that may represent a mechanism similar to that responsible for virus persistency in
the brain of SSPE patients (Doi et al. ~972; Kratzsch et al. I977). All attempts to initiate a
reactivation of virus synthesis in those cultures were unsuccessful. Morphologically, these
cultures contained nucleocapsids and revealed measles antigen. In addition, salt dependent
haemagglutinin antigen was demonstrable on cell surfaces of one cell line. Biochemical
analysis of intracellular RNA demonstrated that the majority of the virus RNA produced
was defective or subgenomic and that the 5oS RNA normally associated with infectious virus
was detectable only in small amounts (Kratzsch et al. i977). These findings indicate an impaired state of virus replication which could be related to the presence of defective interfering
(DI) particles. It has been shown for VSV that DI particles not only interfere with the replication of infectious virus in tissue cultures, but are also capable of influencing a virulent
VSV infection in animals by prolonging the incubation period and modifying, to some
extent, the disease process (Huang, I977). In measles, DI particles cannot be separated biochemically and therefore their presence cannot be directly demonstrated in infected organs
but their interfering potential was indirectly shown in tissue culture (Rima et al. I977a).
The observed biochemical and immunological differences of measles and SSPE virus Mproteins suggest an alternative explanation for the virus-host relationship in this disorder. If
SSPE viruses have arisen from measles wild type virus it is conceivable that a mutation or
modification of the gene region coding for the M-protein has occurred during latency. It is
interesting to consider the implication of such a change occurring in the host. During the
mutation process, it is possible that a non-functional M-protein is produced which cannot
carry out its normal function in virus assembly. This may result in the initiation and maintenance of a non-productive, persistent infection in which no virus would be released. Moreover, this could explain the absence of budding virus in SSPE brain tissue and the high
failure rate (about 8o %) in the isolation of viruses from brain tissue, despite the fact that
brain cells contain large quantities of virus antigens (Katz & Koprowski, I973). Alternatively, if SSPE viruses represent an independent strain of the measles virus group, one
would expect an epidemiological clustering of this disease which has not been observed.
To find an answer to these questions it would be essential to be able to analyse the state of
SSPE virus replication in infected brain tissue as well as to have available an animal model
in which the virus-host relation could be studied.
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) is an uncommon subacute demyelinating disease of the human CNS. A viral aetiology of this disease was postulated by Cavanagh
et al. (I959) and Richardson 0 9 6 0 on the basis of the presence of inclusion bodies and the
association of this disorder with diseases accompanied by an impaired immunological
responsiveness. The first evidence of a virus involvement was provided by the electronmicroscopical studies of ZuRhein & Chou (5965) and Silverman & Rubinstein 0965) who
demonstrated virus structures in oligodendroglia cells which resembled papova viruses. This
observation led to several attempts to isolate viruses from the brain of PML patients by
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
IO
V. T E R M E U L E N A N D W . W . H A L L
inoculation of brain material into cell cultures, small laboratory animals or primates and
embryonated eggs, all without success (Schwerdt et al. r966; Dolman et al. 1967; Gibbs et al.
1969; ZuRhein, I969). Initial isolation of a papova virus was first done by Padgett et al.
(i 97I) and subsequently by Weiner et al. (I972a) which made virological investigation of this
disease possible.
Clinical and neuropathological characteristics
PML is characterized by multiple and varied neurological symptoms depending on the
location of the CNS infection. Neurological signs such as paralysis, mental deterioration,
visual loss, sensory abnormalities and ataxia take a progressive course and the disease usually
leads to death in less than I year. The patients do not reveal any signs of inflammatory infection and have normal cerebrospinal fluid. This disease is considered to be an opportunistic
papova virus infection of underlying disorders such as reticuloendothelial diseases, carcinomas, granolomatous and inflammatory diseases associated with the state of secondary
immunodeficiency (Johnson et al. I977).
In addition, PML has been seen in patients who received immunosuppressive therapy in
the course of renal allografts and for the treatment of systemic lupus erythematosis. However, there have also been a few cases in which neither predisposing disease nor immunological defects were detectable (Rockwell et al. I976; Weiner & Stohlman, ~978) and a
primary PML occurred.
The neuropathological changes consist of non-inflammatory demyelinating lesions in
contrast to the other diseases described in this review. The demyelinating plaques are found
throughout the white matter, revealing loss of oligodendroglia cells and myelin sheaths. The
oligodendroglia cells in the periphery of the plaques are often enlarged and contain intranuclear inclusion bodies which are filled with papova virus-like particles. Immunofluorescent
staining of frozen sections demonstrates papova virus antigen in the nuclei of these cells in
and around the lesions. Within the foci of demyelination, astrocytes occur with abnormal
mitotic figures, bizarre chromatin pattern and multinucleation. These cell formations resemble neoplastic cells to a certain extent (Astr6m et al. 1958).
Papova viruses
Two papova virus strains, designated as JC virus (Padgett et al. 197I) and SV4o-PML
virus (Weiner et al. I972a ) were recovered from PML brain material. JC virus was isolated by
inoculation of homogenized brain tissue in primary cultures of human foetal glial ceils consisting mainly of spongioblasts. The viruses cause a c.p.e, and appear to be highly cellassociated. After this initial isolation, JC virus was isolated from many other PML cases
(Padgett & Walker, 1976; Walker & Padgett, I978). SV4o-PML virus was recovered by
a different technique. Cell cultures from a brain biopsy were established which showed an
apparent transformation after six subcultures. Fusion of these brain cells with primary
African green monkey kidney cells and BSC-I cells yielded infectious virus which resembled
SV4o. So far, this strain of human papova virus has been isolated by the same laboratory
applying similar techniques from only one further case.
Both PML isolates were biochemically and imrnunologically compared to SV4o and the
third human papova virus strain, BK, which was originally recovered from the urine of a
patient following a renal transplant (Gardner et al. I971). This virus is frequently found in
the urine of patients receiving imrnunosuppressive therapy or from children with WiskottAldrich syndrome but so far has not been isolated from PML cases (Gardner, i977). SV4oPML resembles SV4o structurally and antigenically (Weiner et al. ~972b); its DNA is a
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
Review: slow virus infections o f the C N S
II
circular duplex with approximately the same tool. wt. as SV4o DNA. Moreover, it has been
shown that the DNA of both viruses has a close homology both by hybridization and comparison of the restriction enzyme cleavage patterns. Digestion of SV4o-PML DNA with
restriction enzymes from Haemophilus influenza resulted in I I major fragments, 9 of which
co-migrated with 9 fragments of SV4o. Only in a few fragments (C and F) could a different
electrophoretic mobility be observed between these two viruses, indicating that there are two
small deletions in the SV4o-PML genome relative to the genome of SV4o (Sack et al. I973).
However, similar variations have been seen with stable SV4o plaque morphology variants
suggesting that SV4o-PML could be a variant of SV4o.
JC virus, which is similar to SV4o and polyoma virus with respect to size and morphology
of both the virion and the DNA revealed distinct differences by comparative genome analysis. Reassociation kinetics of JC DNA in the presence of a large excess of BK or SV4o
DNAs showed a polynucleotide sequence homology of 25 % between the genomes of JC and
BK and only i 1% between the genomes of JC and SV4o viruses (Howley et al. I976).
Studies on the restriction enzyme cleavage pattern of SV4o, JC and BK DNA showed no
similarities in either number or size of the fragments (Osborn et al. t974).
Immunological studies on the interrelationship between SV4o-PML, JC and BK viruses
have shown an antigenic relationship which can be demonstrated by HI, NT, fluorescent
staining of infected cells or immune agglutination, using hyperimmune sera (Padgett &
Walker, i976). However, monospecific antisera allow identification of these virus strains
(Penney & Narayan, 1973). This observation suggests that these viruses do not possess an
identical group-antigen but rather one or more related ¥ antigens which give rise to cross
immunity (Padgett & Walker, I976). A considerable cross-reactivity between the turnout
(T) antigens of these viruses was found by indirect immunofluorescence (Takemoto &
Mullarkey, 1973; Walker et al. I973; N~tse et al. 1975; Portolani et al. 1975; Van der
Noordaa, I976), immunoperoxidase staining and complement fixation (Dougherty, I976 ).
Recently Beth et al. (I977) studied the degree of relatedness between the T antigens induced
by human papova viruses and were able to show that T antigens possess various subspecificities which are defined as interspecies, species and type-specific antigenic determinants.
This group found that approx. 2o ~o interspecies cross-reactivity exists among JC, BK and
SV4o T antigens. On the other hand, at the level of tumour-specific transplantation immunity
no cross-reaction has been observed which was demonstrated by protection experiments in
hamsters. Hamsters immunized with BK virus failed to protect the animals against challenge
with SV4o or JC virus-induced hamster tumour ceils or vice versa (reviewed by Padgett &
Walker, i976).
Pathogenetic aspects
Transmission ofpapova viruses. In contrast to the rare disease, the agents associated with
this CNS disorder apparently produce a widespread subclinical human infection. Seroepidemiological studies (by Padgett & Walker, I973) have shown that during the first I4 years
of life about 65 % of the tested population had acquired antibodies against JC virus. At
a later age, 7o to 80 % revealed a humoral immune response to this agent. A similar pattern
of antibody distribution was reported from different areas of the world (reviewed by
Padgett & Walker, I976). Antibodies to SV4o are less frequently found and are primarily
dependent on exposure to monkeys or contact with SV4o-contaminated vaccines. However,
SV4o antibodies have been detected at low frequencies (z to 4 %) in humans who neither had
contact with monkeys nor were immunized with contaminated polio vaccines (Shah, I972).
The observation that JC infection occurs most frequently during childhood suggests that
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
I2
V. TER MEULEN AND W. W. HALL
this virus is readily transmissible and is always present in a given population, yet it displays
little virulence. No information about the origin of the infection is available. However, if the
epidemiology of JC virus is similar to other papova viruses it might be speculated that JC
virus is excreted with the faeces or urine of infected persons and enters the body orally.
Recently, Coleman et al. (1977) demonstrated that JC virus could be recovered from the
urine of three patients, two with renal transplants and one pregnant woman. Papova viruses
which could be identified as JC virus were isolated. In the last case, basophilic intranuclear inclusions were observed in urothelial cells which revealed typical virus structures by electron
microscopy. In this patient, a pronounced immune response to JC virus was found. After
delivery, virus could not be isolated from urine specimens, the placenta nor from neonatal
urine. These observations show that JC virus is active in extraneural tissues without an association with PML. On the other hand, successful isolation has been limited to persons with
an immunological deficiency or with slightly reduced immune responses occurring during
pregnancy.
Virus-cell interaction. Although JC virus infects large numbers of people, its full disease
producing potential is not known. So far, the only clinically recognizable disease seems to be
PML. In PML brain, large numbers of virus particles can be detected. It was estimated by
electron microscopic and biochemical analysis that approx, io 1° virus particles per gram of
brain are present in areas revealing lesions (Johnson et aL 1977; D6rries et al. I978). Ultrastructural studies indicate that JC virus particles are most frequently found in oligodendroglia cells and rarely in astrocytes. This observation, together with immunofluorescence data
on papova virus antigen distribution in brain lesions, has led to the interpretation that these
viruses selectively destroy the oligodendroglia cells with loss of their cytoplasmic extensions
leading to demyelination (Johnson et aL 1974). Oligodendroglia cells probably represent a
permissive cell population which allows virus replication and is lysed by the virus. In view of
the oncogenic potential of the papova virus group an effect of these agents on astrocytes has
been suggested but not yet demonstrated. After intracerebral inoculation, JC, SV4o and BK
viruses produce different brain tumours in hamsters. Most of the JC derived turnouts are
medulloblastomas, glioblastomas, ependymomas and pineocytomas (Walker et al. I973;
Padgett & Walker, 1976; Padgett et al. 1977) whereas SV4o and BK viruses are associated
with choroid plexus papillomas (Greenlee et al. I977; Padgett et aL 1977)- Therefore not only
the morphological changes detectable in astrocytes within PML lesions (Astr/)m et aL 1958)
but also the simultaneous occurrence of brain tumours in a few PML cases have been
associated with the papova virus infection. Two patients with PML exhibited coexisting
gliomas (Richardson, 196i ; Castaigne et al. 1974) which in one case appeared to correspond
topographically to the demyelinating loci (Castaigne et al. 1974). In addition, the presence
o f B K DNA in one cerebellar spongioblastoma (Fiori & di Mayorca, 1976) and SV4o DNA
in one glioblastoma multiforme (Smith et al. 1977) and of SV4o T antigen in three mengiomas (Weiss et al. [ 975) have been reported. However, these reports are not confirmed and
further investigations are required to demonstrate a causative relationship between papova
viruses and human brain tumours.
The hypothesis that giant cell astrocytes in PML represent a non-permissive cell population which undergoes transformation as a consequence of JC or SV4o PML virus infection
is only indirectly supported by experiments in cell cultures. Shein 0967) infected cultures
of human foetal glial cells with SV4o and demonstrated lysis of the spongioblast and transformation of foetal brain astrocytes. Recently, this hypothesis was tested by applying hybridization in situ to localize JC virus DNA in PML brain (D6rries et al. I978). Cryostat sections
of PML brain treated with complementary RNA of JC virus revealed a heavy label on many
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
Review: slow virus infections o f the C N S
13
oligodendroglia nuclei along the periphery of lesions. However, only a minority of astrocytes in the centre of these plaques showed a specific label. These data support the observation that many oligodendroglia cells within a lesion are infected by JC virus. However, they
neither prove nor disprove the hypothesis of a non-permissive infection of astrocytes since
this assay is relatively insensitive Compared to other hybridization techniques and therefore
small quantities of virus genomic information present in astrocytes would be overlooked with
this detection method.
The failure to transmit PML by inoculation of JC virus or SV4o-PML virus to laboratory
animals has limited the investigations on the pathogenesis of this disease. However, a
natural occurrence of PML has recently been observed in Rhesus monkeys (Gribble et al.
1975; Holmberg et al. I977). SV4o virus could be isolated from brain material of these
animals and SV4o V and T antigens were demonstrated in brain lesions by immunofluorescence. It is conceivable that these animals will provide an experimental approach to the
investigation of the virus-host relationship of papova viruses in brain cells which lead to
PML.
Other slow virus diseases
There are two additional, naturally occurring CNS disorders associated with conventional viruses which are of interest in the search to understand the pathogenetic mechanisms
in slow virus diseases: canine distemper demyelinating encephalomyelitis in dogs and progressive rubella panencephalitis in man. The available data on these two diseases are very
limited in comparison to the disorders reviewed above.
Canine distemper demyelinating encephalomyelitis
Canine distemper is a widespread disease occurring naturally in dogs and other members
of the canine family. The contagious nature of this disease was first recognized by Carr6
09o5) and the agent identified as a virus some 2o years later (Laidlaw & Dunkin, 1928). The
virus was first placed within the group of influenza viruses by Holmes 0948), based on its
characteristic clinical involvement in respiratory infections. However, Koprowski 0958) and
Imagawa et al. (I96o) later linked it to the measles and rinderpest viruses. The relationship of
this virus to a rare CNS disorder which reveals morphologically certain similarities to SSPE,
and perhaps also to multiple sclerosis (Cook et al. 1978), has recently stimulated new interest
in the investigations on the mechanisms of this virus-host relationship.
Clinical and neuropathological characteristics
Exposure of a sero-negative dog to canine distemper virus (CDV) leads to an acute or subacute disease which is clinically characterized by pyrexia, exanthema and signs of respiratory
and gastrointestinal infections. However, some dogs develop a demyelinating encephalomyelitis with severe neurological symptoms such as tremor, paralysis and convulsion. These
symptoms may appear weeks or months after recovery from the acute infection (Innes &
Saunders, I962; Van Bogaert & Innes, I962; Appel, I969). However, this encephalitis also
occurs in dogs without any preceding acute clinical illness. The CNS disorder observed in
dogs was described as post-distemper encephalitis or subacute diffuse sclerosing encephalitis,
demonstrating the variety of neuropathological lesions observed. In general, the neuropathological changes, either demyelinating or necrotic, primarily affect the white matter of the
cerebellum, brain stern and spinal cord. The demyelinating areas are characterized by loss of
myelin with relative sparring of axons and presence of gitter cells. In the neighbourhood
of demyelinating plaques, perivascular cuffings consisting oflymphocytes and macrophages
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
I4
V. T E R M E U L E N A N D W . W. H A L L
can often be observed. The necrotic plaques frequently resemble a glial scar with astrocytes
forming a network in which macrophages are detectable. Moreover, intranuclear inclusion
bodies of Cowdry type A containing distemper virus nucleocapsids can be observed
(reviewed by Appel & Gillespie, 1972). In addition, a very rare variation of this disease
may develop in aged and/or previously immunized dogs which has been called 'old dog
encephalitis' or 'hard-pad' disease (Appel, I969; Lincoln eta[. 1970.
Virological and pathogenetic aspects
Recent studies have shown that CDV is antigenically related to and shares many biological
and biochemical properties with measles and rinderpest virus (reviewed by Imagawa, i968
and Kingsbury et al. I978). As a result, these viruses have been classified as the morbillivirus
subgroup of the paramyxoviruses. Virological studies on brain material from diseased
animals revealed the presence of canine distemper virus antigen in neuronal glial cell
elements as well as paramyxovirus nucleocapsid structures (Appel, I969; Raine, I972;
Wisniewski et aL I972). Attempts to isolate infectious canine distemper virus from brain
material were only successful when co-cultivation methods were applied on brain tissue
culture cells (Confer et al. I975).
Studies on the pathogenesis of CDV-induced CNS disorders in experimentally infected
dogs proved to be difficult since the available virus strains rarely lead to such a disease. In
one such study (Appel, I969), only two cases among 55 dogs exposed to the virus by aerosol
developed a CNS affection. However, the study provided valuable information concerning
the relationship between the presence of virus and the development of neutralizing antibodies. Virus antigen was first detected in macrophages with a subsequent spread to the
lymphocytes. Viraemia followed and disappeared while neutralizing antibodies were produced with coincident lymphocytopenia lasting 3 to 4 weeks. The author showed that if the
virus reached neuronal tissue before protective antibodies were produced, then a virus persistency may be established. This observation offers some explanation for the development
of a CNS disorder associated with virus persistency.
Recently, the isolation of a neurotropic CDV strain from a naturally occurring case of
demyelinating distemper eliminated many of the problems associated with the induction of
this neurological disease in experimental animals (McCullough et aL I974). Exposure of
gnotobiotic dogs to this virus strain either by intracerebral inoculation or contact with
diseased animals led to an acute or subacute encephalomyelitis in about 5o % of the animals.
The acute form was characterized by focal demyelination without perivascular cuffing but
with intranuclear inclusion bodies present. All of these animals exhibited sustained lymphocytopenia throughout the course of the disease and died within 6 days. Animals having subacute encephalomyelitis with a prolonged clinical course ranging over a period of I2 weeks
revealed only a transient lymphocytopenia. The neuropathological changes in this group
consisted of multifocal areas of demyelination with perivascular cuffing and virus inclusion
bodies. Immunological studies on these animals revealed a depression of peripheral bloodlymphocyte mitogen response probably as a result of lymphocyte infection by CDV. CDVantibodies as well as antibodies to CNS myelin could be detected in the serum and in CSF
specimens. In addition, an elevation of plasmogenase activity in the CNS was already found
before clinical symptoms were detectable (Koestner & Krakowka, I977).
The available data on this subacute demyelinating encephalomyelitis in dogs demonstrates
morphological, virological and, perhaps, immunological similarities with SSPE. Since SSPE
has not yet been successfully transmitted to laboratory animals by a natural route, CDV
infection in dogs, especially with the neurotropic strain, could prove to be a useful experi-
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
Review: slow virus infections o f the C N S
I5
mental model to analyse certain aspects of the human disease. Moreover, the recent suggestion of a possible relationship of CDV with multiple sclerosis makes this model even more
attractive (Cook et al. I978). It can be expected that investigations of this virus-host relationship will contribute to the understanding of virus-cell interactions in the central nervous
system of paramyxoviruses.
Progressive rubella panencephalitis
Progressive rubella panencephalitis (PRP), which was first described in I975 (Townsend
et al. I975, Weil et al. ~975a), is a chronic, inflammatory, progressive CNS disorder in man.
It has been associated with rubella infection appearing either as a delayed reaction of congenital rubella or postnatal rubella infection.
Clinical and neuropathological characteristics
So far, only a few cases have been reported, four with presumptive evidence of intrauterine rubella virus exposure (Townsend et aL ~975; WeiI et al. I975 a) and two as a late
sequelae after early childhood rubella infection (Lebon & Lyon, 1974; Wolinsky et al. I976).
In their second decade of life, these patients developed over a period of several years a
protracted clinical course consisting of seizures, myoclonus, cerebella ataxia and cortico
spinal tract signs. The disease starts with intellectual deterioration before neurological
symptoms are recognizable. Laboratory test revealed high titres of rubella antibodies in
serum and CSF ratio. Moreover, rubella-specific IgM has been observed in serum samples
only at low titres (Weil et al. I976; Wolinsky et al. I978) indicating rubella virus persistency
and an impairment of the shut-off mechanism of IgM synthesis. The CSF showed little or no
pleocytosis with an increase in gamma globulin content. Moreover, in the tested cases, the
occurrence of oligoclonal CSF IgG was seen (Wolinsky et al. i976) which contains rubella
specific antibodies (Vandvik et aL I978) suggesting a local production of immunoglobulin,
in the CNS. Antibodies against measles virus were normal or absent.
The neuropathological investigations showed meningeal and perivascular plasma cells
and lymphocytes, gliosis and glial nodules as well as diffuse neuronal loss. Inclusion bodies
or virus structures, as seen in SSPE or other virus infections of the CNS, were not detected.
In contrast to SSPE, however, amorphous deposits similar to those seen in children dying
with congenital rubella syndrome were present in blood vessel walls throughout white
matter, in the cerebral hemispheres, basal ganglia and cerebellum (Townsend et al. I975;
Townsend et al. i976).
Virological and pathogenetic aspects
Rubella virus was isolated in one instance from brain tissue culture with and without cocultivation of cell cultures susceptible to rubella virus propagation (Cremer et al. I975).
Moreover, rubella virus was also recovered from purified lymphocytes (Wolinsky et al. 1978)
as is common in congenital rubella syndrome (Simons & Jack, I968) as well as postnatal
rubella infection (Alford, I976). However, rubella virus antigen could not be detected in
brain sections even after elution of immunoglobulins by low pH treatment (Cremer et al.
~975). The direct isolation of infectious rubella virus from brain tissue cultures suggests that
infectious virus may be present in the brain in very low concentrations, although the presence
of defective virus particles cannot be excluded.
Immunological studies on the humoral and cell-mediated immune responses have been
carried out in few patients without revealing a consistent defect which would explain the
pathogenesis of this disease (Weil et al. i975b, I976; Schueler et al. ~977; Wolinsky et al.
VIR 4 ~
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
I6
V. T E R M E U L E N A N D W . W . H A L L
I978). Moreover, none of these patients has shown a recognizable immunodeficiency syndrome in relation to other diseases as was described for PML. This indicates that other
mechanisms play a role in the establishment of a persistent infection of the CNS, which
eventually leads to a chronic disorder.
PRP reveals many clinical, neuropathological and immunological similarities to SSPE
suggesting that both diseases may have common pathogenetic factors. It seems that once a
virus which has a tendency to persistency enters the CNS, a disease process may start which
in its clinical/pathological features is more host than virus dependent. Although it is known
from congenital rubella syndrome that rubella virus persists in human tissue for several years
and has an affinity to the CNS, no unique neuropathological features are known which
would explain the development of a progressive neurological disorder.
INTERPRETATIONS AND COMMENTS
In addition to the identification of the causative agents two fundamental processes are
important in understanding slow virus diseases: the mechanism by which the virus persists in
the host without being eliminated by the host defence systems and the events which lead to
a disease process with a slowly progressing clinical course. The successful and repeated isolations of Visna, SSPE and papova viruses from brain material and their presence and localization in brain tissue by different laboratory methods very strongly suggest an aetiological
relationship of these agents to the respective disease. The aetiological association of Visna
virus to the CNS disorder has been clearly established. Visna can easily be induced with the
agent in susceptible animals, whereas in SSPE and P M L all attempts to transmit an identical
disease to a laboratory animal by a natural route have failed. However, it is noteworthy that
Visna can only be induced experimentally in its natural host and not in any other animal
species. This is surprising considering the experiences with slow virus diseases associated
with unconventional agents. These diseases, like scrapie, Kuru or Creutzfeldt-Jakob, can
easily be transmitted to a variety of other laboratory animals (Gajdusek & Gibbs, I977). It is
conceivable that a restricted host range of the conventional agents responsible for slow virus
diseases such as Visna or SSPE and certain host factors prevent the development of the CNS
disorder in other species.
Molecular biological basis of virus persistency
Recent progress in the biochemical analysis of Visna virus infections in animal brains or
tissue cultures, reported by Haase and co-workers 0978), convincingly demonstrated for the
first time the molecular biological mechanism of virus persistency in one of the CNS slow
virus diseases. The unique properties of Visna virus allow the agent to establish a lysogenic
like relationship (Haase, I975) and, due to the genetic restriction at the transcriptional level,
an infected cell cannot be recognized by the host immune system. This peculiar virus-cell
interaction accounts for the long incubation period and provides a plausible basis for virus
persistency. Similar mechanisms have been suggested for SSPE (Zhdanov & Parfanovich,
I974). However, measles virus does not contain a RNA-dependent D N A polymerase as is
the case with Visna virus and this enzyme would have to be provided by the cell, e.g. by
endogenous virus. No laboratory evidence supports this hypothesis and the reported findings of proviral D N A in tissue culture ceils persistently infected with measles virus are not
yet confirmed.
In contrast to Visna, where no defective virus particles have been found, the available
evidence in SSPE, derived from isolation attempts as well as biochemical characterization of
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
R e v i e w : slow virus infections o f the C N S
I7
non-producing SSPE brain tissue cultures (Kratzsch et al. I977), suggests that an impaired
replication might be responsible for virus persistency. In general, the most likely mechanisms
of RNA virus persistency, other than retroviruses in tissue cultures are either the selection of
resistant host cells and avirulent mutants or DI particles (Rima & Martin, I976). However,
temperature sensitive or any other isolated measles virus mutant, have not yet directly been
shown to be involved in the establishment of persistent infections. On the other hand, it was
recently demonstrated that undiluted passages of measles virus not only lead to the formation of DI particles containing subgenomic RNA (Hall et al. i974) but also to a decrease in
yield of infectious virus giving rise to persistent infections affecting about 8o ~o of the cells
(Rima et al. 1977 b). Several hypotheses have been proposed regarding the control mechanisms
by which DI particles may induce or maintain virus persistency (reviewed by Fraser &
Martin, I978). It was suggested that by different intracellular pathways in relation to DI
RNA a regulatory factor is produced which limits the formation of infectious virus
particles, as has been observed in a cell line persistently infected with canine distemper virus
(ter Meulen & Martin, I976 ). For the hypothesis that M-protein could play a pathognomic
role in SSPE, preliminary evidence was reported by Hall et al. (I978) and Wechsler &
Fields (I978) who found biochemical and immunological differences of SSPE and measles
virus M-proteins. Further support for this interpretation could come from the analysis of
M-proteins in non-producing persistently infected cell lines with measles or SSPE viruses.
The mechanism for virus persistency in PML is unknown despite the fact that the molecular biology of the papova viruses is well established and well-tested models are available
to explain virus persistency (Fareed & Davoli, I977). The difficulties in obtaining enough
material from this rare disease and in handling the human strain, JC, in the laboratory has
prevented a biochemical approach to the analysis of the virus cell-interaction in PML brain.
The hypothesis of a permissive and non-permissive infection in different cell types of the
CNS is appealing but not yet proven.
Immune response and disease process
In addition to the biochemical aspects of virus persistency in slow virus diseases, a host
reaction to the infection and its role in the pathogenesis is equally important. From an immunological point of view, the three main CNS diseases discussed in this review differ widely.
In Visna, the immune reactions are not impaired and probably contribute to the development of the lesions (Nathanson et al. I976; Griffin et al. I978). In SSPE, a humoral hyperimmune response against the aetiological agent can always be found in the presence of a
functional cell-mediated immune system, whereas in PML the disease develops only in an
immunologicallycompromised host. The puzzling finding of minimal titres of infectious Visna
virus in sheep in the presence of neutralizing antibodies has been explained elegantly by the
observation of the continuous occurrence of Visna virus mutants (Narayan et al. I977;
Narayan et al. i977 a, b, i978 ). This phenomenon has also been seen with influenza viruses
(Laver & Webster, I968), in equine infectious anaemia (Kono et al. i973) or in chronic
protozoal infections (Vickerman, I974). However, in influenza infections the development
of mutants has never been linked to a recurrent infection in the same host, whereas in equine
infectious anaemia the relapses are directly related to the occurrence of virus mutants.
Similar disease mechanisms have been proposed for the Visna lesions (Narayan et al. I978).
The appearance of Visna mutants and their replication in CNS-cells may be accompanied by
new neuropathological changes which eventually lead to a clinically recognizable disease
when the CNS damage is incompatible with normal brain function.
In SSPE, such a phenomenon has not been observed but it could be shown that SSPE
2-2
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
18
V. TER MEULEN AND W. W. HALL
viruses reveal a lower reactivity in neutralization assays against anti-measles and SSPE sera.
This has been interpreted as being due to antigenic variation and a possible cause of SSPE
(Payne & Baublis, I973). Immunologically, SSPE patients display measles specific oligoclonal antibodies which is very unusual for a virus infection. Normally, a heterogeneous
antibody response is found which is T cell-dependent for most viruses. Since no immunological data are available for the period between acute measles and the onset of SSPE, there
is no way of knowing whether SSPE patients are genetically high responders to measles
antigens. A genetically determined high susceptibility has been discussed but no definite
histocompatability antigen pattern has been observed in SSPE. Moreover, there are three
reports on the occurrence of SSPE in one of a pair of identical twins, arguing against a
genetic basis for this disease (reviewed by Agnarsdottir, I977). The observation that measles
virus infects lymphoid cells and, in acute measles, causes a marked impairment of cellmediated immunity, suggests that a specific unresponsiveness to measles virus as found in
skin tests with SSPE patients could result from a selective depression of the respective T cell
clones. If suppressor cells normally controlling antibody synthesis to measles virus were
affected then a hyperimmune reaction would occur as is indeed found in cases of SSPE. An
explanation for the oligoclonal hyperimmune reaction could be the regulatory involvement
of anti-idiotypic antibodies. Based on preliminary experimental evidence in small laboratory
animals, anti-idiotypic antibodies may lead to either an inhibition of the corresponding
idiotype production or to a marked stimulation of its synthesis depending on the IgG subclass of anti-idiotype antibodies injected (Eichmann & Rajewsky, I975). So far, no evidence
for such an immunological regulatory mechanism has been found in SSPE.
The course of SSPE, as well as the neuropathological lesions, have led to the interpretation that, as in Visna, an immunopathological component may be involved in the development of the disease. No laboratory data support this notion since humoral antibody against
brain antigen could not be unequivocally detected as one would expect if an autoimmune
phenomenon had been triggered by the virus infection (Agnarsdottir, I977). Moreover,
immunosuppressive treatment has not convincingly influenced the course of the disease and
the possible pathogenetic role of antibodies or antigen-antibody complexes is complicated
by reports that SSPE has been observed in patients with hypo gamma globulinaemia and
combined immunodeficiency (Hanissian et al. I972). On the other hand, SSPE brain tissue
reveals a high content of measles antibodies which, in the presence of complement, should
destroy infected CNS cells and arrest the infectious process. Obviously, this defence mechanism does not function in SSPE and it has been proposed that capping of virus antigens on
membranes of infected CNS cells by anti-measles antibodies may be responsible for this
failure (Joseph & Oldstone, 1975). Other reports stress the importance of measles infection
in the presence of protective maternal antibodies which could lead to atypical measles
infection providing a ground for the development of a chronic CNS infection (Agnarsdottir,
1977).
In P M L the majority of reported cases occur in persons with immunological defects, suggesting that in the absence of immunological control mechanisms the virus infection can
spread. However, whether the human papovaviruses remain persistent in the CNS after
childhood infection and may be activated at the onset of PML, or whether P M L represents
the first contact with these agents by immunosuppressed patients is unknown. On the other
hand, epidemiological data indicate that JC virus and SV4o-PML viruses replicate in extraneural tissue from which the virus may infect the CNS under certain conditions. So far, these
viruses have not been detected in tissues other than brain.
The investigations of slow virus diseases over the last decade have yielded important
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
R e v i e w : s l o w virus i n f e c t i o n s o f the C N S
I9
results a n d have d e m o n s t r a t e d the different ways a v i r u s - h o s t i n t e r a c t i o n can result in a
c h r o n i c C N S disorder. H o w e v e r , they have also p o i n t e d out where future research should be
c o n c e n t r a t e d in this field. I n the a r e a o f c o n v e n t i o n a l virus persistency m u c h has been learned
b u t m a n y aspects o f these virus-cell interactions are still n o t u n d e r s t o o d , n o t only in tissue
culture systems b u t also in a m o r e c o m p l e x host, where h o s t factors influence virus expression. In a d d i t i o n , new a p p r o a c h e s are needed in studies on the detection a n d rescue o f persistent viruses in o r d e r to develop a m e t h o d o l o g y which can be a p p l i e d to other h u m a n
d i s o r d e r s suspected o f being slow virus diseases ( J o h n s o n & ter Meulen, I978). O n the o t h e r
h a n d , little is k n o w n a b o u t i m m u n e r e a c t i o n s in the C N S . F r o m an i m m u n o l o g i c a l p o i n t o f
view, the C N S can be c o n s i d e r e d a privileged site. T h e i m m u n e system does n o t have an easy
access to this c o m p a r t m e n t which could a c c o u n t for the failures to c o n t r o l an infectious p r o cess in this organ. There is little i n f o r m a t i o n on the flow o f antibodies, l y m p h o i d cells,
m a c r o p h a g e s , antigens a n d a n t i g e n - a n t i b o d y complexes in a n d o u t o f the CNS. M o r e o v e r ,
h o w a n d where the agents responsible for chronic infections enter the b o d y , escape the
general i m m u n e surveillance a n d reach the C N S is u n k n o w n . O b v i o u s l y , m a n y virological
a n d i m m u n o l o g i c a l p r o b l e m s have to be studied a n d solved before the c o m p l e x i t y o f v i r u s h o s t r e l a t i o n s h i p in these diseases can be interpreted.
W e w o u l d like to t h a n k D r A. T. H a a s e , D r J. S. W o l i n s k y , V e t e r a n s A d m i n i s t r a t i o n
H o s p i t a l , San F r a n c i s c o , Ca., D r L. P. Weiner, U n i v e r s i t y o f S o u t h e r n California, D e p t .
o f N e u r o l o g y , L o s Angeles, Ca., D r O. N a r a y a n , D r D. E. Griffin, D e p a r t m e n t o f N e u r ology, Johns H o p k i n s University, Baltimore, M d . , U S A for allowing us to refer to their
p u b l i c a t i o n s in press. S u p p o r t e d in p a r t b y D e u t s c h e F o r s c h u n g s g e m e i n s c h a f t . T h e
efficient secreterial w o r k o f M s H. Schneider is gratefully a p p r e c i a t e d .
REFERENCES
AGNARSDOTTm, G. (I977). Subacute sclerosing panencephalitis. In Recent Advances in Clinical Virology,
pp. 21-49. Edited by A. P. Waterson. Edinburgh, London, New York: Churchill Livingstone.
AHMED, A., STRONG, D. M.~ SELL, K. W., THU'RMAN, G. B., KNUDSEN, R. C., WISTAR, R., JUN. & GRACE, W. R. (1974).
Demonstration of a blocking factor in the plasma and spinal fluid of patients with subacute sclerosing
panencephalitis. Journal of Experimental Medicine x39, 9o2-924.
ALrORD, C. A., J~N. (I976). In Rubella, Infectious Diseases of the Fetus and Newborn, pp. 7I-IO6. Edited by
J. S. Remington and M. S. Klein. Philadelphia: W. B. Saunders Co.
ALLrN, S., OVVENHEIM,5, BRODV,S. A. & MILLER,J. (I973)- Labile inhibitor of lymphocyte transformation in
plasma from a patient with subacute sclerosing panencephalitis. Infection and Immunity 8, 80-82.
AVVEL, M. J. (1969). Pathogenesis of canine distemper. American Journal of Veterinary Research 30, ~I67I182.
A~'VEL,M. 5. & GILLESPm,J. n. 0972). Canine distemper virus. In Virology Monographs, vol. II, pp. 1-96.
New York, Vienna: Springer-Verlag.
ASTR&~,K. E., ~ANCALL,~. L. & RtCHAV,DSON,E. V., SUN. 0958)- Progressive multifocal leukoencephalopathy:
a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin's disease. Brain 8x,
93-IH.
BARBANTI-BRODANO, G., OYANAGI, S., KATZ, M. & KOPROWSKI, H. (I97o). Presence of two different viral agents in
brain cells of patients with subacute sclerosing encephalitis. Proceedings of the Society for Experimental
Biology x34, 230-236.
BETH, E., CIKES, M., SCHLOEN, L., DI MAYORCA, G. & GIRALDO, G. (I977). Interspecies-, species- and type-specific
T antigenic determinants of human papovaviruses (JC and BK) and of simian virus 40. International
Journal of Cancer 20, 551-559.
BODECHTrL, G. & GtYrTMANN,E. (I929). Diffuse Encephalitis mit sklerosierender Entzfindung des Hemisph~irenmarkes. Zeitschrift fi~r die gesamte Neurologie und Psychiatric x33, 6oi-619.
aOGAERT,L., van (t945). Une leuco-enc~phalite sclerosante subaigue. Journal of Neurology, Neurosurgery and
Psychiatry 8, IoI-I2o.
BOGAERT.L., van & INNES,J. R. M. (I96Z). Subacute diffuse sclerosing encephalitis in the dog. In Comparative
Neuropathology, p. 394. Edited by J. R. M. Innes and L. Z. Saunders. New York: Academic Press.
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
20
V. T E R M E U L E N
AND W. W. HALL
BOtSTHLLE, M., FONTAINE, C., VrDRENNE, C. 8, DELARUE, J. (t 965). Sur u n cas d'enc6phalite subaigue h inclusions.
E t u d e a n a t o m o c l i n i q u e et ultrastrueturale. Revue Neurologique Ix3, 454-458.
BRAHIC, M., rILn'PI, 1"., VIGNE, R. & HAASE, A. T. (I977). Visna virus R N A synthesis. Journal of Virology 24, 7 4 81.
EtrRNET, r. M. (t968). Measles as a n index o f i m m u n o l o g i c a l function. Lancet ii, 6IO-613.
CARRY, n. 0905)" Sur l a m a l a d i e des j e u n e s chiens. Comptes Rendus hebdomadaire des Sdances de l'Acaddmie
des Sciences x4o, 689-69o, 1489-1491.
CASTAIGNE, P., RONDOT, O. & ESCOUROLLE,R. (t974). Leucoenc~phalopathie multifocaIe progressive et ' g l i o m e s "
multiples. Revue Nearologique x3o, 379-392.
CAVANAGH, J. B., GREENBAUM,D., MARSHAL,A. H E. & RLIBINSTEIN, L. J. (t959). Cerebral d e m y e l i n a t i o n associated with disorders o f the reticuloendothelial system. Lancet ii, 524-529 .
COLEMAN, D. V., DANIEL, R. A., GARDENER, S. D., FmLD, A. M. & GIBSON, 1". E. (I977). P o l y o m a v i r u s in urine d u r i n g
pregnancy. Lancet ii, 7o9-71o.
CONFER, A. W., KAHN, D. E., KOESTNER, A. S, KRAKOWKA, S. (I975). Biological properties o f a canine distemper
virus isolate associated with demyelinating encephalitis. Infection and Immunity i x , 835-844.
CONNOLLY, S.H. (I968). Additional d a t a o n measles virus a n t i b o d y a n d antigen in s u b a c u t e sclerosing
panencephalitis. Neurology xS, 87-89.
CONNOLLY, J. I-I., ALLEN, I. V., HURWI'IZ, L. J. & MILLAR, 1. H. D. (I967). Measles-virus a n t i b o d y a n d antigen in
s u b a c u t e selerosing paneneephalitis. Lancet i, 542-544.
COOK, S. D., NATELSON, B. H., LEVIN, B. E., CHAV1S,P. S. & DOWLING, P. C. 0978)- F u r t h e r evidence of a possible
association between h o u s e dogs a n d multiple sclerosis. Annales of Neurology 3, I41-143.
COWDRY, E. V. (t934)- T h e p r o b l e m o f intraunclear inclusions in virus diseases. Archives of Pathology I8,
527-542 .
CREMER, N. E., OSI-HRO L. S., WELL, M. L., LENNETTE, E. H., 1TABASHI, I-1.H. & CARNAY, L. (I975). I s o l a t i o n o f
rubella virus f r o m brain in chronic progressive panencephalitis. Journal of General Virology 28, 143-153.
DAWSON, J.R. (1933). Cellular inclusion in cerebral lesions o f lethargic encephalitis. American Journal of
Pathology 9, 7-16.
DAYAN, A. D. & STOKES, M. I. ( I 9 7 0 . I m m u n o f l u o r e s c e n t detection of measles-virus antigens in cerebrospinalfluid cells in s u b a c u t e s d e r o s i n g panencephalitis. Lancet i, 89I~892.
DAYAN, A. D. & STOKES, M. I. (I972). I m m u n e complexes a n d visceral deposits o f measles antigens in s u b a c u t e
sclerosing panencephalitis. British Medical Journal 2, 374-376.
DETELS, R., BRODY, J. A., McNEW, J. & EDGAR, g. H. (I973). F u r t h e r epidemiological studies o f s u b a c u t e sclerosing panencephalitis. Lancet ii, I t - I 4 .
DOI, Y., SAMSE~T., NAKAJIMA,M., OKAWA, S., KATOH, T., ITOFI, H., SATO~T., OGUCHI, K., KUMANISHI,T. & TSUBAKI,
T. (I972). Properties o f a cytopathic a g e n t isolated f r o m a patient with s u b a c u t e sclerosing p a n e n c e p h a litis in Japan. Japanese Journal of Medical Science and Biology 25, 321-333.
DOLMAN, C. L., FU~RESZ,J. & MACKAY, a. (I967). Progressive multifocal leukoencephalopathy. T w o cases with
electron microscopic a n d viral studies. Canadian Medical Association Journal 97, 8 - I 2 .
D6~RIES, K., JOHNSON, R. T. & V. ter MEULEN (I978). D e t e c t i o n o f p o l y o m a v i r u s D N A in P M L - b r a i n tissue by
in situ hybridization. The Journal of General Virology 4x (in t h e press).
DOUGHERTY, R. M. (1976)- A c o m p a r i s o n of h u m a n p a p o v a v i r u s T antigens. Journal of General Virology
33, 61-7o.
EICnMANN, K. & RAJEWSKY, K. (I975). I n d u c t i o n of T a n d B cell m u t a n t by anti-idiotypic antibody. European
Journal oflmmunology 5, 661-666.
FAREED, G. C. & DAVOLI, D. (1977). Molecular biology of papovaviruses. Annual Review of Biochemistry 46,
471-522.
FIORI, M. & DI MAYORCA, G. (1976). Occurrence o f B K virus DNA in D N A obtained f r o m certain h u m a n
t u m o r s . Proceedings of the National Academy of Sciences of the United States of America 73, 4662-4666.
FRASER, K. a. & MARTIN, S. J. (I978). Measles virus a n d its biology. Edited by K . B. Frazer a n d S. J. M a r t i n .
L o n d o n , N e w Y o r k : A c a d e m i c Press.
FREEMAN, J. M., MAGOFFIN, R. L., LENNETTE, E. FL & HERNDON, R. M. (1967)- Additional evidence o f the relation
between sub-acute inclusion-body encephalitis a n d measles virus. Lancet ii, 129-131.
GAJDUSEK, D. C. & GIBBS, C. J. (I977). K u r u , Creutzfeldt-Jakob disease a n d transmissible Presenile dementias.
In Slow Virus Infections of the CentralNervous System, pp. ~5-49. Edited by V. tel" M e u l e n a n d M. K a t z .
N e w York, Heidelberg, Berlin: Springer Verlag.
GARDNER, S. D. (I977). T h e new h u m a n p a p o v a viruses, their n a t u r e a n d significance. In Recent Advances in
Clinical Virology, pp. 9 t - I I 5 . Edited by A. P. W a t e r s o n . E d i n b u r g h , L o n d o n , N e w Y o r k : Churchill
Livingstone.
GARDNER, S. D., FIELD, A. M., COLEMAN,D. V. & HULME, B. (1971). N e w h u m a n p a p o v a v i r u s (B.K.) isolated f r o m
urine after renal transplantation. Lancet i, I253-I257.
GA'rTL J. M. & GOOD, R. A. (I970). T h e i m m u n o l o g i c a l deficiency diseases. Medical Clinics of North America 54,
281-3o7.
GE~ON, K.L. & HASLAM, R. H. A. 0 9 7 0 . Subtle i m m u n o l o g i c abnormalities in f o u r boys with s u b a c u t e
sclerosing panencephalitis. New England Journal of Medicine 285, 78-82.
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
Review: slow virus infections of the CNS
2I
GIBBS, C. J., JUN., GAJDUSEK, O. e. & ALPERS, M. P. (I969). Attempts to transmit subacute and chronic neurological diseases to animals. Addendum, Archives' of Allergy 36, 519-552.
GREENFIELD, J. G. (I950). Encephalitis and encephalomyelitis in England and Wales during the last decade.
Brain 73, 141-166.
GREENLEE,J. E., NARAYAN,O., JOHNSON, R. T. et al. (I977). Induction of brain tumors in hamsters with B K virus,
a human papovavirus. Laboratory Investigation 36, 636-641.
GRIBBLE, D. H., HADEN, C. C., SCHWARTZ, L. W. & HENRICKSON, R. V. (1975). Spontaneous progressive multifocal leukoencephalopathy (PML) in macaques. Nature, London 254, 602-604.
GRIFFIN, D. E., NARAYAN, O. & ADAMS, R. A- (I978). Early immune responses in visna, a slow virus infection of
sheep. Journal of In[ectious Diseases (in the press).
GUDNADOTT]R, M. (1974)- Visna-Maedi in sheep. Progress in Medical Virology 18, 336-349.
HAASE, A. T. (1975). The slow infection caused by visna virus. Current Topics"in Microbiology and Immunology
72 , lO1-156.
HAASE, A.T. & BARINGER, J.R. (I974). The structural polypeptides of R N A slow viruses. Virology 57
238-250.
H.kASE, A. T., BRAHIC, M., CARROLL, D., SCOTT, J., STOWRING, L., TRAYNOR.~ B., VENTURA~ P. & NARAYAN, O.
(I978). Visna: an animal model for studies of virus persistence. In Persistent Viruses (in the press).
Edited by J. Stevens, G. J. Todaro and C. F. Fox. New York, London, San Francisco: Academic Press.
HAASE, A. T., STOWRING, L., NARAYAN, O., GRIFFIN, D. & PRICE, D. (I977). Slow persistent infection caused by
visna virus: role of host restriction. Science, New York x95, 175-I77.
rtALL, W. W. & ter MEULEN, V. (1976). R N A homology between subacute sclerosing panencephalitis and
measles virus. Nature, London 246, 474477.
IfALL, W. W., MARTIN, S. J. & GOULD, E. (1974). Defective interfering particles produced during replication of
measles virus. Medical Microbiology and Immunology 16o, 155-164.
HALL, W. W., KIESSLING,W. R. & ter MEULEN,V. (I977 a). Studies on the membrane protein of subacute sclerosing panencephalitis and measles viruses. Nature, London 272, 460-462.
rfALL, W. W., KIESSLING, W. R. & ter MEULEN, V. (1977b). Biochemical comparison of measles and subacute
sclerosing panencephalitis viruses. In Negative Strand Viruses and the Host Cell (in the press). Edited by
R. D. Barry and B. W. J. Mahy. London, New York: Academic Press.
HALL, W. W., NAGASHIMA, K., KIESSLING, W. R. & t e r MEULEN, V. (1978). Isolation and properties of the membrane (M) protein of measles virus. In Negative Strand Virusesand the Host Cell (in the press). Edited by
R. D. Barry and B. W. J. Mahy. London, New York: Academic Press.
HANISSIAN, A. S., JABBOUR, J. T., d e LAMERENS, S., GARCIA, J. H. & HORTA-BARBOSA, L. (I972). Subacute encephalitis and hypogammaglobulinemia. American Journal of Diseases of ChiMren 123, 151-155.
HARTER, D. If. (1977). Sheep progressive pneumonia viruses. In Slow Virus Infection of the Central Nervous
System, pp. 54-68. Edited by V. ter Meulen and M. Katz. New York, Heidelberg, Berlin: Springer
Verlag.
HOLMBERG, C. A., GRIBBLE, D. H., TAKEMOFO, K. K., HOWLEY, P. M., ESPANA, C. & OSBURN, B. I. (I977)- Isolation
of simian virus 4o from rhesus monkeys (Macaca mulatta) with spontaneous progressive multifocal
leukoencephalopathy. The Journal of Infectious Diseases x36, 593-596.
HOLMES, F. O. (1948). Order Virales. The filterable viruses (Supplement II). In Bergey's Manual of Determinative Bacteriology, vol. 6, pp. I I27-I2~6. Edited by R. D. Breed, E. G. D. Murray and A. P. Hitchens.
Baltimore, Maryland: Williams & Wilkins.
HORTA-BARE~OSA, L., FUCCILLO, D. A., SEYER, J. L. & ZEMAN, W. (1969). Subacute sclerosing panencephalitis:
isolation of measles virus from a brain biopsy. Nature, London 221,974I-IO'AZLEY, P. M., KHOURY, G., TAKEMOTO, K. K. & MARTIN, M. A. (1976). Polynucleotide sequences common to the
genomes of simian virus 4o and the h u m a n papovavirus JC and BK. Virology 73, 3o3-3o7.
HUANG, A. S. (1977). Viral pathogenesis and molecular biology. Bacteriological Reviews' 4 I, 811-82 I.
IMAGAWA, n. X. (I968). Relationships among measles, canine distemper, and rinderpest viruses. Progress in
Medical Virology io, 16o-193.
IMAOAWA, D. T., GORET, P. & AOAMS, S. M. (1960). Immunological relationship of measles, distemper, and
rinderpest viruses. Proceedings of the National Academy of Sciences of the United States of America
46, II I9-II23.
INNES, J. R. M. & SAUNDEP,S, L. Z. (1962). In Comparative Neuropathology. Edited by J. R. M. Innes and L. Z.
Saunders. New York: Academic Press.
JOHNSON, R. T., NARAYAN,O. & WEINER, L. P. (1974). The relationship of SV 4o related viruses to progressive
multifocal leukoencephalopathy. In Mechanism of Virus Disease, pp. I87-197. Edited by C. W. S.
Robinson and C. F. Fox. Menlo Park, California: W. A. Benjamin.
JOHNSON, R. T., NARAYAN, O., WEINER, C. P. & GREENLEE, S. E. (1977). Progressive multifocal leukoencephalopathy. In Slow Virus Infections of the CARS, pp. 91-1oo. Edited by V. ter Meulen and M. Katz. New
York, Heidelberg, Berlin: Springer Verlag.
JOHNSON, R. T. & ter MEULEN,V. (I978).Slow infections of the nervous system. In Advances in InternalMedicine,
vol. 23, pp. 353-383. Edited by Stollerman. Chicago, London: Yearbook Medical Publishers, Inc.
JOSEPH, B. S. & OLDSTONE, M. B. A. (1975). Immunologic injury in measles virus infection. II. Suppression of
immune injury through antigenic modulation. Journal of Experimental Medicine I42 , 864-876.
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
22
V. TER M E U L E N A N D W. W . H A L L
KATZ, M. & KOPROWSI%H. (1973). The significance of failure to isolate infectious viruses in cases of subacute
sclerosing panencephalitis. Archly far die gesamte Virusforschung 4I, 390-393.
KmLER, R. &ter ME~LEN, V. (1975). Antibody-mediated cytotoxicity after measles virus infection. Journal of
Immunology 114, 93-98.
KIESSLING, W. R., HALL, W. W., YUNG, L. L. & t e r MEULrN, V. (1977). Measles virus specific immunoglobulin-M
response in subacute sclerosing panencephalitis. Lancet i, 324-327 .
K1NGSBURY, D . W . , BR.ATT~ M . A . , CHOPPIN, P. W., HANSON, R. P., HOSAKA~ Y., tee MEULEN, V., NORRBY, E.~
PLOWRIGHT, W., ROTT, R. & WUNNER, W. H. (1978). Paramyxoviridae.Intervirotogy s o , 1 3 7 - 1 5 2 .
KOESTNER,A. & K~KOWKA, S. (1977)- A concept of virus-induced demyelinating encephalomyelitis relative to
an animal model. In Slow Virus Infections of the Central Nervous System, pp. II6-I26. Edited by V. ter
Meulen and M. Katz. New York, Heidelberg, Berlin: Springer Verlag.
KONO, v., KOBAYASm,K. & raZKUNAGA,Y. (I973)- Antigenic drift of equine infectious anaemia virus in chronically infected horses. Arehiv f~r die gesamte Virusforschung 41, 1-1o.
KOPROWSKI,H. (I958). Counterparts of human viral disease in animals. Annals of the New York Academy of
Sciences 70, 369-38I.
KR~TZSCH, V., Ia~L, W. W., NAGASm~, K. &ter MEULEN,V. (1977). Biological and biochemical characterization of a latent subacute sclerosing panencephalitis virus infection in tissue cultures. Journal of Medical
Virology x, 139-154.
KRETH, H. W., K~CKELL,M. Y. &ter MEULEN,V. (1975). Demonstration of in vitro lymphocyte mediated cytotoxicity against measles virus in subacute sclerosing panencephalitis. Journal of Immunology xx4, IO42lO46.
KReTH, H. W. & WleGAND, G. (I977). Cell-mediated cytotoxicity against measles virus in subacute sclerosing
panencephalitis, II. Analysis of cytotoxic effector cell. Journal of Immunology xx8, 296-3oi.
KRETH, H. W., ter MEULEN,V. & ECKeRT, G. (I978). Cell-mediated cytotoxicity against measles virus in HLA
matched lymphocyte-target cells combinations. Medical Microbiology and Immunology (in the press).
LAIDLAW, P. P. & DUNKIN, G. W. (I928). A report upon the cause and prevention of dog distemper. British
Veterinary Journal 84, 596-637.
LAVER,W. G. & WeBSTeR,R. C. (I968). Selection of antigenic mutants of influenza viruses. Isolation and pep tide
mapping of their hemagglutinating protein. Virology 34, 193-202.
LEBON, e. & LYON, G. (I974)- Non-congenital rubella encephalitis. Lancet ii, 468.
LINCOLN, S. D., GORe-rAM,J. R., OTT, R. L. & HEG~BERG, G. A. (1971). Etiologic studies on old dog encephalitis.
Veterinary Pathology 8, 1-8.
McCULLOUGH, B., KRAKOWKA,S. & KOESTNER,A. (1974). Experimental canine distemper virus-induced lymphoid depletion. American Journal of Pathology 74, I55-I66.
MEHTA,P. D., KANE,A. & THORMAR,H. (1977). Quantitation of measles virus-specificimmunoglobulins in serum,
CSF and brain extract from patients with subacute sclerosing panencephalitis. Journal of Immunology
IIS, 2254--226I.
VmULEN,V. ter, eNDeRS-RUClCLE,G., ~LLER, D. & JOPPICH, G. (1967). Immunohistological, microscopical and
neurochemical studies on encephalitides. IIl subacute sclerosing panencephalitis, virological and
immunological studies. Acta Neuropathologica (Berlin) xz, 244-259.
MEULEN,V. ter, MOLLeR,D. & JOPPICH, G. (1967). Fluorescence-microscopy studies of brain-tissues from a case
of subacute sclerosing paneneepbalitis. German Medical Monthly 9, 438-441.
MEULEN,V. ter, KATZ, M. & MOLLER,D. 0972)- Subacute sclerosing panencephalitis. In Current Topic in Microbiology andlmmunology, 57, 1-38. Edited by Arber et al. Berlin, Heidelberg, New York: Springer Verlag.
MEULeN, V. ter & MARTIN,S. J. (I976). Genesis and maintenance of a persistent infection by canine distemper
virus. Journal of General Virology 32, 431-44o.
MeULeN,V. ter, HALL,W. W. & K~TH, H. W. (I978). Pathogenic aspects of subacute sclerosing panencephalitis.
In Persistent Viruses (in the press). Edited by C. J. Stevens, G. J. Todaro and C. E. Fox. New York:
Academic Press.
MOUNTCASTLe,W. e., ~RTER, O. n. & CHOPPIN,P. W. (I972)- The proteins of visna virus. Virology 47, 54z~545.
NARAYAN, O., SILVERSTE1N, A. M., PRICE, D. & JOHNSON, R. T. (I974). Visna virus infection of American
lambs. Science 183, 12o2-12o3.
NARAYAN, O., GRIFFIN, D. E. & SILVERSTEIN, A. M. (I977a). Slow virus infection: replication and mechanisms
of persistence of visna virus in sheep. Journal of Infectious Diseases 135, 800-806.
NARAYAN, O., GRIFFIN, n. E. & CHASE,J. (I977 b) Antigenic shift of visna virus in persistently infected sheep.
Science 197 , 376-378 .
NARAYAN, O., GRIFFIN, D. E. & CLEMENTS, J. E. (I978). Virus mutation during slow infection: temporal development and characterization of mutants of visna virus recovered from sheep. Journal of General Virology
(in the press).
N.~SE, L. M., K.XA~,KKAINEN,M. & M.~NTYJ.~RVI, R. A. (1975). Transplantable hamster turnouts induced with the
BK virus. Acta Pathologica Microbiologica scandinavica 83, 347-352.
NATHANSON, N., PANITCH, H., PALSSON, P. A., PETURSSON, G. & GEORGSSON, G. (1976). Pathogenesis of Visna II.
Effect of immunosuppression upon early central nervous system lesions. Laboratory Investigation 35,
444-45 I.
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
Review: slow virus infections of the CNS
OSBORN~ 1. E., ROBERTSON, S. M., PA.DGETT, B. L., ZuKHEIN, G. M., WALKER, D. L. & WEISBLUM, B.
23
(1974). Com-
parison of JC and B K h u m a n papovaviruses with simian virus 4o restriction endonuclease digestion and
digestion and gel electrophoresis of resultant fragments. Journal of Virology x3, 614-622.
PADGE~% B. L. & WALKER, D. L. (I973). Prevalence of antibodies in h u m a n sera against JC virus, an isolate
from a case of progressive multifocal leukoencephalopathy. Journal oflnfectious Diseases x27, 467-470.
PADGETT, B. L., WALKER, D. L., ZuHREIN, G. M., ECKROADE, R. J. & DESSEL, B. H. (1971). Cultivation of papovalike virus from h u m a n brain with progressive multifocal leucoencephalopathy. Lancet i, I257-126o.
OADGETT, ~. L., WALKER, D. L., ZURHEIN, G. M. et al. (I977). Differential neurooneogenicity of strains of JC
virus, a h u m a n polyoma virus in newborn Syrian hamsters. Cancer Research 37, 718-72o.
PADGETT, B. L. & WALKER, D. L. (1976). New h u m a n papovaviruses. Progress in Medical Virology 22, 1-35.
PAYNE, F. E. & BAUBLIS, J. V. (1971). Measles virus and subacute sclerosing panencephalitis. Perspectives in
Virology 7, 179-192.
I"AYNE, F. E. & BAUBLIS, 1. V. (1973). Decreased reactivity of SSPE strains of measles virus with antibody.
Journal of Infectious Diseases I27, 505-51 I.
PAYNE, F. E., BAUBLIS,J. V. & ITABASH1,H. H. (1969). Isolation of measles virus from cell cultures of brain from
a patient with subacute sclerosing panencephalitis. New England Journal of Medicine 28x, 585-589.
PETTE, H. & D6RING, G. (I939). t3ber eine einheimiscbe Panencephalomyelitis vom Character der encephalitis
japonica. Deutsche Zeitschrift der Nervenheilkunde 149 , 7-44.
PIRQUET, C. von (19o8). Das Verhalten der kutanen Tuberculin-Reaktion wahrend der Masern. Deutsche
Medizinische Wochenschrift 34, 1297-I3OO.
PENNEY, J. B., JUN. & NAKAYAN, O. (I973). Studies of the antigenic relationships of the new h u m a n papovaviruses by electron microscopy agglutination. Infection and Immunity 8, 299-3o0.
PERRIN, L. H., TISKON, g. & OLDS'IONE, M. B. A. 0977)- Immunologic injury in measles virus infection. III.
Presence and characterization of h u m a n cytotoxic lymphocytes. Journal of Immunology xx8,
282-290.
PETURSSON, G., NATHANSON, N., GEORGSSON, G., laANITCH, H. & PALSSON, P.
(1976). Pathogenesis of Visna. I.
Sequential virologic, serologic, and pathologic studies. Laboratory Investigation 35, 4o2-412PORTOLANI, M., BARBANTI-BKODANO,G. & LaPLACA, M. (I975). Malignant transformation of hamster kidney
cells by B K virus. Journal of Virology 15, 420-422.
RAINE, C. S. 0972). Viral infections of nervous tissue and their relevance to multiple sclerosis. In Multiple
Sclerosis, p. 91. Edited by F. Wolfram, G. W. Ellison, J. G. Stevens and. J. M. Andrews. New York,
London: Academic Press.
RICHARDSON, E. 1% JUN. (1961). Progressive multifocal leukoencephalopathy. New EnglandJournalofMedicine
265, 815-823.
RIMA, B. K. & MARTIN, S. J. (I976). Persistent infection of tissue culture cells by R N A viruses. Medical
Microbiology and Immunology x62, 89-I 18.
RIMA, B., DAVIDSON,B. & MARTIN,S. J. (1977a). The role of defective interfering particles in persistent infections
of Vero cells by measles virus. Journal of General Virology 35, 89-97RIMA, B. K., GOULD, E. A. & MARTIN, S. J. (1977b). Variations in protein synthesis during the establishment of
persistent infections with measles virus. In Negative Strand Viruses and the Host Cell (in the press).
Edited by R. D. Barry and B. W. J. Mahy. London, New York: Academic Press.
ROCKWELL, D., RUBENS, F. L., WINKELSTE1N, A. & MENDELOW, H. (1976). Absence of immune deficiencies in a
case of PML. American Journal of Medicine 6x, 433-436.
SACK, G. H., NARAYAN, O., DANNA, K. J., WE1NER, L. ~,. & NATHANS, D. (1973). The nucleic acid of an SV4o-like
virus isolated from a patient with progressive multifocal leukoencephalopathy. Virology 5I, 345-35o.
SCmLDER, P. (1924). Die encephalitis periaxialis diffusa. Archivfi~r Psychiatric 7I, 327-356.
SCHLUEDERBERG, A., CHAVANICH, S., LIPMAN, N. B. & CHARTER,
• (1974). Comparative molecular weight estimates of measles and subacute sclerosing panencephalitis virus structural polypeptides by simultaneous
electrophoresis in acrylamide gel slabs. Biochemical and Biophysical Research Communications 58, 547651.
SCHULLER, E., DELASNERIE, N., ALLINQUANT, B. et al. (1977). Intrathecal rubella and R N A antibody synthesis in multiple sclerosis and plogressive rubella panencephalitis. Biomedicine 27, 139-14I.
SCHWERDT, P. R., SCHWERDT, (3. E., SILVERMAN, L. & RUBINSTEIN, L. J. (1966). Virions associated with progressive multifocal leukoencephalopathy. Virology 29, 511-514.
SELL, K. W., THURMAN, G. B., AHMED, A. & STRONG, D. M. (I973). Plasma and spinal fluid blocking factor in
SSPE. New England Journal of Medicine 288, 215-216.
SHAH, K. V. (1972). Evidence for an SV4o-related papovavirus infection of man. American Journal of Epidemiology 95, 199-2o6.
SHEIN, H. M. (1967). Transformation of astrocytes and destruction of spongioblasts induced by simian tumor
virus SV4o in cultures of h u m a n fetal neuroglia. Journal of Neuropathology and Experimental Neurology
26, 6o-76.
SIGImDSSON, B. (1954). Observations on three slow infections of sheep. Maedi. Paratuberculosis. Rida, a
chronic encephalitis of sheep with general remarks on infections, which develop slowly, and some of
their special characteristics. British Veterinary Journal xxo, 255-27o, 3o7-322, 341-354-
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
24
V. T E R M E U L E N
AND W. W. HALL
SlGURDSSON. B. PALSSON, P. A. & GRIMSSON, It. (I957). Visna. A demyelinating transmissible disease of sheep.
Journal of Neuropathology and Experimental Neurology x6, 389-4o3.
SI~URDSSON, B., THORMAR,H. & PALSSON,V. A. (I960). Cultivation of visna virus in tissue culture. Arehivfi~r die
gesamte Virusforschung rn, 368-38I.
SIGURDSSON, B., VALSSON, P. A. & BO6AERT, L. v a n 0962). P a t h o l o g y o f visna. Acta Neuropathologica i, 343362.
SIMONS, M. J. & JACK, I. (I968). L y m p h o c y t e viremia in congenital rubella. Lancet ii, 953-954.
SILVERMAN, L. & R~BINSTEIN, L. J. (I965). Electron microscopic observations on a case o f progressive multifocal leukoencephalopathy. Acta Neuropathologica 5, zi5-224.
SLOW VIRUS INFECTIONS:
(a) Slow virus diseases. (1974). Progress in Medical Virology x8.
(b) Slow viruses (1976). Edited by D. A. A d a m s a n d T. M. Bell. Massachusetts, U.S.A. : A d d i s o n - W e s l e y .
(c) Slow Virus Diseases in Animals and Man (1976). Edited by Kimberlin. A m s t e r d a m , Oxford: N o r t h
H o l l a n d Publishing C o m p a n y .
(d) Slow Virus Infections of the Central Nervous System. (I977). Edited by V. ter Meulen a n d M. K a t z .
N e w York, Heidleberg, Berlin: Springer Verlag.
SMlrH, R. A., GOLDSTEIN, D. A. & MEINKE, W. J. (I977)- Simian virus 4D-related D N A sequences in a h u m a n
brain tumor. Neurology 27, 343-344.
TAKEMOTO, K. K. & MULLARKEY, M. E. (I973). H u m a n papovavirus, B K strain: biological studies including
antigenic relationship to simian virus 4o. Journal of Virology x2, 625-63I.
TAKEMOTO, K. K. & STONE, L. B. ( I 9 7 0 . T r a n s f o r m a t i o n of m u r i n e cells by two ' s l o w viruses' visna virus a n d
progressive p n e u m o n i a virus. Journal of Virology 7, 77o-775.
TELLEZ-NAGEL,I. & HARTER, D. I-L (1966). Subacute sclerosing leueo-encephalitis: ultra-structure of intranuclear
a n d intracytoplasmic inclusions. Science, New York x54, 899-9oi.
TOWNSEND, J. J., BARRINGER, J. R., WOLINSKY, J. S. et al. (I975). Progressive rubella panencephalitis. Late onset
after congenital rubella. New England Journal of Medicine 292, 99o-993.
TOWNSEND, J. J., WOLINSKY, J. S. & BARrNGER, J. R. (I976). T h e n e u r o p a t h o l o g y of progressive rubella p a n e n cephalitis o f late onset. Brain 99, 8 l - 9 o .
VALDIMARSSON, H., AGNARSDOTTIR, G. & LACHMANN, P. J. 0974). Cellular i m m u n i t y in subacute sclerosing
panencephatitis. Proceedings of the Royal Society of Medicine 67, 1125 1 I29
VANDWK, B & NORRSV, E 0 9 7 3 ) Oligoclonal IgG antibody response in the central n e r v o u s system to different measles virus antigens in s u b a c u t e sclerosing paneneephalitis. Proceedings of the National Academy
of Sciences of the United States of America 7o, I o6o-Io63.
VANDVIK, B., WELL, M.L., GRANDIEN, M. & NORRBY, E. (I978). Progressive rubella-virus p a n e n c e p h a l i t i s synthesis o f oligoclonal virus-specific IgG antibodies a n d h o m o g e n o u s free light-chains in central n e r v o u s
system. Acta Neurologica Scientifica 57, 53-64.
VAN DER NOORDAA, J. (I976). Infectivity, oneogenicity a n d t r a n s f o r m i n g ability o f B K virus a n d B K virus
D N A . Journal of General Virology 3o, 371-373.
VICKERMANN, K. (I974)- Antigenic variation in African t r y p a n o s o m e s in parasites in the i m m u n i z e d h o s t :
m e c h a n i s m o f survival. Ciba Foundation Symposium, vol. 25 pP. 53-8o. A m s t e r d a m : Associated Scientific Publishers.
WALKER, D. e. & PADGETT, ~. L. 0978)- N a t u r a l history of h u m a n p o l y o m a v i r u s infections. Journal of Supramolecular Structure, s u p p l e m e n t 2, 236.
WALKER, D. L., PADGETT B.L. ZURHEIN, G. M., ALBERT A. E. & MARSH, R. r. 0973)- H u m a n p a p o v a v i r u s (JC):
i n d u c t i o n o f brain t u m o r s in hamsters. Science x8x, 674-676.
WECHSLER, S. L. & FIELDS, B.N. (t978). Differences between the intra-cellular polypeptides o f measles a n d
subacute sclerosing panencephalitis virus. Nature, London 272, 458-460.
WELL, M. L., lXABASHI H. H., CREMER, N. E. et al. (I975 a). C h r o n i c progressive panencephalitis due to rubella
virus simulating subacute sclerosing panencephalitis. New England Journal of Medicine 292, 994-998.
WELL, M. L., ITABASHL H. H., ROLA-PLESZCZYNSKI,M. et al. (I975 b). C h r o n i c progressive panencephalitis due to
rubella virus. Archives of Neurology 32, 5oi-5o2.
WELL, M. L., PrRRIN, L., BUIMOVICI-KL~IN,E. et aL (I976). I m m u n o l o g i c abnormalities associated with chronic
progressive panencephalitis due to congenital infection with rubella virus. Clinical Research 24, 185.
WEINER, L. r. & STOHLMAN, ST. A. (I978). I m m u n o - d e f i c i e n c y a n d CNS. I n Clinical Neuroimmunology.
Edited by F. Clifford Rose. L o n d o n : Blackwell Scientific Publications Ltd.
WEINER, L. P., ItERNDON, R. M., NARAYAN, O. & JOHNSON, R. T. (I972b). F u r t h e r studies of a simian virus 4D-like
virus isolated f r o m h u m a n brain. Journal of Virology xo, I47-I49.
WEINER~ L. P.~ HERNDON, R. M., NARAYAN, O.~ JOHNSON, R. T., SHAH, K., RUBINSTEIN, L. J.~ PREZIOSI, T.J. &
CONLEY, F. K. (t972 a). Isolation o f virus related to SV4o f r o m patients with progressive multifocal leukoe n c e p h a l o p a t h y . New England Journal of Medicine 286, 385-39o.
WEISS, A. E,, PORTMANN, R., fiSCHER, It. et al. (I975). Simian virus 4D-related antigens in three h u m a n m e n i n g i o m a s with defined chromoso.'ne loss. Proceedings of the National Academy of Sciences of the United
States of America 72, 6o9-613.
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47
R e v i e w : slow virus infections o f the C N S
25
W H I ~ , R. G. & BOVD, S. V. (I973). T h e effect o f measles o n the t h y m u s a n d o t h e r l y m p h o i d tissues. Clinicaland
Experimental Immunology i3, 343-357WISNIEWSKI H. M., RAINE, C. S. & KAY, W. J. (1972). Observations o n viral demyelinating encephalomyelitis.
C a n i n e distemper. Laboratory Investigation 26, 589WOLINSI(Y, S. S., BERG, B. O. & MAITLAND, C. J. (I976). Progressive rubella panencephalitis. Archives of
Neurology 33, 722-7z3.
ZnDANOV, V. M. & PARFANOVlC~, i . (1974). Integration o f measles virus nucleic acid into the cell g e n o m e .
Arehiv fi~r die gesamte Viruaforschung 45, 225-234ZURnEIN, a. M. (1969)- Association o f papova-virions with a h u m a n d e m y e l i n a t i n g disease (progressive multifocal leukoencephalopathy). Progress in Medical Virology ix, 185-247.
ZURF/EIN, G. M. & CHOU, S. M. (1965). Particles resembling p a p o v a viruses in h u m a n cerebral d e m y e l i n a t i n g
disease. Science, New York I48 , 1477-I479.
(Received 2 0 June I 9 7 8 )
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sun, 14 May 2017 00:27:47