Download Fv1, the mouse retrovirus resistance gene

Rev. sci. tech. Off. int. Epiz., 1 9 9 8 , 1 7 (1), 269-277
Fv1, the mouse retrovirus resistance gene
J.P. Stoye
Division of Virology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1 AA,
United Kingdom
Summary
A n u m b e r of g e n e s w h i c h a f f e c t t h e susceptibility of m i c e t o i n f e c t i o n by
r e t r o v i r u s e s h a v e b e e n d e s c r i b e d . One of t h e m o s t interesting of t h e s e g e n e s is
Fvl (Friend virus susceptibility 1), w h i c h a c t s a t a s t a g e in t h e retroviral l i f e - c y c l e
f o l l o w i n g virus entry into t h e cell but prior to i n t e g r a t i o n a n d f o r m a t i o n of proviral
s t r u c t u r e s . A d e t a i l e d u n d e r s t a n d i n g of t h e m o d e of a c t i o n of Fv1 m i g h t b e
e x p e c t e d to s h e d f r e s h light on e a r l y s t e p s of t h e retroviral r e p l i c a t i o n , a l t h o u g h
p r o g r e s s h a s b e e n s l o w in this a r e a d u e to u n c e r t a i n t y a b o u t t h e n a t u r e of t h e Fv1
g e n e . T h e r e c e n t cloning of Fvl by a positional a p p r o a c h fills this g a p in c u r r e n t
k n o w l e d g e . Fv1 a p p e a r s to be d e r i v e d f r o m a f r a g m e n t of a retroviral g e n o m e , a n
o b s e r v a t i o n t h a t m a y s u g g e s t n o v e l a p p r o a c h e s t o t h e control of retroviral
replication.
Keywords
D o m i n a n t negative m u t a t i o n - Endogenous retroviruses - Genetics susceptibility-1 - Integration - Positional cloning - Provirus - Retroviridae.
Discovery of retroviral
resistance genes in mice
Retroviral infection can have a variety of severe consequences,
which include oncogene activation leading to cancer, cell
death leading to immunosuppression
and germ-line
integrations leading to inherited mutations. Since eukaryotic
evolution has taken place against a background of retroviral
infections, it would be surprising if genetic mechanisms for
controlling retrovirus replication had not evolved.
Studies of leukaemogenesis in mice performed in the 1960s
and 1970s provided ample evidence to support this idea.
Many of these studies utilised the Friend virus (Fv) complex,
an immunosuppressive virus preparation which rapidly
induces malignant erythroleukaemias ( 3 8 ) . A number of
genes controlling responses to Friend virus infection were
identified ( 3 6 ) , including at least five genes controlling
immunological responses as well as six genes for Friend virus
susceptibility,
known
as
Fvl-Fv6,
which
act by
non-immunological means (20).
Friend virus
Health (NIH)-Swiss strain (N) than on cells from BALB/c (B)
mice, while B-tropic viruses grew better on B- than on N-type
cells (19). A third category of virus, NB-tropic, grew equally
well on N- and B-type cells. Both N- and B-tropic viruses grew
poorly on cells from F l hybrids, which implies that resistance
was dominant to susceptibility. Subsequent genetic studies
showed that the in vitro restriction was controlled by a single
genetic locus ( 3 2 ) , which proved to be identical to the Fvl
locus identified in vivo (31) and mapped to the distal region of
mouse chromosome 4 (35).
Table I
The effect ofFV1in vitro
Virus
Genotype of cells
n/n
n/b
100
1
1
1
B-MLV
1
NB-MLV
100
100
100
100
N-MLV
b/b
a) Relative titres in plaque assay (absolute titres are usually approximately 1 0
1 0 infectious units/ml in permissive and restrictive cells, respectively)
N
: National Institutes of Health-Swiss strain
B
: BALB/c strain
M t V : murine leukaemia virus
5
and
3
Resistance genes were also identified by in vitro studies. For
example, it was shown that murine leukaemia viruses (MLV)
could be sub-divided into three categories based on their
ability to grow on cells derived from the embryos of different
strains of mice (Table 1). Some viruses, termed N-tropic,
yielded higher titres on cells from the National Institutes of
Although the block to infection mediated by Fvl is not
absolute, in vitro titres are reduced by a factor of one hundred
to one thousand ( 1 9 ) , and Fvl can confer resistance to
270
Rev. sci. tech. Off. int. Epiz., 17 (1)
naturally-occurring MLV-induced disease (18). The majority
of inbred strains of mice carry either the n or the b allele of Fvl
(25), though two other restrictive alleles, with subtly different
phenotypes, have also been described (4, 28). Most wild mice
do not appear to exhibit F v l restriction (28). To date, there is
no convincing evidence for the presence of F v l restriction in
other species of animal.
containing single-stranded RNA as their genetic material.
Extracellular virus binds to a specific receptor on the target
cell by means of the envelope protein. Following membrane
fusion, the viral capsid enters the cell. Reverse transcription of
the viral RNA takes place to form linear double-stranded
DNA.
This DNA, still associated with remnants of the capsid,
moves to the nucleus where integration of viral DNA into the
host cell DNA occurs, which results in the formation of a
Phenotypic characterisation of
Fv1 restriction
provirus. This DNA is transcribed and the resulting RNA is
translated by the synthetic machinery of the cell. Viral RNA
and protein assemble and bud through the cell membrane,
thereby acquiring an envelope. Proteolytic cleavage then
results in virion maturation.
The observation that F v l restriction is manifested in vitro, in a
dominant fashion, implies that this restriction has a direct
effect on retroviral replication, most likely mediated by an
interaction between the F v l gene product and some
component of the virus. Initial mechanistic studies were
therefore focused on discovering the stage in the retroviral
life-cycle at which it might be acting and in determining the
viral target for restriction.
between rhabdoviruses, such as vesicular stomatitis virus, and
The
stomatitis virus was dependent on the activity of the MLV
Initial studies showed clearly that Fvl did not affect the entry
of virions into cells. Mixed viral pseudotypes can be formed
retroviruses (both of which are enveloped RNA viruses).
Preparations of vesicular stomatitis virus genomes coated with
the envelope protein from an N-tropic MLV grew equally well
on N- or B-type cells ( 2 2 , 3 0 ) . Since replication of vesicular
retroviral life-cycle is shown in schematic form in
Figure 1. Readers are referred to Coffin ( 1 0 ) for a review of
envelope, this experiment shows that Fvl must act at a stage
retroviral replication. Retroviruses are enveloped viruses
in the retroviral life-cycle subsequent to the stages mediated
Fig. 1
Possible sites of action for the Fv1 gene product
The retroviral life-cycle is shown in schematic form illustrating the points at which the Fv1 gene product might act
271
Rev. sci. tech. Off. int. Epiz., 17 (1)
by the envelope protein, in other words at either attachment
to the cellular receptor or uptake into the cell.
A variety of experimental approaches have ruled out the
possibility of Fvl action late in the viral replication cycle.
Immunofluorescence studies showed greatly reduced levels of
viral protein in infected cells, implying that restriction must
act at, or before, translation of novel viral products ( 1 9 ) .
Nucleic hybridisation experiments showed reduced levels of
new viral transcript in restricted cells, which points to a
preintegration or transcriptional block ( 2 7 ) . Finally, direct
measurements of the amount of integrated viral DNA also
showed reduced levels, thereby indicating that Fvl must act
prior to integration and formation of proviruses (26).
Attempts to define more precisely which of the preintegration
steps (reverse transcription, nuclear import and integration) is
affected by Fvl action have yielded conflicting results. Early
experiments showed no reduction in the amounts of freshly
synthesised viral DNA in the cytoplasm of infected cells (26),
but this appears to depend on both the time at which
measurements are made and the cell type examined ( 3 3 ) .
Nuclear association of only slightly reduced levels of viral
DNA has been reported, but it is not clear whether that DNA
was truly within the nucleus (33). Preintegration complexes
isolated from restricted cells appear to have normal
integration activity in vitro, which suggests that no overt
damage to the complex results from the interaction with F v l
gene product ( 3 3 ) . Thus, only careful measurements of the
amounts and precise localisation of the preintegration
complex in restricted cells seem likely to resolve these issues.
Attempts to answer the question regarding the target for F v l
restriction have been more successful. Initial studies showed
that changes in the capsid protein (also known as p 3 0 or CA),
the major protein component of the viral capsid, were
associated with changes in viral tropism ( 2 1 , 3 4 ) . Studies with
'mix and match' recombinants made using cloned viral DNAs
confirmed these observations and showed that the viral
determinants of F v l could be mapped to a pair of amino acids
in CA (Fig. 2) ( 8 , 13). Very recent studies performed using
site-directed mutagenesis reveal that the second of the two
amino acids (arginine/glutamate) is the more important in
determining tropism (29).
The fact that CA is the target for the F v l gene product is fully
consistent with current understanding of the site of action of
Fvl, since CA is known to be present on the subviral complex
in which reverse transcription occurs and which mediates
nuclear import and integration (9). However, further progress
in understanding how Fvl might act was inhibited by a
complete absence of information about the F v l gene product
and for this reason, the keen interest that was shown in-Fvl in
the late 1970s and early 1980s has waned in recent years.
Cloning of Fvl
How might the cloning of Fvl be approached? One method
would be to try to take advantage of what little is known of
Fvl functional properties and to isolate a cellular protein
which binds to MLV-CA, or to clone a gene encoding such a
protein. Several laboratories have attempted to clone Fvl
using the so-called yeast two-hybrid system ( 1 4 ) , which
N : National Institutes of Health-Swiss strain
B : BALB/c strain
Fig. 2
Viral determinants of Fv1 tropism
Simple retroviruses such as murine leukaemia virus (MLV) possess three genes. These are called gag, which encodes the components of the viral capsid
MA (matrix), p12, CA (capsid), NC (nucleocapsid); pol, which provides PR (protease), RT (reverse transcriptase) and IN (integrase); and env, which encodes the
envelope proteins SU (surface) and TM (transmembrane). The primary target for the Fv1 gene product is amino acid 110 of CA-arginine in N-MLV and glutamate
In B-MLV
272
allows the detection of interacting proteins expressed from
complementary DNAs (cDNAs) in yeast. These attempts have
not met with success, perhaps because the CA 'bait' used in
these experiments did not assume the correct conformation
for interaction with the F v l gene product.
An alternative approach, which ultimately proved successful,
was to adopt a genetic approach known as positional cloning.
In essence, positional cloning comprises three steps. Firstly,
the gene in question is mapped as accurately as possible to a
small, defined genetic interval. Then, the DNA from this
interval is cloned. Finally, the genes encoded within these
clones are identified and differences between different alleles
are sought. Though labour-intensive, this approach has met
with considerable success in cloning genes associated with
inherited diseases in man and in a variety of mouse mutations,
in which little was known about the function of the mutated
gene (11).
The possibility of cloning Fvl in this way arose as a result of
observations made in the course of genetic studies with the
endogenous MLVs of mice. If a retrovirus infects a germ cell,
the resulting provirus can Become part of the germ line,
provided that undue harm to the host is not caused by virtue
of expression or by the position of the provirus in the genome.
These inherited elements, which are known as endogenous
retroviruses, are associated with a plethora of biological
phenomena (7). The endogenous retroviruses of a given
species can be classified into a few groups, each containing up
to ten thousand individual members which show a high
degree of nucleotide sequence similarity but differ in their
specific integration sites within the genome. A lower degree of
sequence similarity is seen between different groups. There
are between fifty and one hundred endogenous MLVs in mice
(7). In the course of mapping one MLV sub-family, four
proviruses, called Xmv8, Xmv9, X m v l 4 and Xmv44, were
shown to be tightly linked to Fvl ( 1 5 ) . Since the Fv4
restriction gene was known to correspond to a fragment of a
retrovirus, which prevented infection by competing for the
receptor for virus binding (24), it was suggested that one or
more of these endogenous proviruses might correspond to
Fvl ( 1 5 ) . As described below, this suggestion, though not
correct in detail, contained an element of truth.
To test the possibilities that one of these proviruses might be
Fvl (or if not Fvl itself, might lie close enough to Fvl to allow
positional cloning of the gene), a detailed genetic analysis of
the region of distal chromosome 4 known to contain Fvl was
performed (37). This study ruled outXmv8, Xmv9 and Xmv44
as candidates for F v l . However, Xmv9 and two other markers
(Nppa and lap3rcl 1) showed no recombination with F v l , and
the researchers argued that these markers must lie within
1.2 megabase (Mb) of one another and Fvl, confirming the
feasibility of a positional approach.
The research team set out to clone the chromosomal interval
spanning these markers. Genomic libraries containing large
Rev. sci. tech. Off. int. Epiz., 17 (1)
fragments of DNA derived from C57BL mice (Fvl b/b) cloned
as yeast artificial chromosomes (YACs) were screened for
Nppa and Xmv9. A variety of different YACs were isolated.
Unfortunately, attempts to generate an ordered array of
overlapping YACs failed because many of the YACs were
unstable, probably as a result of multiple copies of a repeated
zinc finger gene.
At this point, the research team decided to abandon a
systematic gene-finding approach and. concentrate on testing
the cloned YACs for Fvl activity in a functional test (Fig. 3),
based on the argument that since Fvl was a dominant gene,
introduction of a YAC containing Fvl into cells should result
in an alteration of their susceptibility to MLV infection. Mouse
cells were fused with yeast carrying Xmv9 or Nppa YACs and
stable clones were isolated. These cell clones were expanded
and infected with N- and B-tropic viral vectors carrying a gene
for resistance to the antibiotic puromycin. By enumerating
puromycin-resistant colonies, the cells could be typed for Fvl
phenotype. Using this approach, a YAC carrying the Nppa
gene was shown also to contain Fvl activity (5). As expected,
given the Fvl
origin of the YAC, the introduced resistance
gene affected N-tropic virus replication but did not inhibit an
NB-tropic virus.
b/b
To isolate the Fvl gene, a cosmid library was prepared from
the YAC and individual cosmids carrying Fvl were identified
in the functional assay. Fragments of a positive cosmid were
retested and a 6.5 kilobase (kb) Fvl-positive clone was
isolated. The DNA sequence of this clone was determined and
a 1.4 kb open reading frame with a predicted protein product
of 4 5 9 amino acids, subsequently shown to possess Fvl
activity restricting the replication of B-tropic virus, was
identified. The corresponding fragment was cloned from a
library prepared from an Fvln/n mouse restricted B-tropic
MLV, thus confirming that the research team had succeeded
in cloning Fvl. The predicted product of the n allele is
nineteen amino acids shorter than that of the b allele; the
alleles also differ at two other amino acid positions (5).
Origin of Fv1
Analysis of the structure and distribution of Fvl revealed a
number of unusual features (Fig. 4 ) ( 5 , Le Tissier et al, in
preparation). Firstly, most genes have multiple exons,
whereas Fvl comprises a single long exon. Secondly, the
presumptive polyadenylation signal is provided by the second
of a pair of short, interspersed nuclear repeats (B2 elements)
located downstream of the open reading frame, rather than by
a 'natural' gene-specific signal. Thirdly, the Fvl gene is present
only in mice and not in rats or humans, which implies a
relatively recent evolutionary origin.
Sequence data bank comparisons provide an explanation for
these findings. The Fvl coding sequence is related to the gag
gene of the endogenous retrovirus family, called HERV-Ls or
273
Rev. sci. tech. Off. int. Epiz., 17 (1)
Normal cells (Fv1n)
Fvl
MLV
N
B
YAC
Puro
:
:
:
:
:
:
Mouse cells fused w i t h YAC carrying Fvf
Friend virus susceptibility 1
murine leukaemia virus
National Institutes of Health-Swiss strain
BALB/c strain
yeast artificial chromosome
puromycin
Fig. 3
Functional cloning of Fvl
The assay used for detecting the Fvl gene in cloned DNA is illustrated in schematic form. YACs carrying the NeoR gene were introduced into mouse cells by
spheroplast fusion (23), and G418 resistant cell clones were isolated. These cells were then infected with equal titres of N-tropic or B-tropic retroviral vectors
carrying the PuroR gene. Reduction in the number of puromycin-resistant colonies as a result of fusion with a specific YAC was indicative of the presence of Fvl
on that YAC
MuERV-Ls, which are themselves highly divergent from MLV
(3, 12). The F v l gene seems to have resulted from the
insertion of all or part of such an element into a M u s
progenitor. Expression is dependent on the chance presence
on either side of the insertion point of cryptic signals.
Transcription utilises a cellular promoter found upstream of
the open reading frame and transcripts are polyadenylated at
an insertion element.
interact during virus assembly, and these proteins have been
Significance and future
prospects
previously been implicated in superinfection
What are the implications of the observation that F v l is
derived from the g a g gene of an inserted retrovirus? Perhaps
the most interesting feature of this result is that it suggests a
possible model of action for the gene. Gag proteins must
the F v l gene product which interact with MLV in order to
shown to bind tightly to one another through complex
interaction domains (1). This suggests that
might
considered as a dominant negative mutation
be
in which
restriction involves an interaction between the F v l gene
product and the CA protein present on incoming virions: an
interaction which would result in inhibition of capsid
function (17). However, the fact that Gag proteins have not
resistance
should be noted, which thus implies unusual properties for
the MuERV-L Gag protein that corresponds to F v l . Stoye and
colleagues are currently attempting to identify the domains of
determine whether CA binding can be dissociated from
inhibition of virus replication. If binding alone results in
restriction, the team will attempt to prepare a peptide, or
peptide mimetic, capable of inhibiting virus replication.
274
MuERV-L
LTR
Fv1
ORF
Rev. sci. tech. Off. int. Epiz., 17 (1)
:
:
:
:
murine endogenous retrovirus with leucine transfer ribonuceic acid (tRNA) primer
long terminal repeat
Friend virus susceptibility 1
open reading frame
Fig. 4
Structure and origin of the Fvl gene
The relative positions of the Fvl promoter and open reading frame are indicated, as well as the B2 repeats, the second of which provides the major
polyadenylation site for the Fvl message. The region of similarity (about 65% identity) to the gag gene of a MuERV-L element is shown
Though expressed at very low levels in cells, Fv1 can still
inhibit viral replication. This suggests that Fvl acts very
efficiently and that the binding of only a few molecules of F v l
is sufficient to inhibit virus replication. This observation is
potentially of considerable significance to the development
and use of dominant negative versions of viral genes to
combat human immunodeficiency virus type 1 (HIV-1), for
example, since it suggests that very low amounts of active
protein might have significant restrictive effects.
Fvl joins a list of at least three other mouse genes (mls, Fv4
and R m c f ) which are derived from retroviruses and can
influence susceptibility to retroviral infection ( 6 , 16). The
demonstration of such activities in mice raises the question of
whether analogous retrovirus restriction systems have evolved
elsewhere, for instance in humans, where the absence of
inbred
strains
would
have
obscured
their
presence.
Tantalising clues for the existence of similar restriction
systems have been reported;
these include intracellular
restriction of asymptomatic isolates of HIV-1 (2) and
Fvl appears to be derived from a retrovirus unrelated to MLV.
Was the anti-MLV activity an inherent property of the
MuERV-L gag, or did the antiviral activity evolve in response
to selective pressures? In other words, was MuERV-L an
anti-virus virus? A tentative answer to this question is
provided by the observation that the Fvl open reading strain
appears to be present in all subspecies of Mus, whereas only a
limited subset of Mus appears to have Fvl activity (28). Stoye
and colleagues speculate that the germ-line infection of mice
by the progenitors of MLVs provided a selective advantage for
mice with mutations leading to antiviral activity in a gene
which did not initially have antiviral activity (S. Ellis e£ al., in
preparation).
Endogenous retroviruses are usually considered as selfish
DNA which provide no benefit to their hosts. However, there
is a possibility that these retroviruses can sometimes afford
selective advantages by providing protection against
exogenous retroviral infection, and that these advantages
might favour the retention of endogenous retroviruses (6).
polymorphic
human
gene(s)
determining
differential
susceptibility to infection by HIV-1 ( 4 0 ) . Although these
reports remain somewhat controversial, it is tempting to
speculate
that
they
represent
Fvl -like
activities.
Unfortunately, the observation that Fvl is a 'neogene' rules
out
simple
genetic
tests
for
linkage
to
the
human
chromosomal region homologous to the Fvl -containing
region. Nevertheless, the possibility that one or more of the
thousands of endogenous viruses ( 3 9 ) present in the human
germ line can affect retroviral replication remains. Addressing
this issue appears to be a formidable, but potentially hugely
rewarding, undertaking.
Rev. sci. tech. Off. int. Epiz., 17 (1)
275
Fvl : le gène de la résistance aux rétrovirus chez les souris
J.P. Stoye
Résumé
Plusieurs g è n e s liés à la sensibilité d e s souris à l'infection par d e s rétrovirus ont
d é j à é t é d é c r i t s . P a r m i c e s g è n e s , l'un d e s plus i n t é r e s s a n t s e s t le Fvl
(sensibilité-1 a u virus de Friend), qui intervient à un c e r t a i n s t a d e du c y c l e
biologique d e s rétrovirus a p r è s l'entrée du virus d a n s la c e l l u l e m a i s a v a n t
l'intégration e t la f o r m a t i o n d e s t r u c t u r e s p r o v i r a l e s . U n e c o n n a i s s a n c e plus
p r é c i s e du m o d e d'action de Fvl p o u r r a i t a p p o r t e r un é c l a i r a g e n o u v e a u
p e r m e t t a n t de m i e u x c o m p r e n d r e les p r e m i è r e s é t a p e s de la r é p l i c a t i o n d e s
rétrovirus ; les p r o g r è s o n t é t é lents d a n s c e d o m a i n e , e n r a i s o n d e s i n c e r t i t u d e s
sur la n a t u r e du g è n e Fvl. Le c l o n a g e de Fvl, e f f e c t u é r é c e m m e n t s e l o n u n e
m é t h o d e de p o s i t i o n n e m e n t , a p e r m i s de f a i r e p r o g r e s s e r la c o n n a i s s a n c e sur ce
point. Fvl s e m b l e ê t r e d é r i v é d ' u n f r a g m e n t d e g é n o m e r é t r o v i r a l , c e qui p o u r r a i t
ouvrir d e n o u v e l l e s v o i e s pour le c o n t r ô l e de la r é p l i c a t i o n d e s rétrovirus.
Mots-clés
Clonage positionnel - Génétique - Intégration - M u t a t i o n négative d o m i n a n t e - Provirus
- Rétroviridés - Rétrovirus endogène - Sensibilité-1 au virus de Friend.
•
Fv1, el gen del ratón que confiere resistencia a los retrovirus
J.P. Stoye
Resumen
S e h a n d e s c r i t o diversos g e n e s q u e influyen s o b r e la s u s c e p t i b i l i d a d de los
r a t o n e s a la i n f e c c i ó n por retrovirus. Uno de los m á s i n t e r e s a n t e s es Fvl
virus susceptibility-1,
(Friend
o g e n de tipo 1 q u e c o n t r o l a la s u s c e p t i b i l i d a d a l e u c e m i a s
i n d u c i d a s por el virus Friend), c u y a a c c i ó n a f e c t a a una f a s e del ciclo vital
retrovírico ulterior a la p e n e t r a c i ó n
del virus e n la c é l u l a
p e r o previa
al
e n s a m b l a j e y la f o r m a c i ó n d e e s t r u c t u r a s p r o v í r i c a s . C a b e e s p e r a r q u e la
c o m p r e n s i ó n d e t a l l a d a del m o d o de a c c i ó n de e s e g e n a r r o j e luz s o b r e las
p r i m e r a s e t a p a s de la r e p l i c a c i ó n r e t r o v í r i c a , y a u n q u e los p r o g r e s o s e n este
c a m p o h a n sido lentos d e b i d o a la i n c e r t i d u m b r e e x i s t e n t e s o b r e la n a t u r a l e z a del
g e n Fvl,
la r e c i e n t e c l o n a c i ó n posicional de Fvl ha v e n i d o a llenar esta l a g u n a .
Fvl p a r e c e d e r i v a r de un f r a g m e n t o de g e n o m a r e t r o v í r i c o , una o b s e r v a c i ó n q u e
podría dar pie a n u e v a s f ó r m u l a s p a r a el control de la r e p l i c a c i ó n r e t r o v í r i c a .
Palabras clave
Clonación posicional - Ensamblaje - Gen de t i p o 1 de la susceptibilidad al virus Friend Genética endógenos.
M u t a c i ó n negativa d o m i n a n t e -
Provirus -
Retroviridae -
Retrovirus
276
Rev. sci. tech. Off. int. Epiz., 17 (1|
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