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Studies regarding a possible function for viruses in the pathogenesis of systemic lupus erythematosus.

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STUDIES REGARDING A POSSIBLE FUNCTION FOR VIRUSES IN
THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS
THEODORE PINCUS
A p o s s i b l e r o l e f o r r e t r o v i r u s e s i n s y s t e m i c luDus
erythematosus (SLE) has been i n v e s t i g a t e d - o n t h e b a $ i s
of c l i n i c a l and l a b o r a t o r y a b n o r m a l i t i e s found i n many
known v i r a l i n f e c t i o n s . The t u b u l o r e t i c u l a r s t r u c t u r e s
seen i n SLE r e n a l d i s e a s e a r e n o t a s p e c i f i c v i r a l o r
s u b v i r a l s t r u c t u r e , b u t a r e a s s o c i a t e d w i t h many t y p e s
o f virus infections.
A n t i b o d y t i t e r s t o many v i r u s e s
a r e e l e v a t e d i n SLE sera, a p p e a r i n g t o r e f l e c t p o l y c l o n a l B c e l l h y p e r a c t i v i t y r a t h e r t h a n responses t o
specific viruses.
Immunofluorescence and v i r u s i s o l a t i o n s t u d i e s i n SLE have been n e g a t i v e , i n d i c a t i n g t h a t
any r o l e f o r v i r u s e s i n the p a t h o g e n e s i s o f SLE i s
complex.
The r e t r o v i r u s e s , w h i c h were i n i t i a l l y i s o l a t e d from lymphomas o f m i c e and o t h e r s p e c i e s , p r o v i d e
a u s e f u l model f o r a n a l y s i s o f complex v i r u s i n f e c t i o n s . The r e t r o v i r u s genome i s found i n a l l normal
mice, b u t i s u s u a l l y expressed as l o w l e v e l s o f v i r a l
s t r u c t u r a l p r o t e i n s , r a t h e r t h a n i n f e c t i o u s v i r u s . New
Zealand m i c e w i t h f e a t u r e s o f SLE show spontaneous
expression o f high l e v e l s o f i n f e c t i o u s xenotropic
r e t r o v i r u s , u n l i k e most o t h e r mouse s t r a i n s . The p r e sence o f i n f e c t i o u s v i r u s i s n o t c o r r e l a t e d w i t h a u t o immunity i n h y b r i d s o f New Zealand mice, b u t h i g h
l e v e l s o f immune complexes c o n t a i n i n g t h e r e t r o v i r a l
s t r u c t u r a l p r o t e i n gp70 a r e a s s o c i a t e d w i t h autoimmune
nephritis.
E x t e n s i v e s t u d i e s i n SLE have n o t r e v e a l e d
a u n i q u e human r e t r o v i r u s i n notmal o r d i s e a s e d i n dividuals.
S t u d i e s o f r e t r o v i r u s e s have p r o v i d e d
i m p o r t a n t i n s i g h t s i n t o mammalian c e l l u l a r r e g u l a t o r y
mechanisms, i n c l u d i n g t h e r e l a t i o n o f t h e m a j o r h i s t o c o m p a t i b i l i t y complex t o disease, h o s t g e n e t i c c o n t r o l
o f v i r u s i n f e c t i o n s and e x p r e s s i o n o f v i r u s p r o t e i n s
Further basic
and v i r u s i n t h e absence o f disease.
r e s e a r c h r e g a r d i n g h o s t r e g u l a t o r y mechanisms i n i n f e c t i o u s processes may c o n t r i b u t e t o p r o g r e s s r e g a r d i n g a
p o s s i b l e v i r a l f u n c t i o n i n t h e p a t h o g e n e s i s o f SLE.
From t h e Department o f Medicine a t Vanderbilt U n i v e r s i t y
Medical Center, Nashville, Tennessee. This study was supported i n p a r t by Grants AM22071 and the Maury County Lupus
Fund.
Requests f o r r e p r i n t s should be addressed t o Theodore
Pincus, M.D., Department o f Medicine, D i v i s i o n o f Rheumatology and Immunology, Vanderbilt U n i v e r s i t y Hospital, Z l s t
and Garland Avenues, Nashville, Tennessee 37232.
Arthritis and Rheumatism, Vol. 25, No. 7 (July 1982)
A p o s s i b l e r o l e f o r v i r u s e s i n SLE has l o n g been
r e g a r d e d as a n a t t r a c t i v e h y p o t h e s i s ( 1 - 5 ) .
Most
c l i n i c a l f e a t u r e s o f i n f l a m m a t i o n i n SLE a s w e l l as t h e
associated
immunologic a b n o r m a l i t i e s o f i n c r e a s e d
humoral and decreased c e l l u l a r immunity c a n be seen i n
known v i r a l i n f e c t i o n s ( 6 ) .
However, e x t e n s i v e e f f o r t s
t o i d e n t i f y a p a r t i c u l a r v i r u s w i t h SLE have n o t been
s u c c e s s f u l t o date.
EFFORTS TO IDENTIFY
A
SPECIFIC V I R U S I N SLE TISSUE
A p e r i o d o f e x t e n s i v e i n v e s t i g a t i o n i n t o a poss i b l e v i r a l e t i o l o g y i n SLE was i n i t i a t e d i n 1969 w i t h
recognition o f tubuloreticular structures i n renal
b i o p s i e s o f SLE p a t i e n t s ( 7 - l o ) , which were i n i t i a l l y
i n t e r p r e t e d i n some r e p o r t s t o be p o s s i b l e paramyxov i r u s nucleocapsids.
The presence o f p a r a m y x o v i r u s
n u c l e o c a p s i d s i n e l e c t r o n m i c r o g r a p h s o f t i s s u e s had
proven a v a l u a b l e m a r k e r i n e a r l i e r s t u d i e s l e a d i n g t o
r e c o g n i t i o n o f measles v i r u s i n subacute s c l e r o s i n g
panencephalitis
(SSPE),
a devastating neurological
d i s e a s e o f p r e v i o u s l y unknown e t i o l o g y . I n SSPE, r e p o r t s o f paramyxovirus nucleocapsids i n b r a i n biopsies
l e d t o s e r o l o g i c and irnmunofluorescence s t u d i e s i n
w h i c h measles v i r u s was i d e n t i f i e d , and measles v i r u s
v a r i a n t s were i s o l a t e d f r o m t i s s u e (11). I d e n t i f i c a t i o n
o f p o t e n t i a l p a r a m y x o v i r u s n u c l o c a p s i d s was viewed as a
p o s s i b l e i n i t i a l c l u e f o r a s i m i l a r approach i n SLE.
Further analysis o f the tubuloreticular structures
found i n SLE, developed l a r g e l y b y D r . P h i l i p G r i m l e y
and c o l l a b o r a t o r s (1'2-14), i n d i c a t e d t h a t t h e s e s t r u c t u r e s do n o t f u l f i l l m o r p h o l o g i c a l c r i t e r i a f o r param y x o v i r u s n u c l e o c a p s i d s : t h e SLE t u b u l o r e t i c u l a r s t r u c t u r e s a r e a p p r o x i m a t e l y 220-280 A u n i t s w h i l e paramyxov i r u s n u c l e o c a p s i d s a r e a p p r o x i m a t e l y 180 A u n i t s ; t h e
SLE t u b u l o r e t i c u l a r s t r u c t u r e s a r e s i g n i f i c a n t l y more
h e l i c a l t h a n t h e more u n d u l a t i n g v i r a l n u c l e o c a p s i d s ;
t h e SLE t u b u l o r e t i c u l a r s t r u c t u r e s s t a i n f o r g l y c o p r o t e i n and n o t RNA, which i s f o u n d i n n u c l e o c a p s i d s ; t h e
SLE t u b u l o r e t i c u l a r s t r u c t u r e s a r e f o u n d i n t h e endop l a s m i c r e t i c u l u m r a t h e r t h e n i n t h e n u c l e o p l a s m and
c y t o p l a s m as i n t h e case o f p a r a m y x o v i r u s nucleocapsids.
The SLE t u b u l o r e t i c u l a r s t r u c t u r e s appear t o be
a l t e r e d endoplasmic r e t i c u l u m , perhaps r e f l e c t i n g some
cellular injury.
They have been f o u n d i n a s s o c i a t i o n
w i t h many v i r u s i n f e c t i o n s , u s i n g a v a r i e t y of d e s i g nations (Table 1).
PI NCUS
Table 2.
V i r u s i n f e c t i o n s i n which
elevated antibody t i t e r s are reported
i n sera o f SLE p a t i e n t s compared t o
normal p o p u l a t i o n s .
Table 1.
Experimental c o n d i t i o n s i n which t u b u l o r e t i c u l a r
st,ructures s i m i l a r t o t h o s e found i n SLE a r e found*
~~
Agent
Rube1 l a
Eps t e i n - B a r r
virus
S t . Louis
encephalitis
Canine h e p a t i t i s
virus
S i z e (A)
Description
270
240-260
Crystal l a t t i c e structure
a) Undulating tubules
M i c r ot u bu 1a r forma t i ons
b) L a c e - l i ke network
c) Reticular arrays
200
not
given
Convoluted membranous
structures
Pol io v i r u s c r y s t a l s
Herpes simplex
200-240
Crystalline arrays
Seml i k i f o r e s t
virus
250-300
M i c r o t u b u l a r r e t i c u 1um
Equine v i r a l
arteritis
200
C r y s t a l l o i d s i n endoplasmic r e t i c u l u m
Rous sarcoma
220
C r y s t a l i n e aggregates
not
given
R e t i c u l a r aggregates
F e l i n e leukemia
*
References
15,16,17,22*
17
17
15,16,17,22
17*, 22*
17,22
17,22
22
DNA V i r u s e s
Adenovirus
Herpes simplex
Cvtomeaalovirus
Gstein-Barr virus
22*
16,22*
22
18,19,21
Undulating tubules
270
Pol i o v i r u s
RNA V i r u s e s
Parainfluenza 1
Parainfluenza 2
Parainfluenza 3
Measles
Mumps
Rubella
Reovirus
Polio
* T i t e r s t o a l l v i r u s e s were h i g h e r i n
a group o f SLE p a t i e n t s compared t o
c o n t r o l groups. A l l r e s u l t s a r e s t a t i s t i c a l l y s i g n i f i c a n t except t h o s e
i h d i c a t e d by an a s t e r i s k , i n .which
case h i g h e r a n t i b o d y t i t e r s were seen
i n SLE sera, though d i f f e r e n c e s between t h e SLE and c o n t r o l group were
not s t a t i s t i c a l l y significant.
Reference 12
Another l i n e o f i n v e s t i g a t i o n i n t o a p o s s i b l e
s p e c i f i c v i r u s i n f e c t i o n i n SLE i n v o l v e d measurement o f
v i r a l antibody t i t e r s as an i n d i c a t o r o f v i r u s i n f e c tion.
SLE sera show r a i s e d a n t i b o d y t i t e r s t o many
v i r u s e s examined, compared t o normal p o p u l a t i o n s (1522), e.g.,
cytomegalovirus, herpes simplex, measles,
parainfuenza 1, r u b e l l a , r e o v i r u s , and p o l i o v i r u s 1,
adenovirus 2 and mumps (Table 2). The r a i s e d a n t i b o d y
t i t e r s t o v i r a l and c e l l u l a r antigens i n SLE may be a
consequence o f t h e p o l y c l o n a l 8 c e l l h y p e r a c t i v i t y
which has been recognized i n t h i s disease, r a t h e r than
responses t o s p e c i f i c v i r u s e s .
V i r u s i s o l a t i o n f o r SLE p a t i e n t s has been attempted i n a number o f l a b o r a t o r i e s using conventional
techniques as w e l l as more s e n s i t i v e c o c u l t i v a t i o n
Table 3.
Techniques used t o
versus SLE
techniques which have allowed v i r u s i s o l a t i o n i n comp l e x v i r a l i n f e c t i o n s (11). A l l such attempts i n many
l a b o r a t o r i e s have proven negative.
I n summary, e f f o r t s t o i m p l i c a t e a s p e c i f i c v i r u s
i n SLE, undertaken on t h e b a s i s o f c l i n i c a l features,
have n o t revealed evidence f o r a s p e c i f i c v i r u s i n f e c t i o n u s i n g e l e c t r o n microscopy, serology,
immunofluorescence and v i r u s i s o l a t i o n techniques (Table 3).
V i r u s i s o l a t i o n techniques used t o d a t e have n o t y i e l d ed p o s l t i v e r e s u l t s , and most l a b o r a t o r i e s i n which
these s t u d i e s have been performed, i n c l u d i n g our own,
a r e n o t p r e s e n t l y engaged i n d i r e c t e f f o r t s t o i s o l a t e
v i r u s e s from SLE p a t i e n t s . Two observations presented
a t t h i s meeting may p r o v i d e new impetus t o s t u d i e s o f
v i r u s i n f e c t i o n i n SLE, i.e., t h e f i n d i n g s o f Friedman
i d e n t i f y virus infections:
comparison o f SSPE
SSPE
SLE
E l e c t r o n microscopy
Paramyxovirus n u c l e o c a p s i d s
i n brain biopsies
Tubuloreticular structures
i n renal b i o p s i e s
Serology
High measles a n t i b o d y t i t e r
i n serum and c e r e b r o s p i n a l
fluid
High antibody t i t e r s
many v i r u s e s
Immunofluorescence
P o s i t i v e f o r measles
antigen i n brain tissue
Non-specific
tissue
Viral isolation
Measles v i r u s v a r i a n t s
isolated
No
positive
in
to
kidney
isolations
VIRUSES IN SLE
Table 4.
849
Some Complex V i r a l I n f e c t i o n s .
Example
Some " a t y p i c a l " v i r u s e s
"Slow" v i r u s
Atypical i d e n t i f i c a t i o n
Virus i n host genome
Virus as immune complex
Reference
25
Scrapie, Kuru
Hepati t i s
26
27
Re t r o v i rus
L a c t i c dehydrogenase
2
virus
Some A t y p i c a l Host Response t o Common Viruses
Viral persistance
Measles i n SSPE
11
Latency and r e a c t i v a t i o n
Herpes simplex
28-29
30
Rubel
l
a
Arthritogenic strains
Carrier s t a t e
Lymphocytic choriomen31
ingitis
Murine r e t r o v i r u s e s
27
Histocompatib i 1 ity (H-2)
l i n k e d h o s t response
t o virus
e t a1 o f r a i s e d i n t e r f e r o n l e v e l s i n SLE sera ( 2 3 ) , and
t h e s t u d i e s r e p o r t e d by L e r n e r e t a1 t h a t c e r t a i n SLE
sera p r e c i p i t a t e d v i r u s s p e c i f i c RNA from v i r u s i n fected c e l l s and n o t from u n i n f e c t e d c e l l s ( 2 4 ) .
If
RNA p r e c i p i t a t i o n occurs i n two types o f i n f e c t e d
c e l l s , t h e r e a c t i o n s may again n o t r e f l e c t a response
t o one s p e c i f i c v i r u s i n f e c t i o n .
The c i r c u m s t a n t i a l
evidence r e g a r d i n g v i r u s i n f e c t i o n i n SLE remains
extensive, b u t a v a i l a b l e evidence t o d a t e has proven
f r u s t r a t i n g l y negative.
The hypothesis o f v i r u s involvement i n SLE r e ceived support d u r i n g t h e l a s t two decades from ident i f i c a t i o n o f v i r u s i n f e c t i o n s which a r e " a t y p i c a l "
compared t o c l a s s i c a l i n f e c t i o n s i n v i r o l o g i c a l prop e r t i e s o r h o s t response (Table 4 ) . The importance o f
b a s i c research i n a n a l y s i s o f pathogenetic mechanisms
can be seen from t h e example o f h e p a t i t i s as a complex
v i r u s i n f e c t i o n . Extensive e f f o r t s t o i s o l a t e an i n f e c t i o u s v i r u s using t h e " l a t e s t " a v a i l a b l e techniques i n
t h e 1 9 5 0 ' s were unsuccessful, and t h e v i r u s has n o t
F i u r e 1. Comparison of t u b u l a r s t r u c t u r e s i n endoplasmic r e t i c u l u m (A,B,C) w i t h cytoplasmic f i l a m e n t s o f p a r a i n f l u e n z a 1 v i r u s
(Dy a t same photographic m a g n i f i c a t i o n (~32,000scale=0.5u). A) Glomerular e n d o t h e l i a l biopsy o f p a t i e n t w i t h SLE. B) Lymphoid
c e l l c u l t u r e d e r i v e d from p a t i e n t w i t h f a m i l i a l c y s t i n o s i s . C) Chick embryo,ce!l i n f e c t e d w i t h S e m l i k i f o r e s t v i r u s f o r 16 hours.
D) Rat kidney c e l l i n f e c t e d w i t h Sendai v i r u s ( p a r a i n f l u e n z a I ) a t 48 hours (12).
PINCUS
850
normal c e l l s a f t e r treatment w i t h a v a r i e t y o f compounds, i n c l u d i n g iododeoxyuridine (41,42) and bact e r i a l 1 i p o p o l y s a c c h a r i d e (43,44).
Expression o f endogenous r e t r o v i r u s genes i s r e g u l a t e d by complex h o s t
g e n e t i c mechanisms (45-47).
The r e t r o v i r u s e s c o n t a i n s i x o r seven s t r u c t u r a l
p r o t e i n s designated as "p" o r "gp" f o r g l y c o p r o t e i n ,
foilowed by a number i n d i c a t i n g t h e molecular weight X
10
I n mouse r e t r o v i r u s e s , t h e major core p r o t e i n is
known as p30, and t h e major envelope g l y c o p r o t e i n as
gp70 o r gp69/71 (48).
The v i r a l s t r u c t u r a l p r o t e i n s
express d i f f e r e n t classes o f a n t i g e n i c determinants,
i n c l u d i n g those which a r e "type s p e c i f i c , " i.e., unique
t o a p a r t i c u l a r v i r u s i s o l a t e ; "group s p e c i f i c , " i. e . ,
common t o those w i t h i n a species such as mouse; " i n t e r species," i.e.,
common t o a l l mammalian type C r e t r o v i r u s e s (48,49).
The gene products seen as v i r a l
s t r u c t u r a l p r o t e i n s a r e coded f o r by f o u r regions i n
t h e v i r a l genome: JXJC
coding f o r the p30 c o r e prot e i n , along w i t h p15, p12 and p10, a l l o f which a r e
cleaved from a precursor p o l y p r o t e i n c o n t a i n i n g reverse
t r a n s c r i p t a s e as w e l l ; pol
coding f o r t h e RNA depend e n t DNA polymerase o r r e v e r s e t r a n s c r i p t a s e ;
coding f o r t h e envelope g l y c o p r o t e i n s which are cleaved
from a d i f f e r e n t precursor p o l y p r o t e i n ; and arc
coding f o r a gene product associated w i t h n e o p l a s t i c
t r a n s f o r m a t i o n (50).
Recent s t u d i e s using h i g h l y
s p e c i f i c n u c l e i c a c i d probes have l e d t o i d e n t i f i c a t i o n
o f s p e c i f i c r e g i o n s w i t h i n d i f f e r e n t v i r u s genomes
which account f o r v a r i o u s v i r a l f u n c t i o n a l p r o p e r t i e s
(51).
Extensive polymorphism o f endogenous r e t r o v i r u s e s
has been recognized on t h e b a s i s o f many c r i t e r i a ,
i n c l u d i n g h o s t range o f v i r u s growth, a n t i g e n i c d e t e r minants on v i r a l s t r u c t u r a l p r o t e i n s , v i r a l n u c l e i c
a c i d sequences, e t c . A n a l y s i s o f h o s t range has l e d t o
s i g n i f i c a n t understanding o f t h e b i o l o g y o f these
viruses, w i t h s i x major c a t e g o r i e s o f mouse endogenous
r e t r o v i r u s e s i d e n t i f i e d t o date:
1 ) N-ecotropic - r e p l i c a t e s i n mouse c e l l s , p r e f e r e n t i a l l y i n c e l l s o f N I H mice and o t h e r s t r a i n s w i t h
t h e "n" a l l e l e a t t h e mouse
g e n e t i c locus (see
below, some r e p l i c a t i o n i n r a t c e l l s b u t none i n r a b b i t
and mink c e l l s ; 2 ) B - e c t r o p i c
r e p l i c a t e s i n mouse
c e l l s , p r e f e r e n t i a l l y i n c e l l s o f BALB/c mice and o t h e r
s t r a i n s w i t h t h e "b" a l l e l e a t t h e mouse
genetic
locus; some r e p l i c a t i o n i n r a t c e l l s b u t none i n r a b b i t
and mink cells;,3)
NB-ectLopic - r e p l i c a t e s w i t h equal
and
mouse c e l l s ; seen o n l y i n
titers i n
laboratory-passaged viruses, as endogenous mouse v i ruses a r e n o t seen o n l y i n l a b o r a t o r y passage viruses,
as endogenous mouse v i r u s e s a r e n o t NB-tropic; 4)
x e n o t r o p i c - does n o t r e p l i c a t e i n mouse c e l l s , b u t
does r e p l i c a t e i n c e l l s o f many o t h e r species, i n c l u d i n g r a t , r a b b i t , mink and human c e l l s ; 5) amphotropic
r e p l i c a t e s i n b o t h mouse and nonmouse c e l l s ;
6) polytropic
s i m i l a r t o amphotropic i n h o s t range,
b u t known t o be recombinant v i r u s o f N-ectropic and
xenotropic virus.
Much knowledge r e g a r d i n g mouse type C r e t r o v i r u s e s
i s d e r i v e d from t h e AKR mouse s t r a i n , w i t h a h i g h
i n c i d e n c e o f spontaneous lymphoma, developed by F u r t h
i n t h e 1930's (34,47).
I n 1951, Gross induced lymphoma
i n t h e low lymphoma C3H/Bi and C57BR s t r a i n s by inocul a t i n g newborn mice w i t h AKR lymphoma t i s s u e (34). AKR
mice show h i g h l e v e l s o f e c t r o p i c v i r u s from l a t e
g e s t a t i o n throughout t h e l i f e t i m e o f t h e mouse (52),
r e s u l t i n g from t h e presence o f Akv genes, chromosomal
l o c i which a r e t h e v i r u s i t s e l f T 3 , 5 4 ) . A t about s i x
.
-
-
Figure 2 . Type C RNA retrovirus (courtesy o f Dr. N Sarkar,
Memorial Sloan-Kettering Cancer Center).
been i s o l a t e d i n v i t r o t o t h i s day. However, s t u d i e s
t o c h a r a c t e r i z e serum lpopulation g e n e t i c markers l e d t o
r e c o g n i t i o n o f t h e A u s t r a l i a a n t i g e n " (26), which
provided a marker f o r t h e v i r u s .
This observation
emerged o n l y from basic research, and e x t e n s i v e c l i n i c a l research would n o t have y i e l d e d a marker f o r hepat i t i s B. F u r t h e r b a s i c research would appear t h e most
1 i k e l y prospect f o r c l i n i c a l l y u s e f u l advances regardi n g v i r u s e s i n SLE as w e l l as o t h e r chronic rheumatic
diseases.
TYPE C RETROVIRUSES AS A MODEL FOR THE STUDY OF COMPLEX VIRUS INFECTION
The r a t i o n a l e f o r a search f o r v i r u s e s i n SLE was
supported f u r t h e r by t h e f i n d i n g o f numerous t y p e C
v i r u s p a r t i c l e s i n New Zealand mice, an e x t e n s i v e l y
studied mouse model f o r SLE (33). The s i g n i f i c a n c e o f
these v i r u s e s i n t h e pathogenesis o f autoimmunity
remains unclear, as w i l l be discussed below. However,
s t u d i e s o f type C r e t r o v i r u s e s p r o v i d e a number o f
i m p o r t a n t p r i n c i p l e s r e g a r d i n g complex h o s t v i r u s
i n t e r a c t i o n s , which w i l l be considered here.
The t y p e C r e t r o v i r u s e s , o r RNA tumor viruses, a r e
found i n many species, i n c l u d i n g b i r d s , mice, cats,
cows and nonhuman primates ( F i g u r e 1 ) . These v i r u s e s
were i n i t i a l l y described i n a v i a n sarcoma and murine
lymphoma (34). I n r e c e n t years, genes of c e r t a i n r e t r o v i r u s e s , known as endogenous viruses, have been ident i f i e d i n t h e normal h o s t c e l l genome o f mice and many
o t h e r species (35,36).
The r e t r o v i r u s e s a r e composed
o f a core c o n t a i n i n g RNA and p r o t e i n , and an envelope
c o n t a i n i n g g l y c o p r o t e i n and l i p i d s .
Type C r e t r o v i r u s e s c o n t a i n a unique enzyme, r e v e r s e t r a n s c r i p t a s e ,
which t r a n s c r i b e s RNA i n t o DNA, l e a d i n g t o t h e design a t i o n r e t r o v i r u s e s (37).
R e t r o v i r a l genes a r e f r e q u e n t l y n o t expressed, o r a r e expressed as v i r a l s t r u c t u r a l p r o t e i n s i n many normal t i s s u e s (38-40).
Endogenous i n f e c t i o u s r e t r o v i r u s e s can be induced from
env
-
-
fv-l
-
-
VIRUSES IN SLE
85 1
GENETIC CONTROL OF ENDOGENOUS RETROVIRUS INFECTIONS
AS A MODEL FOR POLYGENIC CONTROL OF DISEASE SUSCEPT I B I L I TY
months o f age, prelymphomatous mice show an increase i n
l e v e l s o f t h e v i r a l gp70 (55), associated w i t h emergence o f a p o l y t r o p i c recombinant v i r u s tetmined MCF
(mink c e l l focus inducing), which i s found i n a c t u a l
lymphomas (56).
A n a l y s i s o f t h e v i r o l o g y of spontaneous lymphoma
i n t h e AKR mouse provides an i m p o r t a n t example whereby
r e c o g n i t i o n of s u b t l e d i f f e r e n c e s among a p p a r e n t l y
i d e n t i c a l v i r u s p o p u l a t i o n s r e s u l t e d from more d e t a i l e d
studies.
Only a decade ago, a l l endogenous mouse
v i r u s e s were known as "Gross v i r u s , I' w i t h o u t recognit i o n o f e x t e n s i v e d i v e r s i t y . A l l mouse t y p e C r e t r o v i r u s e s a r e s i m i l a r i n morphologic appearance and
s t r u c t u r e , and t h e c a p a c i t y t o recognize widespread
polymorphism w i t h i n t h i s group o f v i r u s e s became apparent o n l y a f t e r e x t e n s i v e i n v e s t i g a t i o n (34,47).
Recognition o f h o s t range v a r i a n t s among t h e endogenous
retroviruses i l l u s t r a t e s the p r i n c i p l e t h a t appropriate
i n d i c a t o r c e l l s are required f o r virus i d e n t i f i c a t i o n .
The presence o f r e t r o v i r u s g e n e t i c i n f o r m a t i o n i n
t h e normal mouse genome has l e d t o suggestions t h a t
these genes may be i n v o l v e d i n normal c e l l u l a r funct i o n s , perhaps in. d i f f e r e n t i a t i o n o r development (57,
58). I n d u c t i o n o f r e t r o v i r u s expression upon treatment
o f spleen- c e l l s w i t h 1ipopolysaccharide, a m i togen
which induces B c e l l d i f f e r e n t i a t i o n (59,60),
has l e d
t o suggestions t h a t r e t r o v i r u s expression may be i n volved i n , o r may be a consequence o f immune d i f f e r e n t i a t i o n (61,62).
The p o s s i b i l i t y t h a t r e t r o v i r u s
expression r e g u l a t e s normal c e l l u l a r f u n c t i o n remains a
speculative but i n t r i g u i n g p o s s i b i l i t y .
Genetic c o n t r o l o f mouse lymphoma was recognized
i n s t u d i e s o f h y b r i d s o f h i g h and low lymphoma s t r a i n s ,
b u t demonstration o f mendel i a n l o c i a f f e c t i n g suscept i b i l i t y o r r e s i s t a n c e t o lymphoma r e q u i r e d r e c o g n i t i o n
of p o t e n t i a l s p e c i f i c g e n e t i c markers i n i n b r e d mouse
strains.
The r e t r o v i r u s e s themselves and t h e major
h i s t o c o m p a t i b i l i t y l o c u s have p r o v i d e d such markers i n
mouse lymphoma l e a d i n g t o : a ) t h e f i r s t demonstration
o f an a s s o c i a t i o n between t h e H-2 m a j o r histocompatib i l i t y l o c u s and a disease; b ) an understanding o f
i n t e r a c t i o n s o f t h e H-2 complex w i t h o t h e r genes i n
c o n t r o l o f pathogenesis; c ) t h e e x i s t e n c e o f h o s t genes
which can be expressed as an i n f e c t i o u s v i r u s (45-47),
which a r e discussed below.
Early studies with the
v i r u s i s o l a t e d by Gross from AKR mice i n d i c a t e d r e s t r i c t e d h o s t range f o r lymphoma i n d u c t i o n , as c e r t a i n
mouse s t r a i n s were q u i t e s u s c e p t i b l e and o t h e r s res i s t a n t . The p o s s i b i l i t y t h a t c o n t r o l o f these suscept i b i l i t y p a t t e r n s may e x i s t a t t h e major histocompatib i l i t y locus, H-2, on mouse chromosome 17, was r a i s e d
by r e c o g n i t i o n t h a t t h e mouse s t r a i n s most s u s c e p t i b l e
t o Gross v i r u s induced lymphoma, C57BR and C3H/Bi, as
w e l l as those w i t h h i g h l e v e l s o f sFontaneous lymphoma,
AKR and C58, a r e a l l o f t h e H-2 haplotype. k L i l l y
found t h e F h y b r i d s R f s u s c e p t i b l e C3H/Bi, H-2 , and
r e s i s t a n t C5$B1/6, H-2 , mice, showed a very low i n c i dence o f Gross v i r u s lymphoma (75).
and backcross
h y b r i d s which were homozygous H-2 /=
showed g r e a t e r
b
-
8
P
'
22
&
I
I
80
70
60
50
40
\
lu 30
b
fi
20
$
10
8
40
60
80 100 120 140 160 180 200
LATENT PERIOD ( daqs )
40
6 0 80 100 120 140 160 I80 200
LATENT PERIOD ( doys )
Figure 3. Incidences o f leukemia induced by Gross virus i n populations o f mice segregating for H-2. Backcross and F generations
from crosses between C3Hf/Bi (susceptible) and C57B1/6 (resistant). Red c e l l s typed for H-2 by hemagglutination. ($1 C3H backcross generation. ( b ) F2 generation ( 6 3 ) .
PI NCUS
852
thas 90% lymphoma inci$ence,,,
w h i l e hetrozygous MK/
o r homozygous H-2 /= h y b r i d s were r e l a t i v e l y
r e s i s t a n t t o 1 y m p h o m Z F i g u r e 3 ) . These r e s u l t s i n d i cated t h a t host range r e s i s t a n c e t o Gross v i r u s i s cont r o l l e d a t an autosomal dominant gene l i n k e d t o H-2,
which was termed Rgv-l ( R e s i s t a n t t o Gross v i r u s ) (64).
The mechanisms o f H-2 associated e f f e c t s on lymphoma remain i n c o m p l e t e l y understood.
H-2 i n f l u e n c e s
l a t e r events i n t h e disease process, subsequent t o
i n i t i a l v i r u s i n f e c t i o n . The H-2 complex i s composed o f
m u l t i p l e genetic l o c i bracketed by two ends, known as K
and 0, w i t h i n which i s t h e I region, a t which i s found
c o n t r o l of immune responses ( 6 5 ) .
I n i t i a l mapping o f
Rgv-l w i t h i n t h e H-2 complex was compatible w i t h t h e
p o s s i b i l i t y t h a t Rgv-l was i n t h e I r e g i o n and m i g h t
a c t as an immune response gene.
However, e f f e c t s on
lymphoma mediated by genes i n t h e D r e g i o n have been
described, suggesting p o s s i b l e H-2 mediated c o n t r o l
mechanisms u n r e l a t e d t o immune f u n c t i o n (66).
Recent
s t u d i e s i n d i c a t e v a r i a t i o n o f v i r u s expression i n
lymphoma c e l l l i n e s according t o H-2 haplotype (67),
r a i s i n g t h e p o s s i b i l i t y t h a t H-2 associated genes may
i n f l u e n c e d i r e c t l y t h e expression and r e p l i c a t i o n o f
i n f e c t i o u s r e t r o v i r u s , and t h a t several H-2 mediated
e f f e c t s may be present i n lymphoma ( F i g u r e 4).
A second mouse genetic locus, u n l i n k e d t o H-2,
c o n t r o l s t h e i n i t i a l i n f e c t i o n o f mouse c e l l s by endogenous e c o t r o p i c r e t r o v i r u s e s . T h i s gene, c a l l e d
was recognized i n a n a l y s i s o f t h e c e l l u l a r b a s i s o f
r e s i s t a n c e t o N-ecotropic and B-ecotropic v i r u s e s (68),
and maps t o chromosome 4 (81). A l l mouse s t r a i n s show
one o f two r e c i p r o c a l p a t t e r n s , s i m i l a r t o e i t h e r N I H
o r BALB/c, w i t h r e l a t i v e r e s i s t a n c e t o e i t h e r B-ecotrop i c o r N-ecotropic viruses, r e s p e c t i v e l y . Studies o f
F and backcross embryo c u l t u r e s i n d i c a t e d t h a t these
p a t t e r n s a r e c o n t r o l l e d by a s i n g l e autosomal g e n e t i c
locus, w i t h dominance f o r r e l a t i v e r e s i s t a n c e (68).
The mechanism o f a c t i o n a t %
does n o t i n v o l v e a
membrane/receptor phenomenon, as v i r u s p a r t i c l e s w i t h
N- and 6 - e c o t r o p i c envelopes and a c o r e c o n t a i n i n g a
c y t o p a t h i c v e s i c u l a r s t o m a t i t i s v i r u s genome (such
p a r t i c l e s a r e c a l l e d pseudotypes) i n f e c t c e l l s o f both
types e q u a l l y e f f e c t i v e l y .
r e s i s t a n c e can be
overcome a t h i g h i n f e c t i o n m u l t i p l i c i t y , and once
i n f e c t i o n i s established, v i r u s y i e l d from s e n s i t i v e
and r e s i s t a n t c e l l s i s s i m i l a r (47).
The i n i t i a l
reverse t r a n s c r i p t a s e products a f t e r i n f e c t i o n , termed
p r o v i r a l DNA, a r e synthesized i n s i m i l a r q u a n t i t i e s i n
both Fv-1 s e n s i t i v e and r e s i s t a n t v i r u s c e l l i n t e r action-70).
DNA e x t r a c t e d from c e l l s i n f e c t e d w i t h
e i t h e r N- o r B-ecotropic v i r u s e s can t r a n s f e c t ( i n f e c t i o n by p u r i f i e d DNA) c e l l s o f e i t h e r J
@
type w i t h
equal e f f i c i e n c y (71).
The most l i k e l y mechanism o f
r e s i s t a n c e appears t o i n v o l v e a r e s t r i c t i o n o f
p r o v i r a l DNA i n t e g r a t i o n i n t o c e l l u l a r DNA t o i n t e r r u p t
the v i r u s 1 i f e c y c l e (70).
A t h i r d c l a s s o f h o s t genes, &genes,
constitute
v i r u s i t s e l f expressed in AKR mice and h y b r i d s c o n t a i n i n g a p a r t i a l AKR background (52-84, 72).
F1 hybrids
anfl c a r r i e d N-ecoof t h e AKR s t r a i n , which i f
s t r a i n s , e:g.,
t r o p i c v i r u s , w i t h mice o f o t h e r
C57BR, C57L, N I H Swiss, DBA/2, show a l e v e l o f v i r u s
comparable t o AKR mice a t s i x weeks o f age, i n d i c a t i n g
t h a t expression o f N-ecotropic v i r u s i n AKR h y b r i d s i s
a dominant t r a i t (72). An a s s o c i a t i o n was found i n
c e r t a i n h y b r i d s between i n f e c t i o u s v i r u s and presence
of t h e a l b i n o ( c ) locus, l e a d i n g t o mapping o f one
v i r u s gene on chromosome 7 (53,72).
H-2
x,
FV-l
FV-l
I
t
1
K
A
B
J
E
C
S
G
D
Tla
.,/-
Rgv-l
I
x .I
A - R o d LV
1
I
I
Rfv-2 7
Rfv-l
MTV
I
7
Rfv-2 ?
Figure 4. The H-2 major histocompatibility complex, illustrating regions within the complex for which genetic
control o f retrovirus infection or associated leukemia has
been demonstrated (47).
fv-l
The &,
and Rgv-l l o c i a r e r e l e v a n t t o
spontaneous lymphoma.
The
genes a r e copies o f
endogenous e c o t r o p i c r e t r o v i r u s , expression o f which i s
p r e r e q u i s i t e t o appearance o f h i g h t i t e r s o f recomb i n a n t v i r u s and h i g h l e v e l s o f spontaneous lymphoma.
i s apparent from r e t r o C o n t r o l o f lymphoma a t
s p e c t i v e a n a l y s i s o f h o s t range s u s c e p t i b i l i t y p a t t e r n s
described i n t h e l i t e r a t u r e w i t h respect t o e a r l y
lymphoma v i r u s i s o l a t e s . The e c o t r o p i c v i r u s o f Gross
and B-ecotropic v i r u s e s o f Tennantnand Kaplan b i n d w e
h i g h lymphoma incidences i n
and
type
s t r a i n s , r e s p e c t i v e l y (47). The H-2 l i n k e d Rgv-l gene
was i d e n t i f i e d i n s t u d i e s o f lymphoma induced by Gross
v i r u s ; i t s p r o p e r t i e s have been i d e n t i f i e d o n l y i n v i v o
i n lymphomas and lymphoid c e l l s l i n e s .
Studies o f mouse r e t r o v i r u s e s i l l u s t r a t e t h a t t h e
q u e s t i o n o f whether a disease has a " v i r a l " o r "genet i c " e t i o l o g y may n o t be meaningful i n c e r t a i n i n stances.
Pathogenesis c l e a r l y i n v o l v e s i n t e r a c t i o n s
between h o s t g e n e t i c and h o s t v i r a l components, and t h e
v i r u s i t s e l f i s a h o s t gene. A n a l y s i s o f h o s t g e n e t i c
c o n t r o l mechanisms i n r e t r o v i r u s i n f e c t i o n remains
under e x t e n s i v e i n v e s t i g a t i o n .
Akv
fv-l
FV-l
CHARACTERIZATION OF RETROVIRUSES I N NEW ZEALAND M I C E
The f i n d i n g o f numerous type C p a r t i c l e s i n e a r l y
e l e c t r o n micrographs o f t i s s u e f o r New Zealand Black
(NZB) and t h e F h y b r i d o f NZB w i t h t h e New Zealand
White (NZBxNZW) & i c e (73,74) has l e d t o a search f o r a
p o s s i b l e r o l e f o r a r e t r o v i r u s i n t h e pathogenesis o f
A r e t r o v i r u s associated a n t i g e n
autoimmune disease.
was found t o increase w i t h age i n New Zealand mice,
w i t h production o f antibody t o the v i r a l antigen l a t e r
i n l i f e , c o i n c i d e n t w i t h t h e onset o f immune complex
n e p h r i t i s ( 7 5 ) . V i r a l a n t i g e n s have been i d e n t i f i e d i n
e l u a t e s o f n e p h r i t i c kidneys, although considerable
immunoglobulin e l u a t e r e a c t s w i t h o t h e r antigens, i n c l u d i n g n u c l e a r antigens (76).
Neither r e t r o v i r u s
i n f e c t i o n n o r autoimmune disease have been t r a n s m i t t e d
t o date by i n o c u l a t i o n o f i n f i l t r a t e s o f New Zealand
mice i n t o o t h e r mouse s t r a i n s .
I n i t i a l e f f o r t s t o i s o l a t e a v i r u s from NZB mice
proved n e g a t i v e b u t puzzling, as o t h e r s t r a i n s showing
VIRUSES IN SLE
q u a n t i t i e s of r e t r o v i r u s p a r t i c l e s and v i r a l antigens
i n t h e range of New Zealand mice r e a d i l y y i e l d e d i n f e c t i o u s v i r u s . T h i s problem was c l a r i f i e d w i t h t h e f i n d i n g t h a t i n f e c t i o u s v i r u s c o u l d be recovered from NZB
t i s s u e o n l y i n nonmouse c e l l s (77), i.e., t h a t t h e NZB
r e t r o v i r u s has a x e n o t r o p i c h o s t range (78).
I f the
r e t o r v i r u s i n NZB mice were a pathogenic agent accord i n g t o Koch's postulates. t r a n s m i s s i o n o f disease t o
o t h e r mice would n o t be expected, as t h i s v i r u s cannot
i n f e c t any o t h e r mouse c e l l s . Spontaneous x e n o t r o p i c
v i r u s expression i s found c o n s i s t e n t l y from b i r t h i n
New Zealand s t r a i n s b u t n o t i n o t h e r mouse s t r a i n s ,
though x e n o t r o p i c v i r u s i s i n d u c i b l e from c e l l s o f
non-New Zealand s t r a i n s (79). The i n d u c i b l e and spontaneously expressed x e n o t r o p i c v i r u s e s i n New Zealand
mice can be d i s t i n g u i s h e d , and t h e p o s s i b i l i t y o f
f u r t h e r polymorphism remains open.
NZB mice express
h i g h l e v e l s o f v i r a l gp70, i n a range as h i g h as any
mouse s t r a i n s , though v a r i a t i o n among organs i s seen
(81-83).
The NZB and o t h e r murine autoimmune s t r a i n s
d i f f e r from o t h e r mouse s t r a i n s i n expressing antibody
a c t i v i t y t o gp70 and o t h e r r e t r o v i r u s p r o t e i n s (75,83).
Spontaneous x e n o t r o p i c v i r u s expression i n NZB
mice appears under g e n e t i c c o n t r o l o f two l o c i ,
and
(84).
a l o n e i s associated w i t h h i g h
l e v e l s o f v i r u s expression, w h i l e low t i t e r s a r e found
i n mice w i t h t h e
gene alone. No c o r r e l a t i o n has
been found between i n f e c t i o u s xenotropic v i r u s and
autoimmune n e p h r i t i s i n h y b r i d s o f NZB mice, suggesting
t h e absence o f any causal r e l a t i o n s h i p between i n f e c t i o u s v i r u s and autoimmunity ( 8 5 ) . By c o n t r a s t , l e v e l s
o f immune complexes c o n t a i n i n g r e t r o v i r a l gp70 a r e
c o r r e l a t e d w i t h autoimmune a c t i v i t y (86,87).
Spontaneous x e n o t r o p i c v i r u s expression and autoimmunity
may be common m a n i f e s t a t i o n s o f an u n d e r l y i n g r e g u l a t o r y disorder.
The NZB mouse s t r a i n remains one o f t h e few
s t r a i n s from which e c o t r o p i c v i r u s has never been
i s o l a t e d , even a f t e r exposure t o various i n d u c t i o n a,
gents. C e l l s o f NZB mice have been c l a s s i f i e d as
type, as t h e y show g r e a t e r s e n s i t i v i t y o f N-ecotropic
than t o B-ecotropic v i r u s e s ( 6 8 ) . However, NZB c e l l s
a r e considerably more r e s i s t y t t o N-ecotropic v i r u s e s
than those o f any o t h e r
s t r a i n , and almost absol u t e l y r e s i s t a n t t o B-ecotropic v i r u s e s , u n l i k e o t h e r
s t r a i n s (68). The f i n d i n g t h a t e c o t r o p i c v i r u s cannot
be recovered from NZB mice may r e s u l t from c e l l u l a r
r e s i s t a n c e t o such viruses, b u t more l i k e l y from t h e
f a c t t h a t genes f o r e c o t r o p i c v i r u s a r e n o t p a r t of t h e
genome o f NZB mice (88). The a n a l y s i s o f r e t r o v i r u s e s
i n NZB mice and t h e i r h y b r i d s has n o t l e d t o d e f i n i t i v e
understanding o f any r e l a t i o n t o autoimmunity i n these
s t r a i n s , b u t has c o n t r i b u t e d s i g n i f i c a n t l y t o understanding o f these viruses.
Nzv-2
Nzv-2
SEARCH FOR A UNIQUE HUMAN RETROVIRUS I N SLE
The f i n d i n g o f x e n o t r o p i c v i r u s i n NZB mice and
t h e i r h y b r i d s has l e d t o a search f o r unique r e t r o v i r u s e s i n human SLE, p a r a l l e l i n g a search f o r r e t r o v i ruses i n human leukemias and lymphomas based on t h e AKR
mouse model. E s s e n t i a l l y a l l techniques used t o demons t r a t e d r e t r o v i r u s e s have been used t o d e t e c t a human
r e t r o v i r u s , and t h e presence o f a unique human r e t r o v i r u s has been suggested on t h e b a s i s o f some p o s i t i v e
r e s u l t s w i t h each technique (89,90).
However, a l l
these f i n d i n g s can be explained on t h e b a s i s o f a l t e r n a t i v e i n t e r p r e t a t i o n s , and t h e e x i s t e n c e o f a unique
human r e t r o v i r u s must be considered unproven a t t h i s
point.
853
An example o f t h e c o m p l e x i t y i n i n t e r p r e t a t i o n o f
data r e g a r d i n g a p o s s i b l e human r e t r o v i r u s can be found
i n experiments i n d i c a t i n g s e r o l o g i c a l r e a c t i v i t i e s o f
human immunoglobulins w i t h whole v i r u s and p u r i f i e d
gp70 p r e p a r a t i o n s from several mammalian r e t r o v i r u s e s
(91).
These s t u d i e s had been suggested by t h e observ a t i o n t h a t normal mouse sera showed such apparent
n a t u r a l a n t i b o d y r e a c t i v i t y w i t h endogenoh mouse
r e t r o v i r u s e s and v i r a l p r o t e i n s (91,92).
I n view o f
h i g h a n t i b o d y t i t e r s i n SLE t o most v i r u s e s (15-22), i t
appeared reasonable t o study SLE i n a serach f o r s i m i l a r a n t i b o d i e s as a p o s s i b l e marker o f r e t r o v i r u s
i n f e c t i o n i n humans. Sera o f SLE p a t i e n t s d i d p r e c i p i t a t e p r e p a r a t i o n s o f p u r i f i e d whole v i r u s and d i s r u p t e d
v i r u s as w e l l as v i r a l gp70 p r e p a r a t i o n s under c e r t a i n
c o n d i t i o n s , b u t normal sera showed comparable react i v i t i e s (93, 94).
Normal human sera showed immunop r e c i p i t a t i o n r e a c t i v i t i e s s i m i l a r t o SLE sera, a
f i n d i n g which nonetheless c o u l d be i n t e r p r e t e d as
evidence o f n a t u r a l l y o c c u r r i n g human exposure t o
endogenous, unique human r e t r o v i r u s e s .
However, r e a c t i v i t i e s o f human sera w i t h v i r u s and
v i r a l p r o t e i n s were seen o n l y i n c e r t a i n l a b o r a t o r i e s
(93,94) and n o t o t h e r s (95,96), and i n t e r p r e t a t i o n o f
t h e r e s u l t s was unclear.
F u r t h e r s t u d i e s o f these
human s e r o l o g i c a l r e a c t i v i t i e s i n d i c a t e d t h a t : a ) t h e
r e a c t i v i t i e s c o u l d be p a r t i a l l y absorbed w i t h f e t a l
c a l f serum p r o t e i n s , which a r e absorbed onto v i r u s e s
and remain even through v i r u s p u r i f i c a t i o n (97); b )
r e a c t i v i t i e s w i t h p u r i f i e d gp70 a r e n o t seen i f bovine
serum albumin i s added t o t h e r e a c t i o n b u f f e r , presumably r e f l e c t i n g a cross r e a c t i n g serum r e a c t i o n t o a
contaminant found i n bovine serum albumin p r e p a r a t i o n s
(98); c ) human sera b i n d g l y c o p r o t e i n p u r i f i e d from
r e t r o v i r u s grown i n nonprimate c e l l s o n l y and show no
b i n d i n g t o v i r u s grown i n p r i m a t e c e l l s (98); d ) react i v i t i e s w i t h v i r a l gp70 c o u l d be absorbed w i t h c e r t a i n
normal animal c e l l s from a v a r i e t y o f sources; e ) human
s e r a a r e n o t r e a c t i v e w i t h gp70 which has been deglycosylated, i n c o n t r a s t i n hyperimmune goat a n t i - g p 7 0
sera, which c o n t i n u e t o b i n d d e g l y c o s y l a t e d r e t r o v i r a l
g l y c o p r o t e i n s (98-100).
These data i n d i c a t e t h a t a
human serum immunoglobulin recognizes r e t r o v i r a l g l y c o p r o t e i n s , b u t o n l y g l y c o p r o t e i n determinants which a r e
d e r i v e d from c e l l s r a t h e r than from t h e r e t r o v i r u s .
The d i f f i c u l t y of i n t e r p r e t i n g d a t a from t h e r e t r o v i r u s
l i t e r a t u r e , p a r t i c u l a r l y i n r e l a t i o n t o a unique human
Table 5.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Type C v i r u s e s :
P r i n c i p l e s p e r t i n e n t t o disease
-
V i r u s i n h o s t c e l l genome
g e n e r a l l y n o t expressed
Host c o n t r o l of v i r u s e x p r e s s i o n and i n f e c t i o n
Incomplete e x p r e s s i o n o f v i r u s genome w i t h o u t i n f e c tion virus
Prolonged l a t e n t p e r i o d w i t h v i r u s e x p r e s s i o n p r i o r t o
disease
I n f e c t i o u s v i r u s w i t h o u t apparent d i s e a s e
S i m i l a r v i r a l s e r o l o g y w i t h and w i t h o u t disease
S t r u c t u r a l polymorphism o f endogenous v i r u s e s
Most endogenous v i r u s e s a r e x e n o t r o p i c i n h o s t range
Organ s p e c i f i c v i r u s e x p r e s s i o n o f recombinant v i r u s
i n thymic lymphoma
I n d u c t i o n o f v i r u s frm c e l l s o f normal mice by chemic a l s , i n c l u d i n g B c e l l mitogens
Ovum borne d i s e a s e t r a n s m i s s i o n
H-2 l i n k e d g e n e t i c c o n t r o l o f d i s e a s e
Non-H-2 l i n k e d g e n e t i c c o n t r o l o f d i s e a s e
Polygenic c o n t r o l o f disease
PINCUS
i s o l a t e , i s a p p a r e n t . S t u d i e s o f r e t r o v i r u s e s s h o u l d be
v i e w e d a s p r o v i d i n g many d i s c o v e r i e s o f i m p o r t a n t
b i o l o g i c a l p r i n c i p l e s ( T a b l e 5),
but w i t h o u t d i r e c t
a p p l i c a t i o n s a t t h i s point t o t h e understanding o f
human d i s e a s e .
18.
19.
CONCLUSION
The s e a r c h f o r a v i r u s a s s o c i a t i o n w i t h SLE h a s
n o t provided evidence f o r a s p e c i f i c pathogenetic
agent.
R e c o g n i t i o n o f complex t y p e s o f v i r u s i n f e c t i o n s and the i m p o r t a n c e o f the h o s t i n v i r a l infect i o u s p r o c e s s e s has y i e l d e d i n s t r u c t i v e b i o l o g i c a l
p r i n c i p l e s f o r t h e study o f a p o s s i b l e v i r a l function
i n SLE. The type C r e t r o v i r u s e s p r o v i d e a p a r t i c u l a r l y
i n s t r u c t i v e model o f complex v i r u s h o s t i n t e r a c t i o n s ,
t h o u g h a s p e c i f i c e t i o l o g i c f u n c t i o n i n human o r mouse
SLE r e m a i n s unproven.
F u r t h e r b a s i c research appears
t o be t h e most l i k e l y p o t e n t i a l s o u r c e o f u n d e r s t a n d i n g
a p o s s i b l e v i r a l f u n c t i o n i n t h e p a t h o g e n e s i s o f SLE.
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