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B i omed i c a lSc i ence

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J Biom ed Sci 1997;4:1-8 Receive d: June 25, 1996Accepted: October 16, 1996

Department o f Life Sciencesan dChem istry, RoskildeUniversityRoskilde, Denm ark

Interactions between Exogenousand Endo genous Retroviruses

ow, ei~ololoo*~i~*Iiooo~**oa*oeQoo*o*l,oe~eJo~oK e y W o r d sRe t r o v i r u s e sE x o g e n o u sE n d o g e n o u sI n t e r a c t i o n s

,*e ,*l ,oo eo, ~oe e*o *t Iol otl **o o** sol ol o * eoooomo*,m *e eeeooloJ* t ~a*t eg,,* *,o* ol* og ooze o* ~O.I**O~*OQ*A b s t r a c tRe t r o v i r u s e s a r e d i s t i n g u i s h e d f r o m o t h e r v i r u s e s b y s e v e r a l f e a tu r e s . N o t a b l y ,s o m e r e t ro v i r u se s a r e p r e s e n t a s n o r m a l e l e m e n t s i n t h e g e n o m e s o f v i r tu a l lya l l v e r t e b r a t e s ( e n d o g e n o u s p r o v i r u s e s ) . O t h e r s a r e e x o g e n o u s , i .e . h o r i z o n -t a l ly t r a n s m i t t e d a g e n t s , ma n y o f w h i c h c a u s e f a t a l d is e a se s . T h e e n d o g e n o u sr e t r o v i r u s e s a r e g e n e t ic a l l y t r a n s m i t t e d a n d t o a l a r g e e x t e n t t h e i r s i g n i f ic a n c ei s u n c e r t a i n . H o w e v e r , t h e r e i s e v i d e n c e s u g g e st in g t h a t t h e y c o n t r i b u t e t o t h ed e v e l o p me n t o f d i s e a s e s i n s e v e r a l a n i ma l s p e c i e s . Mo s t i mp o r t a n t l y , s o mee n d o g e n o u s r e t r o v i r u s e s a r e c a p a b l e o f i n t e r a c t i n g w i t h e x o g e n o u s c o u n t e r -p a r t s t h r o u g h a v a r i e t y o f d i f f e r e n t m e c h a n i s m s w i t h s e r io u s c o n s e q u e n c e s tot h e h o s t . Co n v e r s e l y , o t h e r s a r e a d v a n t a g e o u s i n t h a t t h e y p r o t e c t a g a i n s te x o g e n o u s r e t r o v i r u s e s. I n t h i s r e v i e w v a r i o u s t y p e s o f in t e r a c t i o n s b e t w e e ne n d o g e n o u s a n d e x o g e n o u s r e t r o v i r u s e s a r e d i s c u s s e d , i n c l u d i n g r e c e p t o ri n t e rf e r e n c e , r e c o m b i n a t i o n , p h e n o t y p i c m i x in g , i m m u n o l o g i c a l i n te r a c t io n sa n d h e t e r o lo g o u s trans-activation.

Re t r o v i r u s e s a r e s i n g l e - s t r a n d e d RN A v i r u s e s w i t h aD N A i n t e r m e d i a t e f o r m . D u r i n g i n f e ct io n s w i t h r e tr o v i-r u s e s t h e i r g e n o m e s a r e i n c o r p o r a t e d i n t o t h e c h r o m o -s o me s o f t h e i n f e c t e d c e ll s. I f i n t e g r a t i o n t a k e s p l a c e i ng e r m l i n e c e ll s ( o o c y te s ) o r e a r l y e mb r y o s , t h e r e t r o v i r a lg e n e s a r e ' e n d o g e n i z e d ' , i . e . t h e y h a v e b e c o me a p a r t o ft h e h o s t g e n o m e [ f o r m o r e c o m p r e h e n s i v e i n f o r m a t i o n o nendogenous re t rov i ruses , s ee fo r example 12 , 77 , 87 ] .M o s t l i k e ly , e n d o g e n o u s r e t r o v i r u s e s i n t h i s w a y a r e t h ef o o t p r i n t s o f a n c i e n t r e t r o v i r a l i n f e c ti o n s . A l t e r n a t iv e l y ,e n d o g e n o u s a s w e l l a s e x o g e n o u s r e t r o v i r u s e s d e r i v e f r o ma c o m m o n g e n o m i c a n c e s t o r [ 1 7, 1 9 ].

T h e g e n o me s o f r e t r o v i r u s e s c o n t a i n a r e g u l a t o r y r e -g i o n in b o t h e n d s , i .e . t h e u p s t r e a m a n d d o w n s t r e a m l o n gt e r m i n a l r e p e a t s (L T Rs ) . I n b e t w e e n t h e L T Rs t h e r e a r e a tl e a s t t h r e e ma j o r g e n e s , d e s i g n a t e d gag, pol, a n d env,

e n c o d i n g f o r i n t e r n a l s t r u c t u r a l p r o t e i n s , r e v e r s e t r a n s -c r i p t a s e a n d e n v e l o p e p r o t e i n s , r e s p e c t i v e l y [1 I ] . So m er e t r o v i r u s e s , s u c h a s t h e h u ma n T c e l l l e u k e mi a v i r u s e s( H T L V s ) , a r e m o r e c o m p l e x i n t h e i r c o m p o s i t i o n a ll o w -i n g f o r t h e p r o d u c t i o n o f a d d i t i o n a l p r o t e i n s [ 1 4] .

E n d o g e n o u s r e t r o v i r u s e s a r e i n h e r i t e d i n a c l a s s i c a lM e n d e l i a n f a s h i o n . T h e y a r e p r e s e n t i n v i r t u a l ly a ll v e r t e -b r a t e s a n d r e t r o v i r a l - l i k e e l e me n t s h a v e e v e n b e e n d e -t e c t e d i n l o w e r a n i ma l s s u c h a s Drosophila [20]. Althouglam o s t e n d o g e n o u s r e tr o v i ru s e s p r o b a b ly h a v e b e e n n o r m a lg e n o mi c c o n s t i t u e n t s f o r m i l l io n s o f y e a r s , t h e a c q u i s i t i o no f n e w e n d o g e n o u s r e t r o v i r a l s e q u e n c e s is a n o n g o i n gp h e n o m e n o n a s s ug g e st e d b y o b s e r v a t io n s o f d e n o v oi n t e g r a t i o n i n g e r m l i n e c el ls o f m i c e [ 5 2 , 7 9 ]. M o s t e n d o g -e n o u s r e t r o v i r u s e s c o n t a i n s t o p c o d o n s i n t h e r e a d i n gf r a m e s o r th e y a r e t r u n c a t e d , p r e c l u d i n g t h e i r e x p r e s s io n

K A R G ERE-Mail karger@karger.chFax +41 61 306 12 34http://www.karger,ch

1997 National Science Council, ROCS. Karger AG, Basel1021-7770/97/0041-0001 $12.00/0

H.B. RasmussenDepartment of Life Sciences and Chemistry, Roskilde UniversityP.O. Box 260, DK-4 000 Roskilde (Denmark)Tel. +45 46 75 77 11, Fax +45 46 75 77 21E-Mail hbr@virgil.ruc.dk

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a s v ir a l p a r ti c l e s . H o w e v e r , s e v e r a l a n i m a l s p e c i e s s u c h a sc h i c k e n s [ 1 2] , m i c e [ 1 2] a n d b a b o o n s [ 81 ] h a r b o r e n d o g e -n o u s r e t ro v i r u s e s w h i c h c a n p r o d u c e i n f e c ti o u s p a r ti c le s .

T o a l a r g e e x t e n t , t h e p o s s i b l e s i g n i f i c a n c e o f e n d o g e -n o u s r e t r o v ir u s e s i n t h e d e v e l o p m e n t o f d i se a s e s i s o b -s c u r e b u t t h e r e i s i n c r e a s i n g e v i d e n c e t h a t t h e y a r e c a p a -b l e o f i n d u c i n g d i s e a s e s o r m o d i f y i n g d i s e a s e c o u r s e s [ 4 3 ,6 7 , 7 7] . M o s t i m p o r t a n t l y , t h e y c a n i n t e r a c t w i t h e x o g e -n o u s c o u n t e r p a r t s t h r o u g h a n u m b e r o f d if f e r e n t m e c h a -n i s m s . I n t h e f o l lo w i n g , t h e n a t u r e o f t h e s e i n t e r a c t i o n sa n d t h e i r c o n s e q u e n c e s a r e d i s c u s se d . T h e a i m o f t h i sr e v i e w i s t o f o c u s a t t e n t i o n u p o n e n d o g e n o u s r e t ro v i r u s e sa s f a c to r s p l a y i n g d e c is i v e r ol e s i n t h e d e v e l o p m e n t a n do u t c o m e o f i n fe c t i o n s w i t h e x o g e n o u s r e tr o v i r u s e s a n d i fp o s s i b l e i n d i c a t e n e w l i n e s o f r e s e a r c h w i t h i n t h e f i e l d o fh u m a n r e t ro v i r a l d i se a s es .

Re c e pt or In t e r f e r e nc e a nd H os t Re s is ta nc eFactorsR e c e p t o r i n t e r f e r e n c e r e f e r s t o t h e i n a b i l i t y o f a v i r u s

t o i n f e c t c e l ls w h i c h a l r e a d y a r e i n f e c t e d b y a v i r u s w i t ht h e s a m e s p e c i f i c i t y o f t h e o u t e r s u r f a c e e n v e l o p e g l y co -p r o t e i n [ 86 ] . O f n o t e , e n d o g e n o u s p r o v i r u s e s a r e a b l e t op r o t e c t a g a i n s t i n f e c t i o n s w i t h e x o g e n o u s r e t r o v i r u s e sc a r r y i n g r e l a t e d o r id e n t i c a l e n v e l o p e g l y c o p r o t e i n s . F i n d -i n g s t h a t p r e i n c u b a t i o n o f c e l l s w i t h v i r a l g l y c o p r o t e i n si m p e d e s o r b l o c k s i n f e c t i o n b y a v i r u s w i t h a c o r r e s p o n d -i n g g l y c o p r o t e i n s u g g e s t t h a t c o m p e t i t i o n f o r r e c e p t o r s i si n v o l v e d i n r e c e p t o r i n t e r f e r e n c e [ 8 6 ] . H o w e v e r , t h i s i sn o t t h e o n l y m e c h a n i s m o f im p o r t a n c e . T h u s , a n a v i a nr e t r o v ir u s s e e m s t o p r e v e n t s u p e r i n f e c t i o n w i t h r e la t e dv i r u s e s t h r o u g h b i n d i n g o f i t s g l y c o p r o t e i n s t o t h e c o r r e -s p o n d i n g r e c e p t o r s i n t h e e n d o p t a s m i c r e t i c u l u m [ 1 5 ] .T h i s i n t e rf e r e s w i t h t h e n o r m a l t r a n s lo c a t i o n o f t h e r e c e p -t o r s r e s u l t i n g i n t h e i r a b s e n c e o n t h e s u r f a c e s o f i n f e c t e dce l l s .

I n h e r i t e d r e s i s t a n c e t o r e t r o v i r a l i n f e c t i o n s , a s s o c i a t e dw i t h r e c e p t o r - i n t e r f e r i n g e n d o g e n o u s r e t r o v i r u s e s , h a sb e e n r e p o r t e d i n m i c e [ 6 - 8 , 2 1 , 2 2 ] a n d c a t s [ 5 8 ] . A l s oc h i c k e n s h a r b o r e n d o g e n o u s r e t r o v i ru s e s i n v o l v e d i n re -c e p t o r i n t e r f e r e n c e [ 6 5, 6 9 , 7 5 ]. M o s t l i k e ly , t h e p r i m a r yf u n c t i o n o f th e s e a v i a n e n d o g e n o u s r e t r o v i ru s e s i s t o p r e-v e n t r e i n t e g r a t io n o f r e p l ic a t i o n - c o m p e t e n t e n d o g e n o u sr e t r o v i r u s e s i n t o t h e h o s t c h r o m o s o m e s [6 9 , 7 5 ].

I n m i c e e n d o g e n o u s r e t r o v ir u s e s w h i c h c o n f e r p r o t e c -t i o n a g a i n s t t h e e c o t r o p i c a n d t h e p o l y t r o p i c c l a s s e s o fm u r i n e l e u k e m i a v i r u s e s ( M u L V s ) , r e s p e c t i v e l y , h a v eb e e n d e t e c t e d . T h e e c o t r o p i c c la s s o f M u L V s i s c h a r a c te r -

i z e d b y a n i n a b i l i t y t o r e p l i c a t e i n c e ll s f r o m o t h e r a n i m a ls p e c i e s t h a n m o u s e w h i l e t h e p o l y t r o p i c M u L V s , a l s ok n o w n a s M C F M u L V s ( m i n k c e l l f o c u s - f o r m i n gM u L V s ) , a r e r e c o m b i n a n t v i r u s e s w i t h a b r o a d e r h o s t c e l lr a n g e [ 4 2 ].

T h e F v - 4 g e n e , d e t e c t e d i n p o p u l a t i o n s o f w i l d m i c e ,c o n t r o l s t h e s u s c e p t i b i l i t y t o i n f e c t i o n s w i t h e c o t r o p i cM u L V s [ 2 1 , 22 ]. T h e d o m i n a n t r e s i st a n c e a ll e le a t t h e F v -4 l o c u s is a t r u n c a t e d e n d o g e n o u s r e t r o v ir u s w h i c h e n -c o d e s f o r a g l y c o p r o t e i n c l o s e l y r e l a t e d t o e c o t r o p i cM u L V g p 7 0 [ 3 5] . T h i s g l y c o p r o t e i n s e e m s t o b e t h e p r o -t e c t i v e f a c t o r a c t i n g b y r e c e p t o r i n t e r f e r e n c e a s s u g g e s t e db y o b s e r v a t i o n s w i t h m i c e t r a n s g e n i c f o r t h e F v - 4 e n v g e n e[501.

A n o t h e r g e n e i n m i c e, n a m e l y R r n c f h a s b e e n a s s o c i a t-e d w i t h a r e s t r i c t i o n i n t h e r e p l i c a t i o n o f t h e p o l y t r o p i cM u L V s [ 6 - 8 ] . T h e R m c f r e s i s t a n c e a l l e l e i s p r e s u m a b l ya l so a n e n d o g e n o u s r e t r o v i r u s e n c o d i n g f o r a g l y c o p r o t e inw h i c h c o n f e r s p r o t e c t i o n b y c o m p e t i t i o n f o r r e t r o v i r a lr e c e p t o r s [ 6 , 7 ] . A l t e r n a t i v e l y , i t i s a n o n r e t r o v i r a l g e n er e g u l at i n g th e t r a n s c r i p t io n o f a p r o t e c t i n g e n d o g e n o u sr e t r o v i r u s [ 8 ] .

T h e d e g r e e o f r e s is t a n c e a g a i n s t a r e t r o v i r a l i n f e c t i o nc o n f e r r e d b y r e c e p t o r i n t e r f e re n c e s e e m s t o b e c o r r e la t e dw i t h t h e l e v e l o f e x p r e s s io n o f t h e p r o t e c t i n g e n d o g e n o u sr e t r o v i r a l g e n e [4 i , 5 0 ] . C o n s e q u e n t l y , i n f o r m a t i o n a b o u tt h e t r a n s c r i p t i o n a l r e g u l a ti o n o f t h e s e g e n e s w o u l d b ev a l u a b l e t o h a v e . O f i m p o r t a n c e , t h e r e i s n o u p s t r e a mL T R a s s o c i a t e d w i t h t h e F v - 4 r e s i s t a n c e a l l e le , i m p l y i n gt h a t i t s t r a n s c r i p t i o n i s d e t e r m i n e d b y n o n r e t r o v i r a l cis-a c t i n g s e q u e n c e s [ 3 5 ]. T h i s a l s o s e e m s t o b e t h e c a s e w i t ha n a v i a n e n d o g e n o u s r e t r o v ir u s a c t i n g b y r e c e p t o r in t e r -f e r e n ce [ 1 2 ].

P e r h a p s p r o t e c t i o n b a s e d u p o n r e c e p t o r -i n t e rf e r i n g en -d o g e n o u s e n v g e n e p r o d u c t s r e p r e s e n t s a n a n t i r e tr o v i r a ld e f e n s e m e c h a n i s m u t i li z e d b y a w i d e v a r i e ty o f d i ff e r e n tv e r t e b r a t e s p e c i e s . P r e v i o u s o b s e r v a t i o n s h a v e s u g g e s t e dt h a t t h e h u m a n g e n o m e c o n t a in s a v a r i e ty o f se q u e n c e sr e la t e d w i t h t h e h u m a n i m m u n o d e f i c i e n c y vi ru s t y p e 1( H I V - 1 ) rev a n d e n v g e n e s [ 3 1 ] . H o w e v e r , t h e s e q u e n c e sc h a r a c t e r i z e d t h u s f a r d o n o t s e e m t o b e p a r t o f e n d o g e -n o u s p r o v i r u s e s ; i n s t e a d t h e y m o s t l i k e l y r e p r e s e n t t h ee x o n s o f h i th e r t o u n k n o w n g e n e s . T h e p o s s i b i li t y t h a tt h e s e H I V - r e l a t e d e n d o g e n o u s s e q u e n c e s ar e i n v o l v e d i nr e c e p t o r i n t e r f e r e n c e i s u n l i k e l y s i n c e t h e i r r e l a t i o n s h i pw i t h t h e r e g i o n o f th e H I V g e n o m e , e n c o d i n g t h e s u r fa c eg l y c o p r o t e i n , i s l i m i t e d .

W h e t h e r r e c e p t o r i n t e r f e re n c e c a n b e u t i l i z e d a s a n e wc o n c e p t i n t h e t r e a t m e n t o f re t r o v i r a l d i s e a s e s is a n i n t e r-e s t i n g q u e s t i o n . S o f a r , o b s e r v a t i o n s w i t h m i c e o f f e r t h e r -

2 J B i o me d Sc i 1 9 97 ;4 :1 -8 R a sm u s se n

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a r e c o m b i n a t i o n a l r e p a i r p r o b a b ly d e p e n d s u p o n t h e d e -g ree o f r e l a t i ons h i p be t ween t he r e t rov i r a l s equences i nques t i on .

R e t r o v i r a l r e c o m b i n a t i o n is a l so a p h e n o m e n o n o f r e l-evance i n o t he r con t ex t s . R egard i ng gene t he rapy wi t hre t rov i r a l vec t o r s , one o f t he m a j o r s a fe t y a s pec t s con -c e r n s t h e r i sk o f f o r m a t i o n o f r e p l i c a t i o n - c o m p e t e n t v i-r u s e s b y r e c o m b i n a t i o n a l e v e n t s b e t w e e n t h e v e c t o r a n dthe helper v i rus [ for rev iew, see 13 , 30] . However , a l soendo gen ous r e t rov i ru s es o f t he pack ag i ng ce l l l i ne a re o fi m p o r t a n c e a s p o s s i b le p a r t i c i p a n t s i n r e c o m b i n a t i o n a le v e n t s [ 30 ]. F u r t h e r m o r e , r e c o m b i n a t i o n s b e tw e e n c o n -t a m i n a t i n g r e p l i c a ti o n - c o m p e t e n t v ir u s e s in t h e v e c t o rp r e p a r a t i o n a n d e n d o g e n o u s re t r o v ir u s e s o f th e r e c i p ie n ta re a pos s i b i l it y [16 ]. A no t h e r s a fe t y a s pec t, a l t hough o fm i n o r i m p o r t a n c e , c o n c e r n s t h e p o s s i b il it y o f r e c o m b i n a -t i on be t w een en doge nous r e t rov i ru s es o f t he t a rge t ce ll sand t he vec t o r [13 ].

A l a c k i n h u m a n o r g a n s f o r t r a n s p la n t a t i o n s h a s f o-cus ed i n t e res t upon t he pos s i b i l i t y o f u s i ng xenog ra f t sf r o m p r i m a t e s a n d p i g s . H o w e v e r , x e n o t r a n s p l a n t a t i o ni n v o l v e s i n t r o d u c t i o n o f ' f o r e i g n ' e n d o g e n o u s r e t r o v i -ru s es i n t o a new hos t . Th i s en t a i l s a r is k o f r ecom bi na t i onb e t w e e n t h e s e r e tr o v i r u se s a n d t h e ' n a t iv e ' e n d o g e n o u sre t rov i ru s es o f t he r ec i p i en t [74 ]. O f no t e , s eve ra l an i m a ls pec i es, i nc l ud i ng baboo ns a nd t he i r c l o s e r e l a ti ves , ca r rye n d o g e n o u s r e t ro v i r u se s w h i c h h a v e t h e p o t e n t ia l o f b e in gexpre ssed as par t i c les [81 ] , i .e . a pre requ is i t e for reco mb i -n a t i o n s t o t a k e p l a c e.

A w i d e s p e c t r u m o f e n d o g e n o u s re t r o vi r u se s a r e t r a n -s c r i p t iona l l y ac t i ve. F o r exam pl e , seve ra l hu m an endoge-nous r e t rov i ru s es a re t r an s c r i bed i n pe r i phe ra l b l oodm on on uc lea r cell s [44 , 68] as wel l as bra in t i s sue [68] .Obv i ous l y , t he exp res s i on o f a va r i e t y o f d i f f e ren t endoge-nous r e t rov i r a l t r an s c r i p t s p rov i des a r i ch and d i ve r s es o u r c e f o r r e c o m b i n a t i o n a l e x c h a n g e o f g e n e t ic i n f o r m a -t i on w i t h exogeno us r e trov i ru s es .

t w e e n t h e e n v e l o p e g l y c o p r ot e in s o f t h e i n v a d i n g v i r u sand t he co r re s pond i ng ce ll s u r face r ecep t o rs . C ons eq uen t -l y , t he fo rm a t i on o f v i r a l pa r t i c l e s con t a i n i ng enve l opeg l y c o p r o t e i n s e n c o d e d b y a n o t h e r v i r u s m a y p r o v i d et hes e pa r t i c le s w i t h a nov e l hos t ce l l t rop i s m .

P h e n o t y p i c m i x i n g b e t w e e n d i s ta n t ly r e l at e d r e t r o v i-ru s es i s u s ua l l y con f i ned t o e nve l o pe g l ycop ro t e i n s [51 ].T h e r e a r e s e v e r al o b s e r v a t i o n s o f p h e n o t y p i c m i x i n g b e-t w e e n e n d o g e n o u s a n d e x o g e n o u s re t ro v i ru s e s . F o r e x a m -p l e , HIV i s capab l e o f u t i li z i ng s u r f ace g l ycop ro t e in s f rome n d o g e n o u s M u L V s r e s u lt i n g in t h e a p p e a r a n c e o f p s e u -do t ypes w i t h a no ve l hos t ce ll range , i nc l ud i ng C D 4- ce ll sand var ious an imal cel l s [9 , 47 , 55 , 76] . There i s a l so anacce l e ra t ed r ep l i ca t i on o f HIV i n C D4+ ce l l s co i n fec t edwi t h M uLV s , pe rhap s r e f lec t i ng a m o re e f f i c ien t ad s o rp -t i on o f HIV ps eu do t yp es t o t he t a rge t ce ll s [9, 55 , 76 ] .O b v i o u s ly , t h e p o t e n t i a l o f h u m a n e x o g e n o u s r e t ro v i r u se st o f o r m p s e u d o t y p e s w i t h e n v e l o p e g l y c o p ro t e in s o f e n -doge nous r e t rov i ru s es r ai s es ques t i ons w i t h r ega rd t o t hev a l u e o f a n i m a l s a s m o d e l s y s t e m s f o r s tu d i e s o f h u m a nr e t ro v i r a l i n f e c ti o n s. W h e t h e r h u m a n e x o g e n o u s r e t ro v i -ru s es a l so pa r t i c i pa t e i n phe no t y p i c m i x i ng wi t h endog e-n o u s c o u n t e r p a r t s f r o m t h e h u m a n g e n o m e is n o t k n o w n .B y ana l ogy wi t h t he above obs e rva t i ons , t h i s pos s i b i li t ycan ce r t a i n l y no t be d i s m i s s ed .

S i n c e p h e n o t y p i c m i x i n g d o e s n o t i n v o l v e e x c h a n g e o fg e n e t ic i n f o r m a t i o n , p e r m a n e n t l y m o d i f i e d v i ra l p r o g e -n i e s a r e n o t p r o d u c e d . N e v e r th e l e s s, p h e n o t y p i c m i x i n gb e t w e e n e x o g e n o u s a n d e n d o g e n o u s r e t r o v i r u s e s m i g h th a v e i m p o r t a n t c o n s e q u e n c e s t h r o u g h t h e f o r m a t i o n o fv i r i ons w i t h an exp and ed hos t ce ll range , pe rhaps a l l ow-i ng fo r t he t r ans m i s s i on t o o t he r s pec i es . Moreover , ani n v a d i n g r e t r o v ir u s , w h i c h h a s a c q u i r e d e n v e l o p e p r o -t e i n s e n c o d e d b y a n e n d o g e n o u s re t ro v i r us , m a y e s c a p ea t t a c k b y t h e h o s t i m m u n e s y s t em . F i n a ll y , th e r e s c u e o f ar e p l ic a t io n - d e f e c ti v e p r o v ir u s b y p h e n o t y p i c m i x i n g m a yp r o v i d e t h i s p ro v i r u s w i t h a n o p p o r t u n i t y t o r e c o m b i n ewi t h t he he l pe r v i ru s.

Phenotypic MixingP h e n o t y p i c m i x i n g r e fe r s t o t h e f o r m a t i o n o f v i r io n sc o n t a i n i n g p r o t e in s w h i c h a r e n o t e n c o d e d b y t h e e n c a p s i-

da t e d v i r a l genom es [89 ]. In t he ex t r em e , v i ra l genom esa re packaged i n t o pa r t i c l e s cons i s t i ng o f s t ruc t u ra l p ro -t e in s e n t i r el y e n c o d e d b y a n o t h e r v i ru s . B y p h e n o t y p i cm i x i n g h e l p e r v i ru s e s m a y s u p p l y a d e f e c t iv e v i r u s w i t hp ro t e i n s neces s a ry fo r r ep l i ca t i on and pa r t i c le fo rm a t i on[27 ]. Th i s i s a ls o know n as com p l em en t a t i on . Th e i n i t i a ls t ep o f a r e t rov i r a l i n fec t i on i nvo l ves i n t e rac t i ons be -

Imm unological Self-Tolerance, EpitopeRestriction and Antigenic Mim icryAn t i bod i es aga i n s t va r i ous end oge nous type C r e t rov i -

ru s es a re na t u ra l l y occu r r i ng i n va r i ous i nb red m ous es t r a i n s [1 , 49 , 62 ]. N a t u ra l an t i bod i es aga i n s t r e trov i r a lc o m p o n e n t s a re a l s o c o m m o n i n h i g h e r p r i m a t e s [ 18 ].Th e s pec i f ic i t y o f t hes e a n t i bod i es a r e r e s t r ic t ed t o ep i -t o p e s o n t h e s u r f a c e g l y c o p r o te i n a n d t h e t r a n s m e m b r a n eprote in [18 , 34] whi le there seems to be se l f - to lerance to

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o t h e r e n d o g e n o u s r e t r o v i r al g e n e p r o d u c ts . S i n c e s o m e o ft h e n a t u r a l l y o c c u r r i n g r e t r o v i r a l a n t i b o d i e s i n m i c e a n dp r i m a t e s h a v e n e u t r a l i z i n g c a p a c i t y t h e y c o u l d b e a c t i n ga s a d e f e n s e me c h a n i s m a g a i n s t e x o g e n o u s r e t r o v i r u s e s[18,341.R e a c t i v i ty a g a i ns t o n e o r a f e w o f t h e m a j o r a n t i g e n s o fH T L V [ 4 6 ] a n d H I V [ 3 7 , 8 2 ] , mo s t f r e q u e n t l y g a g g e n ep r o d u c t s , i s d e t e c t a b l e i n a r e l a t i v e l y s ma l l f r a c t io n o f s e r af r o m h e a l t h y h u m a n s w i t h n o o t h e r e v i d e n c e o f h a v i n g ar e t r o v i r a l i n f e c t io n . M o s t l i k e ly , s o me o f t h e s e s e r o i n d e -t e r mi n a t e r e a c t i v i t i e s a r e d u e t o a u t o a n t i b o d i e s d i r e c t e da g a i n s t e n d o g e n o u s r e t r o v i ru s e s [ 4 6 , 8 2] . T h i s a s s u m p -t i o n i s s u p p o r t e d b y o b s e r v a t i o n s t h a t a p r o t e i n , e n c o d e db y a n H T L V - r e l a t e d h u m a n e n d o g e n o u s r e tr o v ir u s , m a yac t as an au toan t igen [4 ].

T h e g e n o m e s o f r e t r o v i r u s e s c o n t a i n c o n s e r v e ds t r e t c h e s . I n p a r t i c u l a r , c e r t a i n s t r e t c h e s w i t h i n t h e p o /g e n e a r e c o n s e r v e d [ 3 8 , 6 1 ] b u t a l so a s t r e t c h i n t h e t r a n s -m e m b r a n e p r o t e i n s e e m s t o b e s u b j e c t e d t o a l i m i t e dd e g r e e o f v a r i a t i o n b e t w e e n d i f f e r e n t r e t r o v i r u s e s [ 6 1 ] .T h e r e i s e v i d e n c e t h a t t h e o c c u r r e n c e o f i d e n t i c a l o r r e la t -e d e p i to p e s b e t w e e n e n d o g e n o u s a n d e x o g e n o u s r e tr o v i-r u s e s r e s u l t s i n a r e s t r i c t e d a b i l i t y t o r a i s e a n i mmu n er e s p o n s e a g a i n s t t h e e x o g e n o u s r e t r o v i r u s i n q u e s t i o n[59] . Observa t ions wi th av ian l eukos i s v i ruses ind ica tet h a t e n d o g e n o u s r e t r o v i r u s e s in t e r f e r e w i t h t h e a b i l i ty o ft h e i m m u n e s y s t e m t o e l i m i n a t e i n v a d i n g r e t r o v i r u s e s[75 , 85]. Br i e f ly , t he e nve lope g lycopro te ins o f endoge -n o u s a v i a n l e u k o s i s v i r u s e s c o n t a i n e p i t o p e s w h i c h a r ea l s o p r e s e n t i n t h e e x o g e n o u s a v i a n l e u k o s i s / s a r c o mav i r u se s . Ch i c k e n s c a r r y i n g th e s e e n d o g e n o u s r e t r o v i r u s e sd o n o t r e s p o n d w i t h t h e p r o d u c t i o n o f a n t ib o d i e s t o t h ec o m m o n e p i t o p e s u p o n i n f e c t i o n w i t h t h e e x o g e n o u sr e t r o v i r u s e s . T h i s i s o p p o s e d t o c h i c k e n s l a c k i n g t h ee n d o g e n o u s e n v l o c i in q u e s t i o n . C o n s e q u e n t l y , t h e r e i s al o w e r s u s c e p t i b i li t y t o i n f e c t i o n s w i t h t h e a v i a n l e u k o s i s/s a r c o m a v i r u s e s in t h e l a t t e r g r o u p o f c h ic k e n s .

A r e s t r i c t i o n i n t h e n u m b e r o f a v a i la b l e e p i t o p e s o f a ni n v a d i n g r e t r o v i r u s c o u l d a l s o h a v e i mp l i c a t i o n s f o r t h ed e v e l o p m e n t o f v a c c i n e s a g a i n s t t h a t v i r u s . Mo r e o v e r , t h eo c c u r r e n c e o f s h a r e d o r c r o s s - r e a c t i v e e p i t o p e s b e t w e e ne n d o g e n o u s a n d e x o g e n o u s r e t r o v i r u s e s r e p r e s e n t s a p o -t e n t i a l s o u r c e o f f a l s e - p o si t iv e o r i n d e t e r m i n a t e r e a c t i v i-t i es in the se rod iagn os i s o f re t rov i ra l i n fec t ions [46 , 82 ] .

A b r e a k d o w n o f s e lf - t o le r a n c e t h r o u g h a n t i g e n i c m i mi -c r y m a y o c c u r i f a n i n f e c t i o u s a g e n t i s d i s ti n c t f r o m b u ts u f f i c i e n tl y r e l a t e d t o h o s t e p i t o p e s t o i n d u c e a c r o s s -r e a c t in g i m m u n e r e sp o n se . A n u m b e r o f d i f fe r e n t in f e c-t i o u s a g e n t s po s s e ss s t r e t c h e s o f a m i n o a c i d h o m o l o g i e sw i t h h o s t c e l l c o mp o n e n t s s u g g e s t i n g a p o t e n t i a l f o r

i n d u c t i o n o f a u t o i m m u n i t y [ 63 ]. W h e t h e r e x o g e n o u s r e -t r o v ir u s e s a r e c a p a bl e o f i n d u c i n g a u t o i m m u n i t y a s ar e s u l t o f a n a n t i g e n i c r e l a t i o n s h i p w i t h e n d o g e n o u s c o u n -t e r p a r t s i s n o t k n o w n . R e c e n t l y , th i s p o s s i b il i ty w a s e x a m -i n e d b y i m m u n i z a t i o n o f r a ts w i t h M u L V [2 9]. A u t o i m -mu n e d i s e a s e s w e r e n o t o b s e r v e d i n t h e s e r a t s , b u t t h e yr e s p o n d e d w i t h t h e p r o d u c t i o n o f a n t i b o d ie s p o s s e ss in g ar e a c t iv i t y t o p r o t e i n s e n c o d e d b y t h e i r o w n e n d o g e n o u sr e t r o v i ru s e s . I n t e r e s ti n g l y , H I V - 1 i n f e c t i o n s a r e a c c o m p a -n i e d b y t h e a p p e a r a n c e o f a u t o a n ti b o d ie s . T h e s e a u t o a n t i -b o d i e s a r e p r i m a r i l y r e a c t i v e w i t h r e g u l a t o r y mo l e c u l e s o ft h e i m m u n e s y s t e m [ 7 3 ] . F u t u r e s t u d i e s m i g h t r e v e a lw h e t h e r a u t o i m m u n e r e s p o n s e s a g a i n s t e n d o g e n o u s r e -t r o v i r a l a n t i g e n s c a n a l s o b e d e t e c t e d d u r i n g r e t r o v i r a lin fec t ions .

SuperantigensSu p e r a n t i g e n s a r e s u b s t a n c e s c h a r a c t e r i z e d b y a n a b i li -

t y t o s t i mu l a t e a n d / o r d e l e t e T c e l l s w i t h p a r t i c u l a r V I 3c h a i n s [ 2 , 5 6 ]. T h e y a r e s u b d i v i d e d a c c o r d i n g t o t h e i r o r i -g i n . T h e e x o g e n o u s ( mi c r o b i a l ) s u p e r a n t i g e n s i n c l u d e v a r -i o u s b a c t e r i a l s u b s t a n c e s b u t a l so s e v e r a l v i r u s e s s u c h a si n f e c t i o u s M M T V [ 2, 5 6] , t h e d e f e c t i v e M u L V s t r a i na s s o c i a t e d w i t h MA I D S [ 3 3 ] a n d H I V [ 4 8 ] h a v e b e e nl i n k e d w i t h t h e p r o d u c t i o n o f f a c to r s p o s se s s in g s u p e r a n -t i g e n a c t iv i t y . So fa r , e n d o g e n o u s s u p e r a n t i g e n s h a v e o n l yb e e n d e t e c t e d i n m i c e . T h e m u r i n e s e l f s u p e r a n ti g e n s a r ee n c o d e d b y a n o p e n r e a d i n g f r a m e in t h e 3 ' L T R o f en d o g -e n o u s M M T V . T h e h u m a n g e n o m e d o e s n o t s e e m t oe n c o d e h o m o l o g u e s o f t h e m u r i n e e n d o g e n o u s s u p e r a n -t i g e n s [ 3 ] a l t h o u g h h u ma n T c e l l s r e s p o n d t o MMT Vs u p e r a n t i g e n s [ 4 5] . Re c e n t l y , i s o la t i o n o f a h u m a n e n d o g -e n o u s r e t r o v i ra l s e q u e n c e p e r h a p s e n c o d i n g f o r a s u p e r a n -t i g e n w a s r e p o r t e d [ 36 ], b u t c o n f i r ma t i o n o f i t s b io l o g ic a la c t i v i t y is n e e d e d .

E x o g e n o u s M M T V s a r e t ra n s m i t t e d b y t h e m i lk . A f t e rh a v i n g c r o s s e d t h e g u t o f t h e s u c k l i n g mo u s e , t h e y i n f e c tsuscep t ib l e t a rge t ce l l s , p resumably B ce l l s i n the Peyerpa tches [28 , 39 ] . Mos t l i ke ly , t he nex t s t eps in the es t ab -l i s h me n t o f t h e i n f e c t i o n i n v o l v e e x p r e s s i o n o f v i r a l s u p e r -a n t i g e n o n t h e s u r f a c e o f t h e i n f e c t e d c e l l s r e s u l t i n g i ns t i mu l a t i o n a n d a c t i v a t i o n o f T c e l ls w i t h t h e a p p r o p r i a t eV[3 cha ins . The se s t im ula ted T ce l ls a re be l i eved to cause al o c al e x p a n s i o n o f i n f e c t e d B c e l ls f o l lo w e d b y s p r e a d i n g o ft h e i n f e c t i o n t o o t h e r l y mp h o c y t e s u b se t s a n d f i n a ll y t o t h em a m m a r y g la n d s [ 84 ]. A d i f f e r e n t s c e n a r io w i t h s u p e r a n -t igen-s t im ula ted T ce l l subse t s se rv ing as the p ro x im al t a r -g e ts o f M M T V h a s a l s o b e e n p r o p o s e d [ 25 ].

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I r r e s p e c t i v e o f t h e e x a c t n a t u r e o f t h e i n i t i a l s te p s o ft h e i n f e c t i o n , mo u s e s t r a i n s i n w h i c h T c e l l V [3 s u b s e tsh a v e b e e n d e p l e t e d b y s e l f s u p e r a n t i g e n s a r e r e s i s t a n t t oi n f e c ti o n s w i th M M T V s e n c o d i n g s u p e r an t ig e n s o f t h es a m e s p e c i fi c i ti e s a s t h o s e o f t h e s e l f s u p e r a n t i g e n s [ 2 5,2 8 ] . W h e t h e r s u c h a me c h a n i s m p r o t e c t s a g a i n s t i n f e c -t i o n s w i t h o t h e r r e t r o v i r u s e s t h a n MMT V i s s t i l l u n c e r -t a i n . Fu t u r e f i n d i n g s t h a t h u ma n r e t r o v i r u s e s u t i l i z e s u -p e r a n t i g e n s mi g h t s e r v e t o s t i mu l a t e r e s e a r c h i n t o n e wt h e r a p i e s b a s e d u p o n s p e c i f ic d e p l e t i o n o f t h e p r o x i ma ltarget cel ls .

H e te ro logous T r a n ~ A c t i v a t i o n and PossibleInteract ions on the Posttranscript ional Leve lH e t e r o l o g o u s t r a n s - a c t i v a t i o n m a y o c c u r i n c e l ls h a r -

b o r i n g t w o d i f f e r e n t v ir u s e s , i .e . t h e t r a n s c r i p t i o n o f o n eo f t h e v i r u s e s i s a c t i v a t e d b y t r a n s c r i p t i o n a l f a c t o r s p r o -d u c e d b y t h e o t h e r o n e . W h e t h e r t h e t r a n s c r i p ti o n a l f a c-t o r s e n c o d e d b y v a r i o u s e x o g e n o u s r e t r o v i r u s e s t r a n s - a c t i -v a t e e n d o g e n o u s r e t r o v i r u s e s i s n o t k n o w n . H o w e v e r ,e x o g e n o u s r e t r o v i r u s e s ma y i n d i r e c t l y c a u s e a c t i v a t i o n o fe n d o g e n o u s r e t r o v i r u s e s t h r o u g h a c t i v a t i o n o f v a r i o u sc e l l u l a r g e n e s . N o t a b l y , t h e H T L V t a x p r o t e i n t r a n s - a c t i -v a t e s g e n e s e n c o d i n g c e l l u la r t r a n s c r i p t i o n f a c t o r s [ 24 ].

A p p a r e n t l y , t h e h u m a n g e n o m e d o e s n o t c o n t a i n e n -d o g e n o u s h o m o l o g u e s o f t a x [ c i t e d i n 4 3 ] . O n t h e o t h e rh a n d , a r e c e n t s t u d y r e p o r t e d t h e d e t e c t i o n o f a d o u b le -s p l ic e d h u m a n e n d o g e n o u s r e t r o v ir a l tr a n s c r i p t , e n c o d i n ga p r o t e i n r e l a t e d w i t h r e v o f t h e l e n t v ir u s e s a n d r e x o fH T L V - I [ 5 3 , 5 4] . Fu r t h e r s t u d i e s a r e n e e d e d t o r e v e a l th ea c t i v i ti e s o f t h i s e n d o g e n o u s f a c t o r , i n c l u d i n g p o s s ib l emo d u l a t i n g e f f e c t s o n t h e n u c l e a r e x p o r t a n d p r o c e s s i n go f t r a n s c r ip t s o f h u m a n e x o g e n o u s re t r ov i r us e s .

C onc lud ing R e ma rk s a nd Pe rs pe c t iv e sE n d o g e n o u s a n d e x o g e n o u s re t r ov i r u se s m a y i n te r a c t

t h r o u g h a v a r i e t y o f d i f f e r e n t me c h a n i s m s . T h e r e i s e v i-d e n c e t h a t e n d o g e n o u s r e t r o v i r u s e s a f f e c t t h e s u s c e p ti b il i -t y t o r e t r o v i r a l i n f e c t i o n s a n d t h e c o u r s e s o f t h e r e t r o v i r a ld i se a s es . T h a t is , s o me e n d o g e n o u s r e t r o v i r u s e s a r e c a p a -b l e o f e n h a n c i n g t h e p a t h o g e n i c i t y o f e x o g e n o u s re t r o v i-r u s e s w h i l e o t h e r s c o n f e r p r o t e c t i o n a g a i n s t i n f e c t i o n sw i t h h i g h l y p a t h o g e n i c e x o g e n o u s c o u n t e r p a r t s . Mo s ts t ri k in g l y , e n v e l o p e g l y c o p r o t e i n s o f e n d o g e n o u s r e t r o v i-r u s e s c a n c o n f e r p r o t e c t i o n a g a i n s t r e t r o v i r a l i n f e c t io n s ,b u t t h e y h a v e a l s o b e e n a s s o c i a t e d w i t h a r e s t r i c t io n i n t h ea b il it y o f t h e i m m u n e s y s t e m t o c o m b a t s u c h i n fe c ti o n s.Fu r t h e r , t h e r e a r e e x a mp l e s t h a t i n d i v i d u a l v a r i a t i o n s inthe suscep t ib i l i ty to re t rov i ra l in fec t ions re f l ec t gene t i cv a r i a t i o n a t c e r t a i n e n d o g e n o u s r e t r o v i r a l l o ci .

T o a l a r g e e x t e n t , t h e i s s u es o f t h is r e v i e w h a v e b e e nb a s e d u p o n o b s e r v a t i o n s w i t h a n i ma l r e t r o v ir u s e s , in p a r -t i c u l a r mu r i n e r e t r o v i r u s e s . S t i l l t h e q u e s t i o n o f c o r r e -s p o n d i n g i n t e r a c t i o n s b e t w e e n e n d o g e n o u s a n d e x o g e -n o u s r e t r o v i r u s e s t a k i n g p l a c e i n ma n e s s e n t i a ll y r e m a i n su n e x p l o r e d . A c o mp l i c a t i n g a s p e c t c o n c e r n s t h e l a r g en u m b e r o f h u m a n e n d o g e n o u s r e tr o v i ru s e s a n d t h e i rd i v e r s e n a t u r e .

A c k n o w l e d g e m e n t sT h i s p u b l i c a t i o n i s p a r t o f a r e t r o v i r u s r e s e a r c h p r o g r a m s u p p o r t -

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