M E D iC A L
JO U R N A L
"
.
R E V I E \ "
&
.:
.
U P D A T I N G
M a ria d o S o c o rro P o m b o d e O liv e ira , N e ls o n H a m e rs c h la k , C a rlo s C h ia tto n e , P a u la L o u re iro
H T L V · I in fe c tio n a n d a d u lt T .c e llle u k e m ia
in B r a z il: A n o v e r v ie w
Cell Markers Laboratory of Cancer Hospital - Rio de Janeiro, Brazil
Service of Hematology
and Hemotherapy
of Albert Einstein Hospital-
Slio Paulo, Brazil
Department
of Hematology
and Hemotherapy
of Hospital Santa Cas a da Misericordia
- Slio Paulo, Brazil
Department
of Hematology
of HEMOPE
- Recife, Brazil
H u m a n T -ce ll Iym p h o tro p ic V iru s T yp e I (H T L V -I) is th e e tio lo g ic fa cto r fo r a d u lt T -ce ll le u ke m ia /lym p h o m a (A T L ). H T L V -I in fe ctio n ca n a lso le a d to o th e r d ise a se s, su ch a s H T L V -I-a sso cia te d m ye lo p a th y/tro p ica l sp a stic p a ra p a re sis (H A M IT S P ), u ve itis, a rth ro p a th y a n d in fe ctio u s d e rm a titis. S tu d ie s o f th e in fe ctio u s m o d e o f tra n sm issio n o f H T L V -I a n d risk fa cto rs fo r H T L V -I-re la te d d ise a se s h a ve b e e n co n d u cte d in se ve ra l co u n trie s, a n d d iffe re n ce s in th e p re va le n ce , a g e p a tte rn s, e th n ic g ro u p s a n d clin ica l p re se n ta tio n o f th e re la te d d ise a se s h a ve b e e n d e scrib e d w o rld w id e . B a se d o n th e g e o g ra p h ica l ch a ra cte ristics o f B ra zil a n d d a ta fro m th e lite ra tu re , w e h a ve su m m a rize d th e d istrib u tio n o f se ro p re va le n ce in b lo o d d o n o rs in d iffe re n t sta te s a ro u n d th e co u n try, a s w e ll a s th e in cid e n ce o f A T L in re g a rd s to th e e n d e m ic fo c i. A T L in B ra zil h a s th e sa m e ch a ra cte ristics a s th o se d e scrib e d e lse w h e re , b u t is re p o rte d m o re fre q u e n tly a t a yo u n g e r a g e . In o rd e r to b e tte r e va lu a te A T L in B ra zil, a re g istry h a s b e e n e sta b lish e d a t th e se ve ra l h e m a to lo g ic ce n te rs u n d e r th e sp o n so rsh ip o f th e In stitu to N a cio n a l d e C a n ce r a n d th e B ra zilia n S o cie ty o f H e m a to lo g y a n d H e m o th e ra p y, fo r th e p u rp o se o f re co rd in g a ll ca se s o rig in a lly d ia g n o se d in B ra zil.
UNITERMS: A d u lt T -ce ll le u ke m ia /lym p h o m a . H T L V -I in fe ctio n .
INTRODUCTION
T
he infectionT -Iym photropicand relatedV irus diseasesT ype IIIIcaused(H T L V -1)by hum anare reported w orldw ide, w ithendemicfoci
in southern Japan, Jam aica and other C aribbean islands, and in parts of A frica w here 10 to 20 percent of the population hasAddress for correspondence:
M a ria d o S o c o rro P o m b o d e O liv e ira L a b o ra t6 rio d e M a rc a d o re s C e lu la re s In s titu to N a c io n a l d o C a n c e r
P ra 9 a C ru z V e rm e lh a , 2 3
R io d e J a n e iro /R J - B ra s il - C E P 2 0 2 3 0 -0 3 0
been show n to have antibodies to the virus.I
-3 S tudies of the infectious m ode of transm ission of H T L V -1 and the risk factors for H T L V -I related diseases have been conducted in several countries.4
•5
S ince the discovery of H L T V -I in 1980, and the increasing inform ation about its geographical distribution in different parts of the w orld som e serosurveys of H L T V -1 have been reported in B razil in w hich the endem icity of the infection has been inferred by the presence ofH T L V -1 associated diseases.(i-X E arly findings, and the great deal of attention that have been focused on retroviruses have led to an attem pt to clarify the epidem iological situation of the H T L V infection and related diseases in B razil. M andatory screening for H T L V antibodies in blood banks w as initiated in N ovem ber 1993.
O L IV E IR A , M .S .P .; H A M E R S C H L A K , N .; C H IA lT O N E , C . & L O U R E IR O , P . - H T L V -I in fe ctio n a n d A d u lt T -ce ll le u ke m ia in B ra zil: A n o ve rvie w
D u rin g th e S e c o n d a n d T h ird In te rn a tio n a l
S y m p o s iu m s o n H T L V in B ra z il, w h ic h to o k p la c e in R io
d e J a n e iro (1 9 9 2 ) a n d R e c ife (1 9 9 3 ), s e v e ra l s e s s io n s w e re
d e v o te d to s e ro p re v a le n c e in b lo o d d o n o rs , w ith
d is c u s s io n s a b o u t th e ra te o f s e ro p o s itiv ity in d iffe re n t
s ta te s o f th e c o u n try , b u t v e ry fe w re p o rts o f A T L w e re
p re s e n te dlJ (a n d P o m b o d e O liv e ira , u n p u b lis h e d
o b s e rv a tio n ).
T h e m a i n o b je c ti v e o f th is re p o rt is to d e s c rib e
H T L V in fe c tio n in B ra z il, b rin g in g to g e th e r n e w
in fo rm a tio n o n H T L V -I a n d a d u lt T -c e ll le u k e m ia /
ly m p h o m a (A T L ), a s w e ll a s s p e c u la tin g o n th e
re tro v iru s o rig in b a s e d o n th e g e o g ra p h ic a l d is trib u tio n
o f d iffe re n t e th n ic g ro u p s , s o c ia l b e h a v io u r a n d
m ig ra tio n w ith in th e c o u n try .
U N D E R S T A N D I N G B R A Z I L 'S G E O G R A P H I C
A N D S O C I A L C H A R A C T E R I S T I C S
T h e g e o g ra p h ic p e c u lia rity o f H T L V -I1 II c a rrie rs
in J a p a n , th e U n ite d S ta te s a n d in tro p ic a l c o u n trie s
s u c h a s J a m a ic a a n d C o lo m b ia , h a s b e e n c o n s id e re d to
b e a s p e c ific m o d e o fH T L V -I tra n s m is s io n a m o n g th e s e
e th n ic g ro u p S .IO -1 3 E v e n in a h ig h ly e n d e m ic a re a , th e
p re v a le n c e o f in fe c tio n a n d a s s o c ia te d d is e a s e s a re
v a ria b le fro m o n e p a rtic u la r re g io n to a n o th e r, a n d
g e n e tic fa c to rs m ig h t h a v e a p o s s ib le re la tio n s h ip to
im m u n o re s p o n s e to H T L V -I in fe c tio n . A H L A
h a p lo ty p e lin k e d to th e im m u n e re s p o n s iv e n e s s to
H T L V -I in fe c tio n in a s s o c ia tio n w ith A T L a n d H A M /
T S P h a s b e e n d e s c rib e d .1 4
T o u n d e rs ta n d th e fa c to rs th a t m a y re g u la te th e
tra n s m is s io n o f th e v iru s th ro u g h o u t B ra z il, it is
im p o rta n t to b e fa m ilia r w ith th e c o u n try 's h is to ric a l
a n d g e o g ra p h i c a I c h a ra c te ri s ti c s . T h e B ra z i Ii a n
p o p u la tio n , th e la rg e s t in S o u th A m e ric a , w ith 1 5 0
m illio n in h a b ita n ts c o n c e n tra te d a lo n g th e E a s te rn
S e a b o a rd , is c h a ra c te riz e d b y its ra p id g ro w th , d iv e rs e
o rig in a n d g e o g ra p h ic m o b ility . T h e re h a s b e e n
s u b s ta n tia l m ig ra tio n fro m ru ra l a re a s to th e c o a s ta l
c itie s , a n d a ra p id g ro w th in u rb a n p o p u la tio n s .
T h e s e ttle m e n t o f w h a t is n o w B ra z il b e g a n m a n y
th o u s a n d s o f y e a rs a g o w ith th e a rriv a l o f th e firs t trib e s
o f P a le o -A m e ric a n In d ia n s , m ig ra n ts fro m N o rth
A m e ric a w h o w e re p ro b a b ly o f A s ia o rig in . O c c u p y in g
th e b e s t la n d s o f th e A m a z o n a n d P a ra g u a y riv e r s y s te m s
a n d m o s t o f th e c o a s ta l p la in s , th e y m a d e u p th e m o re
th a n 2 m illio n n a tiv e in h a b ita n ts w h e n th e E u ro p e a n s
a rriv e d . P e rh a p s o n e -th ird o f a ll B ra z ilia n s h a v e s o m e
In d ia n a n c e s try , a fa c t p a rtic u la rly a p p a re n t a m o n g th e
p e o p le liv in g in th e m id -w e s t, n o rth a n d th e n o rth e a s te rn
re g io n s .
A s p a rt o f c o lo n ia l p o lic y , b e tw e e n th e 1 6 th a n d
th e 1 9 th c e n tu rie s th e s la v e tra d e b ro u g h t 3 to 4 m illio n
A fric a n s to B ra z il. T h e p rin c ip a l g ro u p s c a m e fro m W e s t
A fric a a n d A n g o la , a n d w e re d is p e rs e d a ll o v e r th e
c o u n try in o rd e r to p ro v id e th e la b o r re q u ire d o n s u g a r
c a n e p la n ta tio n s in th e N o rth e a s t, a n d in th e m in in g o f
g o ld a n d p re c io u s s to n e s in th e S o u th e a s t.
E u ro p e a n e le m e n ts c o n s titu te a m a jo rity o f th e
B ra z ilia n p o p u la tio n , a re s u lt o f th e in flu x o f th e
P o rtu g u e s e to a ll re g io n s . T h e m o s t n u m e ro u s o f th e
n o n -P o rtu g u e s e E u ro p e a n i m m ig ra n ts w e re Ita l i a n s
w h o s e ttle d in la rg e n u m b e rs in S a o P a u lo , R io G ra n d e
d o S u i a n d E s p irito S a n to . T h e le s s n u m e ro u s
im m ig ra n ts w e re th o s e fro m S p a in a n d M id d le E a s te rn
c o u n trie s s u c h a s S y ria a n d L e b a n o n , a s w e ll a s J e w s
(A s h k e n a z i) b o rn in W e s te rn a n d E a s te rn E u ro p e a n
c o u n trie s .
T h e J a p a n e s e im m ig ra tio n s a fte r th e W o rld W a rs I
a n d II a d d e d fu rth e r d iv e rs ity to th e e th n ic m ix . In c o n tra s t
to th e M e d ite rra n e a n p e o p le s ,' it to o k th re e g e n e ra tio n s
fo r th e J a p a n e s e c o m m u n ity to b e c o m e a s s im ila te d .
B e s id e s th e w id e r c u ltu ra l g a p th a t s e p a ra te d th e m fro m
th e g e n e ra l p o p u la tio n , th e y w e re fo r m a n y y e a rs
p h y s ic a lly is o la te d in ru ra l a re a s o f S a o P a u lo , P a ra n a
a n d M a to G ro s s o .
T o d a y , th e d a rk e r-s k in n e d m e m b e rs o f th e
p o p u la tio n te n d to b e a t th e lo w e r e n d o f th e e c o n o m ic
h ie ra rc h y . T h is s itu a tio n is s a id to b e d u e to th e
p e rp e tu a tio n o f g e n e ra tio n s o f b la c k s in re g io n s th a t
o ffe r fe w e r e c o n o m ic a n d s o c ia l o p p o rtu n itie s . B la c k s
a re m o re n u m e ro u s in th e s ta te s o f B a h ia , R io d e J a n e iro ,
P e rn a m b u c o , M a ra n h a o a n d M in a s G e ra is .
A N U P D A T E O F H T L V E P I D E M I O L O G I C A L
S T U D I E S I N B R A Z I L
T h e firs t s tu d y o f H T L V -I in fe c tio n in B ra z il w a s
c o n d u c te d b y K ita g a w a e t a !., w h o re p o rte d o n th e
p re v a le n c e o f a n tib o d ie s to H T L V -I in J a p a n e s e
im m ig ra n ts fro m O k in a w a liv in g in C a m p o G ra n d e ,
M a to G ro s s o . S e ru m s a m p le s fro m 4 6 J a p a n e s e
im m ig ra n ts (Is e i) a n d 5 0 o ffs p rin g s (N is e i), a n d 5 1
J a p a n e s e im m ig ra n ts (n o t fro m O k in a w a ) liv in g in S a o
P a u lo , w e re a n a ly z e d fo r H T L V -I a n tib o d ie s . T h is s tu d y
S a o P a u l o M e d i c a l J o u r n a l / R P M 1 1 4 ( 3 ) : 1 1 7 7 - 1 1 8 5 , 1 9 9 6 O L I V E I R A , M . S . P . ; H A M E R S C H L A K , N . ; C H I A T I O N E , C . & L O U R E I R O , P . - H T L V - I i n f e c t i o n
1179
Proietti et al. 1 9 9 4
M oreira et al. 1 9 9 3
M aloney et al. 1 9 9 2
Lal et al. 1 9 9 2
Franca et al. 1 9 9 0
N agauchi et al. 1 9 9 0
Costa et al. 1 9 9 1
O liveira et al. 1 9 9 0
K itagaw a et al. 1 9 8 6
Cortes et al. 1 9 8 9
Lee et al. 1 9 8 9
Serpa et al. 1 9 8 9
Source
Table 1
Profile of HTLV-I/II studies performed in Brazil
revealed that ten of 96 (l 0% ) Isei and N isei from
O kinaw a w ere H TLV -I positive, w hile all of the 5 1
im m igrants from other parts of Japan w ere
seronegati ve.'s
Later, in
1987,
the incidence of H TLV -I w asevaluated am ong 1 1 6 G uajajara Indians in M aranhao, and 44 patients w ith hem atological disease in Rio de
Janeiro. A ll these sam ples w ere seronegative, leading
to the incorrect conclusion that H TLV -I infection w as
not endem ic in Brazil.'6 Then, a study perform ed in
groups at risk for A cquired Im m unodeficiency
Syndrom e (A ID S) from Rio de Janeiro, M inas G erais and Sao Paulo, show ed that the prevalence of H TLV -I
antibodies ranged from 1 to 1 3 percent am ong blood donors, hom osexual m en, prostitutes, and hem ophiliacs
and their w ives.6
Since the begining of
1990,
several studies have been conducted
regarding the occurence of H TLV -I
i nfecti on am ong both urban and
isolated populations in Brazil. Indian
com m unities living in the A m azon
region w ere found to be positive for
H TLV -I and II, as w ell as w ere
individuals treated for m alaria at
clinics in the state of Para, and
hospitalized patients in Bahia. The
prevalency rate in these groups range from
1.8
to31.4
percent,IJ.17-22 assum m arized in Table I.
Recently, M A LO N EY et al.
tested plasm a and cell pellets from
K ayapo and K rano Indians of all
ages using a polym erase chain
reaction, revealing overall H TLV -II
prevalency rates of
33.3
and12.2
percent, respectively, w ith
increasing prevalence am ongst the
older and fem ale participants. The
Indians of these tribes had had little
contact w ith outside groups, and so
this data helped to postulate that
H TLV -II could be an ancient, N ew
W orld hum an virus.23
These studies lead the N ational
H ealth Service to establish guidelines
for serological tests to screen H TLV
-lIII antibodies in blood donors.
~~~~~~~~~~~~~~~~~~~~F_e_IT_e_ir_a_J_r_.e_t_a_I_. 1 _ 9 _ 9 ~ 4Routine screening of blood donors
has been perform ed in all blood
centers in Brazil since N ovem ber
1993,
and the prelim inary results dem onstrate thepresence of H TLV -lIII w ith prevalence ranging from
0.17
to1.8
percent. These varying percentages m ay bea reflection of differences in sam ple sizes and
m ethodology, as w ell as in the socio-econom ic status and ethnicity of the populations, according to the reports
of the Third International Sym posium on H TLV in
Brazil, held in Recife in Septem ber
1994
(Table2).
Curiously, M IN IZ et al. studied 1 7 2 individuals over IS-years old from an isolated A frican com m unity
in Espirito Santo (Southeast), and found tw o fem ales
aged
50
and80,
seropositive (W B) to H TLV -I, for aprevalence of
1.1
percent. Further, V eronesi et aI.carried out a new seroprevalence survey of Japanese
im m igrants from O kinaw a, living in the northeast region of Sao Paulo, and found a rate of 1 3 percent
Characteristics N um ber H TLV -I
of group studied of cases (+) ( % )
Japanese im m igrants 1 4 1 1 0 7 . 0 0
from O kinaw a and 9 6 1 0 1 0 . 0 0
other areas of Japan 5 1 0 0 . 0 0
Blood donors, RJ 2 , 1 3 8 9 0 . 4 2
Patients at high 5 4 8 2 0 3 . 6 0
risk for retroviroses from RJ, SP, M G
Patients w ith 2 1 5 8 3 . 7 0
m alignant diseases, RJ
Indians and 1 3 7 4 3 3 1 . 3 0
cancer patients 4 3 1 0 2 3 . 2 0
from Belem , PA 2 8 0 5 3 1 8 . 9 0
Patients from SP w ith 1 5 0 4 6 3 0 . 6 0
neurological disorders
Patients w ith A TL, RJ 1 4 1 1 7 9 . 0 0
H ealthy individuals 5 9 3 3 0 . 5 0
from Ceara
Patients w ith a 1 8 6 2 1 . 0 0
m alaria risk, PA
Indians from 1 3 tribes, 6 2 4 1 0 9 1 7 . 0 0
A M , PA , M T
H ealthy individuals 3 2 7 6 1 . 8 0
and patients, BA 3 3 7 6 2 1 8 . 4 0
Blood donors, M G 2 , 1 0 0 1 0 0 . 5 0
Blood donors, SP 1 7 , 0 6 3 3 0 0 . 1 7
O L I V E I R A , M . S . P . ; H A M E R S C H L A K , N . ; C H I A T f O N E , C . & L O U R E I R O , P . - H T L V - I in f e c t io n a n d A d u lt T - c e ll le u k e m ia in B r a z il: A n o v e r v ie w
Table 2
Seroprevalence studies of HTLC-I/II in blood banks.
Blood Bank Year Number of HTLV-I/II (%) Source samples ELiSAlWB
HEMO-AM 1994 1,200 0.08 Health Ministry
HEMO-PA 1990 809 4 0.49 Dr.
Saraiva
HEMO-RJ 1993 15,318 66 0.43 Dr. Reis
HEMO-SP 1993 46,183 217 0.47 Dr. Alquezar
Santa Casa-SP 1993 10,535 89 0.84 Dr. Gomes
HEMO-CE 1993 10,535 89 0.84 Dr. Gomes
HEMO-PR 1994 29,903 39 0.13 Dr. Baldanzi
SSE-RG 1994 4,991 21 0.42 Dr. Mena-Barreto
HEMO-PE 1994 45,747 376 0.82 Dr. Schneiber
HEMO-MG 1994 1,877 6 0.32 Dr. Proietti
HEMO-BA 1994 1,040 14 1.35 Health Ministry
* Data from reports of the second and third International Symposium of HTLV in Brazil.
s e ro p o s i tive In th e to ta l g ro u p o f Is e i a n d th e i r o ffs p rin g .
In th e g e n e ra l p o p u la tio n o v e r 3 0 -y e a rs o ld , th e
p re v a le n c y ra te s o fH T L V -I a n tib o d ie s a m o n g fe m a le s a re
c o n s is te n tly h ig h e r th a n m a le s . S u c h d is c re p a n c ie s b y
g e n d e r h a v e b e e n n o te d in J a p a n a n d J a m a ic a , a n d a re
d u e to th e tra n s m is s io n o f H T L V -I fro m m a le to fe m a le
b y s e x u a l c o n ta c t, a s w e ll a s to in fe c tio n v ia b lo o d
tra n s fu s io n , w h ic h is a d m in is te re d m o re fre q u e n tly to
fe m a le s th a n to m a le s .5
.2 4 It is w o rth w h ile to m e n tio n th a t th e s tu d ie s c a rrie d o u t o n b lo o d d o n o rs h a v e a n
e p id e m io lo g ic b ia s , a s fe m a le s a re p o te n tia l c a rrie rs o f
th is v iru s , b u t th e y te n d to b e th e m in o rity c a s e s (9 : 1 ) in th e s e s tu d ie s .
A lth o u g h a m in o rity o f in d iv id u a ls in fe c te d w ith H T L V -I w ill d e v e lo p A T L , p ro s p e c tiv e s tu d ie s a re
n e c e s s a ry to id e n tify w ith p re c is io n th e m a in ro u te o f tra n s m is s io n o f H T L V in B ra z il, a n d th e ris k fa c to rs fo r
th e d e v e lo p m e n t o f A T L in c a rrie rs .
THE POSSIBLE ROUTE AND MOLECULAR
EPIDEMIOLOGY OF HTLV-I INFECTION
T h e H T L V s a re c la s s ifie d a s a T y p e C re tro v iru s o n
th e b a s is o f th e ir b u d d in g in u ltra -m o rp h o lo g y . H T L V -I
a n d H T L V -II a re c lo s e ly re la te d v iru s e s .2 5 S e ro s u rv e y s
c o n d u c te d o n v a rio u s p o p u la tio n s w o rld w id e h a v e u s e d
d iffe re n t s a m p lin g s c h e m e s , a s w e ll a s d iffe re n t s e ro lo g ic
a s s a y s , w ith v a ry in g s e n s itiv ity a n d s p e c ific ity . T h e re fo re ,
th e s e ro p re v a le n c e ra te b e tw e e n th e s e tw o v iru s e s h a s
b e e n d iffic u lt to c o m p a re . H o w e v e r, th e m o re re c e n t u s e
o f te s ts th a t a llo w fo r d iffe re n tia tio n b e tw e e n th e m , 1 n
a d d itio n to th e is o la tio n a n d m o le c u la r c h a ra c te riz a tio n
o f H T L V -I a n d II in d iffe re n t p o p u la tio n s , h a s b e e n
p ro v id in g n e w in s ig h t in to th e g e o g ra p h ic a l d is trib u tio n o f th e H T L V S .lll.2 6
S o fa r, fo u r s u b ty p e s o f H T L V -I a n d tw o o f H T L V
-II h a v e b e e n id e n tifie d : T h e H T L V -I, S u b ty p e I, c o m p ris e s
m a in ly A fric a n s tra in s ; S u b ty p e 2 a re is o la te s fro m
d iffe re n t p a rts o f th e w o rld ; S u b ty p e 3 in c lu d e s m a in ly
J a p a n e s e is o la te s ; a n d s u b ty p e 4 c o n s is ts o f is o la te s fro m
A u s tra lia a n d M a la y s ia th a t a re th e m o s t d iv e rg e n t fro m
th e o th e r s u b ty p e s o n th e n u c le o tid e s e q u e n c e (u p to 8
p e rc e n t). T h e tw o s u b ty p e s o f H T L V -II a re th e p ro ty p e
is o la te H T L V -IIM o (S u b ty p e A ) a n d N L A (S u b ty p e B ),
w h ic h d iffe r b y 5 p e rc e n t. B o th a re fo u n d in in tra v e n o u s d ru g a b u s e rs , a n d S u b ty p e B b a s b e e n fo u n d in N o rth
A m e ric a n In d ia n s .26
B a s e d o n its d e m o g ra p h ic p ro file , it is h ig h ly
p ro b a b le th a t H T L V -IIII c a m e to B ra z il v ia o n e o r m o re
o f th re e fo llo w in g ro u te s : 1 ) H T L V -IIII w a s a lre a d y
p re s e n t in th e n a tiv e A m e rin d ia n p o p u la tio n th a t c a m e
fro m A s ia , 2 ) it a rriv e d la te r th ro u g h th e tra d in g o f
A fric a n s la v e s , o r la s tly , 3 ) b y th e J a p a n e s e im m ig ra tio n
sao Paulo Medical Journal/RPM 114(3): 1177-1185, 1996 OLIVEIRA, M.S.P.; HAMERSCHLAK, N.; CHIAlTONE, C. & LOUREIRO, P. - HTLV-I infection
1181
in the begining of the 1900s's (F ig. 1). T he H T L V -I
strains obtained in B razil thus far show that 5 out of 6
isolated from a tight cluster, and are distinct from
Japanese and C aribbean isolates.27 H ow ever,
S E G U A R D O et al. has recently dem onstrated that the
genom ic variation of H T L V -I strains am ong patients
w ith H A M /T S P and H T L V -I, asym ptom atic carriers
from S ao P aulo city, w ere H T L V -I S ubtype II; the sam e
variant founded in patients from the C aribbean region
(data presented at the T hird International S ym posium
on H T L V in B razil).
THE PATHOGENESIS OF HTLV-IINFECTION
AND THE DEVELOPMENT OF ATL
T he m olecular and biological aspects of H T L V -I
are im portant in the pathogenesis of adult T -cell
leukem ia/lym phom a (A T L ) and H T L V -I associated
m yelopathy (H A M /T S P ). D ifferences in age patterns
in ethnic groups, and in the clinical presentation of these
related diseases, have been described w orldw ide. T he
reasons for these differences are unknow n, and the m ost
reasonable hypothesis is that these differences m ay be
due to genetic m odifiers and environm ental factors,
rather than to different strains of H T L V _1.12.13
E n d e m ica l a re a o f H T L V -I/II -.... P o ssib le ro u te s o f first m ig ra tio n s
-... T ra d e o f A frica n sla ve s a n d Ja p a n e se im m ig ra tio n s
Figure 1 -P o ssib le ro u te s o f H T L V -I/II to B ra sil
A lthough the precise nature of the interactions
betw een viral products and cellular transcription factors
in the pathogenesis of A T L is still unclear, the tax and
envelope proteins of H T L V -I are both im plicated in
inducing T -cell proliferation. M olecular cloning of
H T L V -I show ed that the proviral D N A is flanked by
5'and 3' long term inal repeats (L T R s) integrated into
cellular D N A .28
T ax is a protein (p40ta x
) that transactivates
transcription activation of the viral L T R from a num ber of
cellular genes such as transcriptase factors (E G R -l ,E G R
-2,c-fos),m em brane receptors (a-chain of IL -2 receptor as
w ell as IL -2 a-chain p75), and interleukines (IL -2, IL -4,
IL -6,IL -9, G M -C S F , M ID -la).25.29
A s a result of cellular gene activation, H T L V -I is
capable of activating nai've T -cells from a slight to a
high proliferation. T ax does not bind directly to the
enhancer D N A s, and there are no hom ologies betw een
tax and any other know n oncogene.3D
It is w ell know n that H T L V -I infected cells pass
through a series of m olecular changes leading to the
leukem ic state, and a m ultistage period is im plicated
in the developm ent of A T L .22.3I C arriers of the H T L V
-I virus have poor m ediated im m unity and behavior of
im m une deficiency syndrom e, and are susceptible to
opportunistic infections, suggesting that certain
infections m ay be acting as cofactors in the progression
to A T L .32.33
A T L w as fi rst descri bed
clinically in Japan in 1977 by
T A K A T S U K I et al.34 L ater, this
m alignancy w as found to be
associated w ith H T L V -I,35 based on
several param eters, such as
geographical clusters of high
incidences of A T L corresponding to
a high prevalence of H T L V -I
infection; that H T L V -I im m ortalises
hum an T cells (C D 4+ ), and m ainly,
that H T L V -I proviral D N A is found
in A T L abnorm al lym phoid cells. A ll
patients w ith A T L have antibodies
against H T L V _1.36.37
T he clinical features of A T L
include enlargem ent of the lym ph
nodes, liver and spleen, frequent
skin lesions, hypercalcem ia and a
high incidence of opportunistic
infections. A T L often presents a
leukem ic feature, but lym phom a is
very frequent in C aribbean people.
P eripheral blood sm ears usually
O L IV E IR A , M .S .P .; H A M E R S C H L A K , N .; C H IA T IO N E , C . & L O U R E IR O , P . - H T L V -I in fe ctio n a n d A d u lt T -e e " le u ke m ia in B ra zil: A n o ve rvie w
sAo PAULO: Same cl1ar,lclcristics of Rio tie J,meiro with most
numerous communities01Italians and Japanese people.
H T L V -lill =0 ,1 7 '0 ,5 0 %
tiAMfTSP very frequcnt among neurologic pallenls
A T L :1 4 cases
fA B A : mixed population with Indian ancestors; HTLV.I/ll inf~ctioo:0 ,4 9 .1 7 %
A T L :.:: 2c a S t)S
~: Same characteristics
of Pernambuco.
H T L V .l!lI : 0 ,5 0 .0 ,8 4 %
A T L ::2 casos
MINAS GERAIS: Mixed population with
large community 01black people.
tiT l.V ..I:::0 .3 2 ..0 .5 0 % A T l.:6Cllses
fA B A N A :Most European immigrants from Western and Easl.ern countries. JlIp,mesc immigrants in rural Meas
tiT L V .1 =0,13% ATL: 2 cascs
Figure 2 -HTLV-I and ATL in Brazil.
sh o w p le o m o rp h ic ly m p h o c y te s w ith c o n v o lu te d n u c le i,
w h ic h m a y re se m b le S e z a ry c e lls a n d o th e r p o lilu b u la te d ,
so -c a lle d
flower
cells.
H isto lo g ie s o f ly m p h n o d e s a n dsk in le sio n sp e c im e n s a re n o t p a th o g n o m o n ic , b u t a re
m a in ly c h a ra c te riz e d a s p le o m o rp h ic , la rg e -c e ll
ly m p h o m a o r m ix e d la rg e - a n d sm a ll-c e ll ly m p h o m a . It
h a s b e e n re c o g n iz e d th a t A T L e n c o m p a sse s a v a rie ty o f
c lin ic a l p re se n ta tio n s w h ic h a re so m e tim e s d iffic u lt to
d istin g u ish in so m e c u ta n e o u s T -c e ll ly m p h o m a s (C T c L ),
su c h a s m y c o sis fu n g o id e s a n d S e z a ry sy n d ro m e (M F /
S S ), a n d in o th e r fo rm s o f p e rip h e ra l T -c e ll n o n
-H o d g k in 's ly m p h o m a .lo .3 8 .3 9
It is c u rre n tly c le a r th a t H T L V -I in fe c tio n is a d ire c t
c a u se o f A T L , a n d th a t m o th e r-to -c h ild tra n sm issio n o f
H T L V -I h a s b e e n th e m a in ro u te o f in fe c tio n le a d in g to
A T L . T h is fa c t im p lie s th a t su rro u n d in g th e re p o rte d
A T L c a se s, w e m a y id e n tify a re la tiv e ly la rg e p o p u la tio n
o f in fe c te d in d iv id u a ls. In a d d itio n , it is im p o rta n t to
q u a n tify th e risk fo r A T L in th e H T L V -I in fe c te d
p o p u la tio n a n d to c la rify th e fre q u e n c y o f A T L a m o n g
o th e r T -c e ll d iso rd e rs, a s g e o g ra p h ic a l d iffe re n c e s in
th e fre q u e n c y o f c lin ic a l m a n ife sta tio n s a n d v a rio u s
im m u n o p a th o lo g ic a l fo rm s o f A T L h a v e b e e n d e sc rib e d
w o rld w id e .
B e c a u se o f th e o v e rla p p in g fe a tu re s b e tw e e n A T L
a n d o th e r T -Iy m p h o p ro life ra tiv e d iso rd e rs, th e d ia g n o sis
o f A T L is b a se d o n a m u ltip a ra m e te r a p p ro a c h th a t ta k e s
in to a c c o u n t c lin ic a l a n d la b o ra to ry p a ra m e te rs, su c h a s
h y p e rc a lc e m ia , th e m o rp h o lo g y o f th e a b n o rm a l
ly m p h o id c e lls, th e e x p re ssio n o f C D 2 5 o n th e c e ll
PERNAMBUCO :lIery mixed population black and indian ancestors
tiT lV -I: seroprevalence:!l,4 { I ..!l,B 4 %
ATL: 9 C,lses
M.I:llA: mixed population with numerous blacks from African origin
SeroprevaleoceotH llY .lil!:"La.tH%
A T l.: 1 6cas~s
EspfRITO SANTO: Europe,m descendents are majority. African comunlty living isolated showed a seroprevalence of
HTLV.! antibodies ot1 .1 %
A T L ::: acases
RIO DE JANEIRO: Great influx of people from nil regions.
H llY .lill" 0 ,.1 0 -0 .0 0 %
A ll: 3 5cases
m e m b ra n e , H T L V -I se ro lo g y a n d th e m o n o c lo n a l
in te g ra tio n o f H T L V -I p ro v ira l D N A in th e m a lig n a n t
c e lls.1 8 .4 o
ATL IN BRAZIL
T -c e ll m a lig n a n c ie s in B ra z il h a v e a h ig h
se ro p re v a le n c e ra te o f H T L V -I a n tib o d ie s.41 In 1 9 9 0 , 1 4
p a tie n ts w ith A T L w e re id e n tifie d in R io d e Ja n e iro o v e r
a tw o -y e a r p e rio d . A t th e sa m e tim e , S P IN A -F R A N C A
e t a l. re p o rte d a h ig h in c id e n c e o f H A M /T S P in S a o
P a u lo , a n d it b e c o m e a p p a re n t th a t H T L V -I re la te d
d ise a se is fre q u e n t in B ra z il.7 .x
A lth o u g h d e ta ile d stu d ie s in J a p a n 4 2 a n d Ja m a ic a
h a v e p ro v id e d im p o rta n t d a ta o n p a th o lo g ic a l a n d
e p id e m io lo g ic a l c h ra c te ristic s o f A T L , B ra z il h a s b e e n
h a m p e re d b y d iffic u ltie s in th e d ia g n o sis o f th is d ise a se .
R e c e n tly , w e in v e stig a te d 188 p a tie n ts w ith T
-c e ll d ise a se s, b a se d o n c lin ic a l a n d la b o ra to ria l
fin d in g s, to d isc rim in a te th e c lin ic o p a th o lo g ic a l
d iffe re n c e s b e tw e e n H T L V -I p o sitiv e a n d n e g a tiv e
c a se s.4 3 W e fo u n d th a t 5 4 o f th e 188 c a se s w e re A T L
in d iffe re n t c lin ic a l fo rm s. C a se s e v a lu a te d in th is
stu d y w e re re fe rre d fro m se v e ra l so u rc e s a n d a
q u e stio n n a ire re c o rd in g d a te a n d p la c e o f b irth , a s w e ll
a s d e m o g ra p h ic fe a tu re s a n d la b o ra to ria l d a ta , w a ~
re q u e ste d fro m re fe rrin g p h y sic ia n s. A c a se d e fin itio n
Sao Paulo Medical Journal/RPM 114(3): 1177-1185, 1996 OLIVEIRA, M.S.P.; HAMERSCHLAK, N.; CHIATTONE, C.&LOUREIRO, P. - HTLV-I infection
1183
l
w a s a p p lie d fo llo w in g th e M a tu te s a n d C a to v s k y s c o re
s y s te m .IS
T a k in g in to a c c o u n t th e d a ta o f th e 5 4 c a s e s
id e n tifie d a t th e C a n c e r H o s p ita l, a n d th e 3 5 p a tie n ts
id e n tifie d th ro u g h th e B ra z ilia n lite ra tu re s e a rc h , A T L
w a s p a rtic u la rly p ro m in e n t in a g e o g ra p h ic a re a o f
in c re a s e d H T L V -I p re v a le n c e , a s s h o w n in F ig u re 3 .
H ig h p re v a le n c e s o f H T L V in fe c tio n a n d A T L c a s e s
w e re re c o rd e d in th e s ta te o f R io d e J a n e iro (3 5 c a s e s ),
B a h ia (1 6 ), S a o P a u lo (1 4 ), P e rn a m b u c o (9 ), M in a s
G e ra is (6 ); fo llo w e d b y E s p irito S a n to (3 ), C e a ra (2 ),
P a ra (2 ) a n d P a ra n a (2 ).
A T L in B ra z il h a s th e s a m e c h a ra c te ris tic s a s th o s e
d e s c rib e d e ls e w h e re , w ith th e a p p a re n t d iffe re n c e
b e tw e e n B ra z ilia n , J a p a n $ s e a n d C a rib b e a n c a s e s b e in g
a g e . T h e B ra z ilia n p a tie n ts w e re y o u n g e r th a n J a p a n e s e
(1 .8 to 7 1 , m e d iu m o f 4 1 y e a rs ). In 5 0 p e rc e n t o f th e s e
p a tie n ts , s k in le s io n s s u c h a s e ry th e m a , p la q u e a n d
c u ta n e o u s n o d u le s w e re th e m a in d is e a s e m a n ife s ta tio n .
T h e v a lu e o f a s y s te m a tic s c re e n in g o f H T L V -I
in th e s e c a s e s w a s th a t it d is c lo s e d A T L c a s e s w h ic h
h a d b e e n c o n fu s e d w ith o th e r ly m p h o p ro life ra tiv e
d is o rd e rs , a n d , in p a rtic u la r, w ith c u ta n e o u s T -c e ll
ly m p h o m a a n d /o r th e p u re ly m p h o m a fo rm s .31
B e c a u s e o f th e s im ila ritie s b e tw e e n A T L a n d
c u ta n e o u s ly m p h o m a (C T c L ), b o th g ro u p s w e re
c o m p a re d , a n d th e o u ts ta n d in g d iffe re n c e s b e tw e e n
th e m w e re : m a le p re d o m in a n c e in C T c L , le u k e m ia
a n d h y p e rc a lc e m ia in A T L , b u t lo w in C T c L ; th e
p h e n o ty p e in 9 2 p e rc e n t o f A T L c a s e s o v e re x p re s s e d
C D 4 /C D 2 5 , a n d in C T c L o n ly s ix c a s e s w e re C D 4 /
C D 2 5 + ; p o o r p ro g n o s is in A T L w ith m e d ia n s u rv iv a l
o f 6 m o n th s , b u t g o o d p ro g n o s is in C T c L w ith
s u rv iv a l o f 3 6 to 7 0 m o n th s . P ro v ira l D N A o f H T L V
-I w a s d e m o n s tra te d in tu m o r c e lls o f A T L c a s e s , b u t
fa ile d to b e d e m o n s tra te d in C T c L .
In th e s e s e rie s , th re e p a tie n ts , tw o m a le s a n d o n e
fe m a le , w ith th e d ia g n o s is o f A T L s m o u ld e rin g a n d
c h ro n ic ty p e , h a d : d iffic u lty in w a lk in g ; s p h in c te r
d is tu rb a n c e ; s p a s tic p a ra p a re s is lo w e r-lim b
h y p e rre fle x ia ; a n d b ris k re fle x e s . A ll th e s e c lin ic a l
s ig n s fu lfille d th e d ia g n o s is o f H A M /T S P
c o n c o m ita n tly to A T L .
T o c o n firm th e s ig n ific a n c e o f in tra -fa m ilia l
tra n s m is s io n o f H T L V -I in fe c tio n a m o n g p a tie n ts w ith
A T L (n = 1 9 ) a n d o th e r in fe c te d in d iv id u a ls (H A M /
T S P ,n = 7 , p o litra n s fu s e d p a tie n ts , n = 8 ), w e a ls o s tu d ie d
9 3 fa m ily m e m b e rs o f 3 4 p a tie n ts , d is trib u te d a s
fo llo w s : 2 4 h u s b a n d s a n d /o r w iv e s , 1 2 m o th e rs , tw o
fa th e rs , 2 5 s o n s a n d d a u g h te rs , a n d 3 0 s ib lin g s .
H T L V -I a n tib o d ie s w e re fo u n d in 8 /1 2 (6 6 .6
p e rc e n t) o f m o th e rs o f A T L p a tie n ts , a s w e ll a s in 1 6 /
2 4 (6 6 .6 p e rc e n t) o f h u s b a n d s o r w iv e s o f A T L .a n d
H A M /T S P p a tie n ts . T h e in te re s tin g th in g is th a t
m o th e r-to -c h ild tra n s m is s io n w a s n o t th e m a in ro u te
o f H T L V -I in fe c tio n in fo u r p a tie n ts w ith A T L , a s th e i r
m o th e rs w e re n e g a tiv e . T h re e p a tie n ts w e re b re a s t-fe d
b y a n " a m a d e le ite ," o r w e tn u rs e , a n d o n e p a tie n t h a d
re c e i v e d s e v e ra l b lo o d tra n s fu s io n s d u rin g c h i Id h o o d
fo r s ic k le -c e ll d is e a s e .
F o r tw o p a tie n ts , a fa m ilia l s tu d y w a s p e rfo rm e d
o n th e ir h u s b a n d s (b o th H T L V -I+ ), s ib lin g s (a ll H T L V
-I n e g a tiv e ), a n d c h ild re n . T h e m o th e rs o f th e s e p a tie n ts
w e re n o t s tu d ie d , a s th e y w e re d e c e a s e d . W e b e lie v e
th a t b o th p a tie n ts w e re c o n ta m in a te d b y th e ir
h u s b a n d s , b a s e d o n th e fa c t th a t a ll th e ir s ib lin g s w e re
n e g a tiv e , a n d th a t tw o o f th e ir c h ild re n , a g e s 1 7 a n d
2 4 , w e re p o s itiv e . T w o p a tie n ts w ith A T L h a d tw o
s is te rs w ith H A M /T S P . O n e c a s e w a s m e n tio n e d
a b o v e , a s th e p a tie n t h a d b o th c h ro n ic -ty p e A T L a n d
H A M /T S P .4
In o rd e r to c h a ra c te riz e A T L c a s e s ,
The Brazilian
Group for the Study of ATL
h a s re c e n tly s e t u p a re g is tryfo r th e p u rp o s e o f re c o rd in g p a tie n ts w ith A T L
d ia g n o s e d in d iffe re n t B ra z ilia n s ta te s . T h is p o te n c ia l
c a s e c o lle c tio n a n d la b o ra to ry e v a lu a tio n w ill p ro v id e
im p o rta n t b io lo g ic a l in fo rm a tio n a b o u t H T L V -I
in fe c tio n a n d th e g e o g ra p h ic c o fa c to rs to th e
d e v e lo p m e n t o f A T L .
N o te : S in c e th e re v ie w o f th is m a n u s c rip t s e v e ra l
re p o rts h a v e b e e n p u b lis h e d re g a rd in g H T L V -I a n d
H T L V -II in fe c tio n s in B ra z il. In a d d itio n , th e b ra z ilia n
g ro u p fo r th e s tu d y o f A T L h a s re c o rd e d 1 3 4 c a s e s o f
A T L in d iffe re n t c lin ic a l s u b -ty p e s . T h e s e c a s e s w e re
d ia g n o s e d in R io d e J a n e iro , S a o P a u lo , S a lv a d o r,
P o rto A le g re , R e c ife a n d F o rta le z a .
O LIV E IR A , M .S .P .; H A M E R S C H LA K , N .; C H IA T T O N E , C . & LO U R E IR O , P . - H T LV -I infection
and A dult T -cell leukem ia in B razil: A n overview
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I . B la ttn e r W A , K a ly a n a r a m a n V S , R o b e r t- G u r o f M . T h e
h u m a n T y p e C r e tr o v ir u s , H T L V , in b la c k s f r o m th e
C a r ib b e a n r e g io n a n d r e la tio n s h ip to a d u lt T - c e I l le u k e m ia /
ly m p h o m a . I n t J C a n c e r 1 9 8 2 ;3 0 :2 5 7 - 6 4 .
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th e h u m a n r e tr o v ir u s ( H T L V /A T L V ) in O k in a w a w h e r e
a d u lt t- c e I l le u k e m ia /ly m p h o m a is h ig h ly e n d e m ic . G a n n
1 9 8 6 ;7 7 :2 I - 3 .
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M . H T L V - I a s s o c ia te d n e u r o lo g ic m a n if e s ta tio n s in f o u r
g e n e r a tio n s o f a B r a z ilia n f a m ily . J A I D S 1 9 9 3 ;6 :2 I 3 - 1 7 .
5 . T a jim a K , T o m ig a S , S u c h i T . E p id e m io lo g ic a l a n a ly s is o f
th e d is tr ib u tio n o f a n tib o d y to a d u lt T - c e I l le u k e m ia v ir u s
a s s o c ia te d a n tig e n : P o s s ib le h o r iz o n ta l tr a n s m is s io n o f a d u lt
T - c e I lle u k e m ia v ir u s . G a n n 1 9 8 2 ;7 3 :8 9 3 - 9 0 I .
6 . C o r te s E , D e te ls R , A b o u la f ia D , 'e t a l. H I V - I , H I V - 2 , a n d
H T L V - I in f e c tio n in h ig h - r is k g r o u p s in B r a z il. N E n g l J
M e d 1 9 8 9 ;3 2 0 :9 5 3 - 8 .
7 . P o m b o d e O liv e ir a M S , M a tu te s E , F a m a d a s L C . A d u lt T
-c e ll le u k a e m ia /ly m p h o m a in B r a z il a n d its r e la tio n to
H T L V - I . L a n c e t 1 9 9 0 ;3 3 6 :9 8 7 - 9 0
8 . S p in a - F r a n c a A , L iv r a m e n to J A , M a c h a d o L R , G o m e s H R .
H T L V - I a n tib o d ie s in s e r u m a n d c e r e b r o s p in a l f lu id in
tr o p ic a l s p a s tic p a r a p a r e s is in B r a z il. A r q u iv o s d e N e u r o
-P s iq u ia tr ia 1 9 9 1 ;4 8 :4 4 1 - 7 .
9 . M a tu te s E , S c h u lz T , A n d r a d a S e r p a M J , C a m p o s - A r a u jo
A Q , P o m b o d e O liv e ir a M S . R e p o r t o f th e S e c o n d
I n te r n a tio n a l S y m p o s iu m o n H L T V in B r a z il. L e u k e m ia ,
1 9 9 4 ;8 : 1 0 9 2 - 4 .
1 0 . B la ttn e r W .A E p id e m io lo g y o f H T L V - I a n d a s s o c ia te d
d is e a s e s I n : B la ttn e r W A , e d . H u m a n R e tr o v ir o lo g y : H T L V
N e w Y o r k : R a v e n P r e s s , 1 9 9 0 :2 5 1 - 6 5 .
I I . G ib b s W N , L o f te r s W , C a m p b e I l M , e t a l. N o n - H o d g k in
L y m p h o m a in J a m a ic a a n d its r e la tio n to a d u lt T - c e ll
le u k e m ia - ly m p h o m a . A n n a l I n te r M e d 1 9 8 7 ; 1 0 6 :3 6 1 - 8 .
1 2 . H a n c h a r d B , G ib b s W N , L o f te r s W . A d u lt T - c e I lle u k e m ia /
ly m p h o m a ( A T L ) in J a m a ic a . I n : W A B la ttn e r , e d . H u m a n
R e tr o v ir o lo g y : H T L Y . N e w Y o r k : R a v e n P r e s s , 1 9 9 0 : 1 9 7 3
-8 3 .
1 3 . L e v in e P H , J a f f e E S , M a n n s A , M u r p h y E L , C la r k J ,
B la ttn e r W A . H u m a n T - c e I lle u k e m ia v ir u s ty p e I a n d a d u lt
T - c e ll le u k e m i a /ly m p h o m a o u ts id e J a p a n a n d th e
C a r ib b e a n B a s in . Y a le J B io i M e d 1 9 8 8 ;6 1 :2 1 5 - 2 2 .
1 4 . S o n o d a S . G e n e tic a n d im m u n o lo g ic d e te r m in a n ts o f H T L V - 1
a s s o c ia te d d is e a s e s 1 9 9 0 . I n : B la ttn e r W A , e d . H u m a n
R e tr o v ir o lo g y : H T L Y . N e w Y o r k : R a v e n P r e s s , 1 9 9 0 :3 /5 - 2 6 .
1 5 . K ita g a w a T , F u jis h ita M , T a g u s h i H , M iy o s h i I , T a d o k o r o
H . A n tib o d ie s to H T L V - I in J a p a n e s e im m ig r a n ts in B r a z il.
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