immunological risks of adult t-cell leukemia at primary htlv-i infection

Immunological risks of adult T-cellleukemia at primary HTLV-I infectionMari Kannagi, Takashi Ohashi, Nanae Harashima, Shino Hanabuchi and

Atsuhiko Hasegawa

Department of Immunotherapeutics, Medical Research Division, Tokyo Medical and Dental University, Tokyo 113-8519, Japan

A small percentage of human T-cell leukemia virus

type-I (HTLV-I)-infected individuals develop adult T-cell

leukemia (ATL). In animal experiments, inoculation of

HTLV-I via the oral route, which is the main route of

mother-to-child viral transmission in humans as a result

of breastfeeding, induced host HTLV-I-specific T-cell

unresponsiveness and resulted in increased viral load.

This strongly suggested that the known epidemiologi-

cal risk factors for ATL (i.e. vertical HTLV-I infection and

elevated viral load) are linked by an insufficient HTLV-I-

specific T-cell response. Recent findings on the anti-

tumor effects of Tax-targeted vaccination in rats and

the reactivation of Tax-specific T cells in ATL patients as

a result of hematopoietic stem cell transplantation

imply promising immunological approaches for the

prophylaxis and therapy of ATL.

Human T-cell leukemia virus type-I (HTLV-I) is etiologicallylinked to adult T-cell leukemia (ATL) [1,2] and is found inJapan, the Caribbean, South America, Africa, Melanesiaand the Middle East [3]. In Japan, it is estimated thatapproximately one million people are infected with HTLV-I,and that 1–5% of infected individuals develop ATL [4]. Mostother HTLV-I carriers are asymptomatic throughout theirlives, however, a small fraction develop a chronic inflam-matory neurological disorder termed HTLV-1-associatedmyelopathy/tropical spastic paraparesis (HAM/TSP) [5,6] orother inflammatory disorders.

HTLV-I transmission occurs via both vertical andhorizontal routes. The main vertical transmission routeis via breastfeeding [7,8]. Horizontal transmission routesinclude sexual transmission (mainly from male to female)and blood transfusion or intravenous injection of contami-nated blood [9]. HTLV-I infection occurs mainly throughcell-to-cell contact of infected cells with a wide variety oftarget cells in vitro [10]. Sera from HTLV-I-infectedindividuals are capable of neutralizing HTLV-I-mediatedmembrane fusions [11]. Recently, it was shown that theubiquitous glucose transporter, known as GLUT-1, is aspecific component of the HTLV receptor and plays anessential role in HTLV envelope-mediated infection [12].

ATL is characterized by CD4þ and CD25þ matureT lymphocyte phenotypes, disease onset during middle ageor later, immune suppression and poor prognosis as a

result of resistance to combination chemotherapy [13,14].Recently, hematopoietic stem cell transplantation (HSCT)was applied to a limited number of ATL patients. Initialstudies of autologous HSCT revealed a frequent recur-rence of ATL [15], however, more recent reports haverevealed that allogeneic HSCT can produce better results,although there is a risk of graft-versus-host disease(GVHD), which is sometimes lethal [16]. Further improve-ments or new approaches are therefore required fortreatment of ATL.

HTLV-I Tax, one of the viral proteins, transactivatesand interacts with many cellular proteins that regulate ordysregulate cell growth [17], partly accounting for themechanisms of HTLV-I-induced leukemogenesis. How-ever, it has been suggested that in half of the cases of ATLthe leukemia cells might not be able to express Tax becauseof mutations and deletions, mainly within the 50 longterminal repeat (LTR) region of the gene [18,19]. In theremainder of ATL cases, leukemia cells retain the ability toexpress HTLV-I antigens, but the viral antigens are onlydetectable after several hours of in vitro cultivation[20–22]. A similar transient silencing of HTLV-I isobserved not only in leukemia cells but also in peripheralblood mononuclear cells (PBMCs) of HAM/TSP patientsand HTLV-I carriers [23,24]. These observations suggestthat although Tax contributes to the early steps of HTLV-Ileukemogenesis, multiple additional steps that substitutefor Tax functions might be required for ATL development.Constitutive activation of nuclear factor (NF)-kB [25] andJAK–STAT (Janus kinase–signal transducers andactivators of transciption) [26] pathways has beenshown in ATL cells. It remains to be clarified whetheranything in addition to Tax is activating these path-ways in ATL cells.

Although consistent differences have not been observedamong HTLV-I strains isolated from ATL and HAM/TSPpatients [27,28], immunological studies have found a cleardifference in HTLV-I-specific T-cell immune responsesamong HTLV-I-related diseases. HTLV-I-specific cytotoxicT lymphocytes (CTLs) are highly activated in HAM/TSPpatients and can be induced from PBMCs of asymptomaticcarriers but only rarely from those of ATL patients in vitro[23,29–33]. The nature of insufficient HTLV-I-specificT-cell immunity in ATL patients is not fully understood. Arecent report indicated that some CD8þ HTLV-I-specificCTLs persist in ATL patients although they mostly fail to

Corresponding author: Mari Kannagi ([email protected]).

Available online 4 June 2004

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respond ex vivo [34], suggesting the involvement ofimmune suppressive or tolerating mechanisms.

In HAM/TSP, the co-presence of Tax mRNA and anactivated HTLV-I-specific T-cell response in the centralnervous system strongly indicates the involvement ofimmunopathological mechanisms [35,36]. Neurologicalsymptoms improve in response to oral prednisone treat-ment in less advanced cases of HAM/TSP [37]. The use ofanti-retroviral treatment for HAM/TSP patients partlyreduces HTLV-I proviral load, suggesting that HTLV-Imight spread from cell-to-cell in these patients [38].Spontaneous HTLV-I infection in peripheral HTLV-I-specific CTLs from some HAM/TSP patients [24] alsoindicates active interaction between host immunity andthe virus.

HTLV-I core, envelope, polymerase, Tax, Tof and Rofproteins are known to be recognized by HTLV-I-specificCTLs [31,32,39–41]. Among these antigens, HTLV-I Tax(a crucial viral protein for T cell immortalization) is themost popular target for HTLV-I-specific CTLs in infectedindividuals [31,39]. Infrequent sequence variations arefound in the Tax gene, even in HAM/TSP patients [42],indicating the importance of this protein for maintenanceof the virus. HTLV-I Tax-specific CTLs are capable oflysing short-term cultured ATL cells in vitro [23,33]. Thesefindings together with the insufficient HTLV-I-specificCTL response in ATL patients suggests that HTLV-I-specific CTLs contribute to anti-tumor surveillance inHTLV-I-infected individuals, and that an insufficiency ofT-cell immune responses to HTLV-I might be a risk factorfor ATL development.

To attest this hypothesis and understand the mechan-isms of HTLV-I leukemogenesis in vivo, a series of ratmodels for HTLV-I infection and T-cell lymphomas wereinvestigated. From these experiments, as described later,it was discovered that the route of HTLV-I transmissionseriously affects host immune responses [43,44], and thatthe proviral load increases under insufficient HTLV-I-specific T-cell responses. Furthermore, HTLV-I Tax waswidely recognized by rat and human CTLs, and vacci-nation directed at Tax eradicated ATL-like lymphomas inrats [45,46].

More recently, HTLV-I Tax-specific CTL responses werefound to be strongly reactivated in ATL patients followingHSCT [47], also supporting the notion that HTLV-I-specificT-cell immune responses contribute towards the surveil-lance of HTLV-I-infected lymphoproliferative disease.

Risk factors for ATL development

In cohort studies of HTLV-I carriers, it appears that therisk factors for ATL might include vertical HTLV-Iinfection, gender (male . female) and increasing numbersof abnormal lymphocytes [48,49]. Because the proportionof vertically infected female HTLV-I carriers is relativelylow compared with male carriers (owing to horizontal viraltransmission from husbands to wives), the higher inci-dence of ATL in male HTLV-I carriers is attributed tovertical infection [9]. Genetic analysis has indicated thepresence of typical human leukocyte antigen (HLA)haplotypes for ATL in an endemic area [50,51], whichalso implies that vertical infection might transmit some

determinants of HTLV-I leukemogenesis. Althoughimmunological studies have pointed out clear differencesin the magnitude of HTLV-I-specific cytotoxic T-cellresponses between ATL and HAM/TSP patients, longi-tudinal studies on T-cell immunity in HTLV-I carrierstoward ATL development have never been conducted.Therefore, it is not known whether the insufficiency inHTLV-I-specific T-cell responses in ATL patients isspontaneously associated or acquired after the onset ofATL. The reasons for the wide variety of immuneresponses to HTLV-I among carriers of the virus are alsounknown. One possibility is the influence of verticalHTLV-I infection, as ATL occurs mainly in verticallyinfected individuals but not in those who become infectedlater in life [9]. To assess this possibility, animalexperiments have been conducted to examine the variousroutes of HTLV-I infection.

Immune unresponsiveness to HTLV-I in animal models

Rats can be persistently infected with HTLV-I [52]. Toexamine whether the route of primary HTLV-I infectionaffects host T-cell immunity to HTLV-I, 5 £ 107 MitomycinC (MMC)-treated MT-2 cells were inoculated into immu-nocompetent adult rats either orally or intraperitoneally.HTLV-I-specific antibody responses were significantlylower in orally infected rats [43,44]. Significant levels ofHTLV-I-specific T-cell immune responses were detected byT-cell proliferation or interferon (IFN)-g production inintraperitoneally infected rats but scarcely in orallyinfected rats. The responses of T cells from rats inoculatedorally were indistinguishable from those of naive rats. Thisclearly indicates that the conditions of primary infection,especially when occurring via the oral route, severelyaffect host immune responses to HTLV-I, even if thegenetic backgrounds of the host are identical.

By contrast, real-time PCR analysis revealed that theHTLV-I proviral load in the spleen cells of orally infectedrats was significantly higher than that detected inintraperitoneally infected rats, although some individualdifferences did exist. Such variation in the levels of T-cellimmunity and proviral loads detected implies that the lowimmune response in orally infected rats is not due to ascarcity of antigens.

When rats were orally or intraperitoneally inoculatedwith low doses of HTLV-I (50 MMC-treated MT-2 cells),viral-specific antibody responses were undetectable in allthose infected, and slight IFN-g production was detectableonly in Tcells from intraperitoneally infected rats. Some ofthe rats orally inoculated with 50 cells showed high levelsof proviruses, whereas intraperitoneally infected rats hadlow provirus levels. Therefore, a scarcity of viral antigensin vivo might explain the poor immune responses of theintraperitoneally infected rats but not those orallyinfected.

Some of the rats that had been orally inoculated with 50cells showed elevated levels of viral load. This suggeststhat even when the initial number of HTLV-I-infected cellsis extremely small, once such cells begin to grow in vivo,the orally infected host might not have any control overthem. The initial amount of virus used at primary infectiondid not markedly affect the persistent proviral load within

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either the orally or the intraperitoneally infected group.This observation suggests that the route of infection morestrongly influences the persistent HTLV-I load in the hostthan does the amount of virus delivered.

Relationship between HTLV-I load and virus-specific

T-cell immunity

In the above rat experiments, the relationship betweenHTLV-I proviral load and T-cell proliferative responses toHTLV-I was analyzed. As shown in Figure 1, the rats canbe roughly divided into three groups: (A) a high viral loadand low T-cell response group, (B) a low viral load and lowT-cell response group, and (C) a low viral load and highT-cell response group. Group A and C consisted exclu-sively of orally and intraperitoneally infected rats,respectively, whereas group B contained both. Overall,there is an inverse correlation between HTLV-I pro-viral load and HTLV-I-specific T-cell proliferation, sug-gesting that HTLV-I-specific T-cell immune responsesmight contribute to the limited expansion of HTLV-I-infected cells in vivo, and that the magnitude of hostimmune response at primary infection might be acrucial determinant of persistent HTLV-I levels in vivo.

In humans, vertical HTLV-I infection, high viral loadand low T-cell responses to HTLV-I are incidentallyassociated with ATL. This exhibits a striking similarityto the oral HTLV-I infection profile demonstrated in the ratexperiments. Because oral infection is a major route ofvertical HTLV-I transmission, a similar immune unre-sponsiveness to HTLV-I and subsequent enlargement ofthe HTLV-I-infected cell population might also occur in

humans, providing conditions that favor the evolution ofinfected cells towards more malignant phenotypes.

Recovery of HTLV-I-specific T-cell immunity in orally

infected rats

It remains unclear how HTLV-I infection occurs throughintestinal mucosa and why T-cell responses are insufficientin orally infected rats. Oral administration of proteinantigens is known to induce peripheral tolerance, in whichhost immunity does not respond to challenge adminis-tration of the original inoculum. [53,54]. However, HTLV-I-specific T-cell responses in orally infected rats wererestored when they were re-immunized with syngeneicHTLV-I-infected cells. Therefore, such immune unrespon-siveness might differ from the typical oral toleranceobserved in the case of non-infectious protein antigens.Alternatively, the syngeneic HTLV-I-infected cells used asa challenging immunogen could be strong antigen-pre-senting cells that are able to break T cell anergy.

HTLV-I-specific cellular immune unresponsivenessassociated with oral infection was reversible, suggestingthat potential immune tolerance in human babies infectedthrough maternal milk might also be reversible. Restor-ation of HTLV-I-specific cellular immunity by vaccinationin the early stage of their lives might reduce theunderlying risk of ATL. However, it appears thatsuch T-cell immunity restoration might also occurspontaneously in human HTLV-I carriers.

In addition to oral infection, there are some other minorroutes of vertical infection such as perinatal or transpla-cental infection, as a small percentage of children born byHTLV-I-infected mothers, but which are bottle-fed, areinfected with HTLV-I [55]. The immunological status ofthese children remains unknown.

Anti-tumor effects of Tax-specific CTL in animal models

Because HTLV-I exists mainly in association with cells andnot as a free virus in vivo, an increase in the levels ofproviruses implies HTLV-1-infected cell proliferation orcell-to-cell infection. However, even though there might besome expansion of infected cells in persistently HTLV-I-infected rats, malignant tumors failed to develop withintwo years of observation. This is partly explained by thetime taken for clonal evolution of the infected cells.

Several animal models have been developed to studythe pathogenesis of ATL by inoculating syngeneic HTLV-I-infected T-cell lines into newborn rats [56] or rabbits [57],or by inoculating human leukemia cells from ATL patientsinto immunodeficient mice [58]. However, there were somelimitations in applying these models for immunologicalstudies on HTLV-I-associated tumors. To analyze anti-tumor immunity during HTLV-I infection, another experi-mental model of HTLV-I-infected T-cell lymphomaswas established [59]. In this model, athymic F344/NJcl-rnu/rnu (nu/nu) rats were subcutaneously inoculatedwith the HTLV-I-transformed CD4þ T-cell line FPM1,derived from the thymocytes of a syngeneic nu/þ rat.Although FPM1 failed to cause tumors in the nu/nu rats,the cell line underwent phenotypic progression throughseveral passages in newborn nu/nu rats, resulting in theestablishment of a sub-line FPM1-V1AX; this sub-line

Figure 1. The relationship between human T-cell leukemia virus type-I (HTLV-I)

proviral loads and Tax-specific T-cell responses. A mild inverse correlation

(r ¼ 20.315, p ¼ 0.094) was observed between the relative copy number of HTLV-I

proviruses (vertical axis) and HTLV-I Tax-specific T-cell proliferative index (hori-

zontal axis) of rats that were inoculated intraperitoneally (circle) or orally (triangle)

with either 50 (open symbol) or 5 £ 107 (closed symbol) MMC-treated MT-2 cells

[44].

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2

3

4

-10 5 10 25 100

5

6

50

HT

LV-I

pro

vira

l loa

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T-cell proliferation index

A

B C




reproducibly caused fatal systemic lymphomas in adultnu/nu rats with infiltration in the lymph nodes, lungs,liver and occasionally the ovaries and skin, as well as locallesions at the site of inoculation, within two months ofreceiving the inoculum. However, FPM1-V1AX failed togrow in syngeneic immunocompetent nu/þ rats.

The outline of the rat model of HTLV-I-infected T-celllymphomas is shown in Figure 2. The development ofFPM1-V1AX lymphomas in nu/nu rats was inhibited byadoptively transferred T-cell lymphocytes from syngeneicnu/þ rats that had been immunized with FPM1-V1AX.The effector Tcells that caused anti-tumor effects consistedof CTLs that predominantly recognized HTLV-I Tax [45].Fine mapping analysis revealed that Tax180–188(GAFLTNVPY) is the central target epitope of CTLs thatare restricted by the rat major histocompatibility complexclass I (MHC-I) molecule, known as RT1.Al. Furthermore,freshly prepared T cells from nu/þ rats vaccinated withTax180–188 oligopeptides prevented the development ofFPM1-V1AX-induced lymphomas in nu/nu rats [45].Similarly, DNA vaccinations with plasmids encoding TaxcDNA evoked effective anti-tumor T-cell immunity in vivo[46]. These results indicated that Tax is a major target ofHTLV-I-specific CTLs in rats as well as humans, and thatTax-specific CTLs play a crucial role in surveillanceagainst HTLV-I-infected tumor development in vivo.

Activation of Tax-specific CTLs in ATL patents following

HSCT

Although Tax-targeted vaccines in rat models of HTLV-I-induced T-cell lymphomas shows promising anti-tumoreffects, the rat model differs from the human disease inmany aspects. The most apparent difference is in viralexpression. FPM1-V1AX cells express much higher levelsof Tax than leukemia cells from ATL patients, and theirgrowth in vivo depends on Tax [60]. In another mousemodel with artificially expressed Tax–enhanced greenfluorescent protein (EGFP) fusion proteins that wereunder the control of the HTLV-I LTR, tumor growth was

suppressed in vivo by Tax-specific CTLs, whereas thetumor cells with low Tax–EGFP expression remained [61].

To investigate anti-tumor immunity in ATL, the T-cellresponses in ATL patients who underwent completeremission following non-myeloablative allogeneic periph-eral blood HSCT from HLA-identical sibling donors wereanalyzed [47] (Figure 3). These patients were presumed tohave raised T-cell immunity mediating graft-versus-hostand graft-versus-leukemia effects. As a target of suchresponses, a phytohemagglutinin (PHA)-stimulated inter-leukin (IL)-2-dependent T-cell line (ILT) derived from anATL patient before HSCT was established. ILT cells werespontaneously infected with HTLV-I. When PBMCs iso-lated from the same patient after HSCT were stimulatedwith autologous ILT cells in vitro, CD8þ CTLs capable ofkilling autologous ILT cells proliferated vigorously.Further analysis revealed that these CTLs predominantlyrecognized a single epitope Tax11–19 restricted withHLA-A2 (Figure 3). They also contained a minor popu-lation probably related to the graft-versus-host response.PBMCs obtained from the same patient before HSCT didnot respond to autologous ILT cells.

The reconstituted T-cell immunity derived from theHLA-identical donor, but not the original ATL patient,strongly reacted with HTLV-I Tax in the ATL patientsfollowing HSCT, indicating that the insufficiency ofHTLV-I-specific CTLs in the original ATL patient wasnot related to HLA or the absence of Tax expression.A similar oligoclonal expansion of Tax11–19-specific CTLshas been reported in HLA-A2 þ HAM/TSP patients [62],reflecting a highly activated host CTL response. Althoughthe direct contribution of Tax-specific CTLs to graft-versus-leukemia effects in the ATL patient remainscontroversial, a similar reactivation of Tax-specific CTLswas observed in other ATL patients who obtained completeremission following HSCT, supporting the notion thatthese CTLs might participate in the maintenance ofremission from ATL.

Hypothetical dynamics of HTLV-I-specific T-cell immune

conversion

For the previously described ATL patient who receivedHLA-identical HSCT, a new balance between host immu-nity and HTLV-I-infected cells was established. Thevigorous HTLV-I-specific CTL response observed in thispatient was very similar to that in HAM/TSP patients. Inthis sense, allogeneic HSCT converted HTLV-I-specificT-cell immunity in the recipient from one extreme tothe other, whereby host immunity might control themalignant expansion of HTLV-I-infected cells in vivo.

The immune unresponsiveness observed in orallyinfected rats might partially mimic insufficient T-cellresponses in some human HTLV-I carriers. Infants thatare born to HTLV-I-carrying mothers are estimated tointake,1 £ 108 HTLV-I-infected cells before weaning [63],and several infantile carriers remain seronegative forHTLV-I for a certain period of time [64], suggesting thatimmunological tolerance for HTLV-I infection might beestablished during this period. The majority of theseHTLV-I-infected individuals exhibit seroconversion withina few years [65]. Although T-cell immune responses to

Figure 2. A syngeneic rat model of human T-cell leukemia virus type-I (HTLV-I)-

infected lymphomas and tumor vaccines. An HTLV-I-transformed rat T-cell line

FPM1-V1AX derived from F344 Jcl rnu/þ (nu/þ) rat causes fatal systemic lympho-

mas in syngeneic athymic Jcl rnu/rnu (nu/nu) but not nu/þ rats when subcu-

taneously inoculated. Transfer of the spleen T cells from nu/þ rats inoculated with

FPM1-V1AX cells can eradicate tumors. By using this system, anti-tumor effects of

vaccines with Tax-coding DNA or synthetic peptides were observed [45,46,59].


nu/nu nu/+(no tumor)

nu/+

Fatallymphoma

Tumorregression

SpleenT-cell

VACCINEInfected cellTax-DNATax-peptide

FPM1-V1AX

(Inoculation)

(Transfer)




HTLV-I in children have not been investigated, it ispossible that they might also recover spontaneously laterin life, as many adult HTLV-I carriers exhibit HTLV-I-specific T-cell responses.

Figure 4 schematically demonstrates our currenthypothesis on immunological risks of ATL in the naturalcourse of HTLV-I infection. Vertically infected HTLV-Icarriers harbor risks of ATL (i.e. insufficient HTLV-I-specific T-cell responses and expansion of infected cells),although the levels can vary among individuals. However,such risks might be reduced in many of HTLV-I carriers byspontaneous recovery of HTLV-I-specific T cells. OnceT-cell immunity to HTLV-I recovers, the magnitude ofthe immune response would positively correlate withpre-existing viral load in vivo [66,67].

Some HTLV-I carriers within the low-risk group for ATLdevelop HAM/TSP. It remains unclear what determinesthe risk of HAM/TSP, but genetic factors might be involved[68]. The presence of a large amount of viral load andelevated levels of HTLV-I-specific immunity in HAM/TSPpatients might be partially explained by T-cell immuneconversion long after the establishment of persistent viralloads following vertical infection.

Nevertheless, a small population of vertically infectedHTLV-I carriers remains in a state consisting of low T-cellresponses to HTLV-I despite an abundant viral load, untillater in life. We assume that this population might be thehigh-risk group for ATL. This hypothesis should beattested by a wide survey of cellular immune responsesin HTLV-I carriers, especially at young ages. This is alsorequired for identification of high-risk groups for ATL.

Concluding remarks

Although the exact mechanisms of ATL developmentremain unclear, these results indicate that immuneunresponsiveness to HTLV-I might be established at avery early stage of HTLV-I infection, and that it is one

Figure 3. Analysis of T cell immunity in adult T-cell leukemia (ATL) patients following hematopoietic stem cell transplantation (HSCT). Peripheral blood mononuclear cells

(PBMCs) from an ATL patient after HSCT were co-cultured with formalin-treated HTLV-I-infected T-cell line (ILT) cells that had been established from the same patient

before HSCT. In this culture, HLA-A2-restricted Tax11–19-specific CD8þ CTLs capable of killing ILT cells predominantly proliferated. Reproduced, with permission, from

Ref. [47].

CD8

HLA-identicaldonor

HTLV-I+

T-cell line (ILT)

ATL patientafter HSCT

(complete remission)

ATL patientbefore HSCT

HSCT

PBMC

Coculture in thepresence of IL-2 H

LA-A

2/Ta

x11-

19 T

etra

mer 63%

101

102

103

104

100

100 101 102 103 104

Figure 4. Hypothesis on immunological risks for adult T-cell leukemia (ATL) in the

natural course of human T-cell leukemia virus type-I (HTLV-I) infection. Vertically

infected HTLV-I carriers harbor risks of ATL (i.e. insufficient HTLV-I-specific T-cell

response and expansion of infected cells). At a later time-point, HTLV-I-specific

T-cell responses spontaneously recover in most of these carriers and the risks for

ATL decrease. However, a small population remains in the high-risk group. HTLV-I

carriers infected through other routes might have less risks of ATL. Under insuffi-

cient T-cell immunity, HTLV-I-infected cells accumulate additional mutations

towards ATL.


Vertical infection

AsymptomaticHTLV-I carriers

(high risk group)

HAM/TSP

ATL

Additionalmutations

(Risk for ATL)

AsymptomaticHTLV-I carriers(low risk group)

Immunetoleranceto HTLV-I

Expansion ofinfected cells

Horizontalinfection

T-cell immuneconversion

Prophylacticvaccine

Therapeuticvaccine?

Escapemutants?

Immunesuppressive

reagents




of the risk factors of ATL as it allows the expansion ofHTLV-I-infected cells. In this regard, the reactivationof HTLV-I Tax-specific T-cell immunity by vaccinationsmight contribute to prophylaxis for ATL developmentand also to ATL therapy to some extent.

AcknowledgementsWe thank Atae Utsunomiya (Imamura Bun-in Hospital, Kagoshima),Ryuji Tanosaki (National Cancer Center Hospital, Tokyo) and MasatoMasuda (University of the Ryukyus, Okinawa) for clinical collaborationand their excellent bedside achievements.

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Free journals for developing countries

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The science publishers, Blackwell, Elsevier, the Harcourt Worldwide STM group, Wolters Kluwer International Health and Science,

Springer-Verlag and JohnWiley,were approachedby theWHOand theBritishMedical Journal in 2001. Initially,more than 1000 journals

will be available for free or at significantly reduced prices to universities,medical schools, research and public institutions in developing

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Gro HarlemBrundtland, director-general for theWHO, said that this initiativewas ’perhaps the biggest step ever taken towards reducing

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immunological risks of adult t-cell leukemia at primary htlv-i infection

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