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Abstract

  1. Top of page
  2. Abstract
  3. Control of HTLV-1 by HTLV-1-specific T-cell responses
  4. Control of HTLV-1 by innate immunity
  5. Double control of HTLV-1 by innate and acquire immunity
  6. Conclusions
  7. Acknowledgments
  8. References

Human T-cell leukemia virus type 1 (HTLV-1) is the causative retrovirus of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1-specific T-cell responses elicit antitumor and antiviral effects in experimental models, and are considered to be one of the most important determinants of the disease manifestation, since they are activated in HAM/TSP but not in ATL patients. The combination of low T-cell responses and elevated HTLV-1 proviral loads are features of ATL, and are also observed in a subpopulation of HTLV-1 carriers at the asymptomatic stage, suggesting that these features may be underlying risk factors. These risks may potentially be reduced by vaccination to activate HTLV-1-specific T-cell responses. HAM/TSP and ATL patients also differ in their levels of HTLV-1 mRNA expression, which are generally low in vivo but slightly higher in HAM/TSP patients. Our recent study indicated that viral expression in HTLV-1-infected T-cells is suppressed by stromal cells in culture through type-I IFNs. The suppression was reversible after isolation from the stromal cells, mimicking a long-standing puzzling phenomenon in HTLV-1 infection where the viral expression is very low in vivo and rapidly induced in vitro. Collectively, HTLV-1 is controlled by both acquired and innate immunity in vivo: HTLV-1-specific T-cells survey infected cells, and IFNs suppress viral expression. Both effects would contribute to a reduction in viral pathogenesis, although they may potentially influence or conflict with one another. The presence of double control systems for HTLV-1 infection provides a new concept for understanding the pathogenesis of HTLV-1-mediated malignant and inflammatory diseases. (Cancer Sci 2011; 102: 670–676)

It has been three decades since the discovery of human T-cell leukemia virus type 1 (HTLV-1) as the causative retrovirus of adult T-cell leukemia (ATL).(1,2) ATL develops during middle age or later mainly in a small portion of vertically HTLV-1-infected populations.(3,4) HTLV-1 also causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in another small population of infected individuals.(5,6) Some other inflammatory diseases such as uveitis and arthritis are also associated with HTLV-1 infection.(7,8) New therapeutic approaches such as hematopoietic stem cell transplantation (HSCT),(9,10) an antibody therapy targeting CCR4,(11) and antiviral therapy with interferon-alpha and zidovudin(12) partly improved the prognosis of ATL. However, ATL still shows high mortality, and HAM/TSP remains to be an intractable disease.

Enormous amounts of research findings have been accumulated regarding the virus-mediated pathogenesis. HTLV-1 Tax, a virus-encoded regulatory gene product, mediates cell activation, proliferation and resistance to apoptosis by transactivation through NF-κB, cAMP response element binding protein (CREB) and serum response factor (SRF), and by inactivation of tumor suppressors,(13–15) which would be involved in leukemogenesis and inflammation in HTLV-1 infection. Another minus-strand HTLV-1-encoded gene product, HTLV-1 basic leucine zipper factor (HBZ), is continuously expressed in infected cells in vivo regardless of the disease and may also be involved in the growth ability of infected cells.(16)

However, many unsolved questions still remain regarding the pathogenesis of HTLV-1 infection, for example, how the same virus causes totally different diseases such as ATL and HAM/TSP, why only small portions of HTLV-1-infected populations develop diseases, and why it takes more than 40 years to develop ATL. The answers to these questions would provide hints for predicting disease risks as well as aiding the development of prophylactic and therapeutic strategies.

HTLV-1-specific T-cell responses that contribute to antiviral and antitumor surveillance could be one of the most important determinants of the diseases. In fact, HTLV-1-specific T-cells are activated in HAM/TSP but not in ATL.(17–19) Oral HTLV-1 infection induces T-cell tolerance to HTLV-1 and increased proviral loads,(20,21) consistent with the epidemiological finding that vertical HTLV-1 infection is one of the risk factors for ATL.(3) Therefore, the individual status of HTLV-1-specific T-cell responses is expected to be an indicator of risk for ATL.(22) Although the pathological significance of HTLV-1-specific T-cells in HAM/TSP remains controversial,(23,24) advantages for HLA-A02-positive individuals in protection against HAM/TSP have been reported, and interpreted through the association of this HLA with strong CTL responses to a major epitope of HTLV-1 Tax.(25)

Elevation of proviral loads is also a risk factor for ATL. Given the fact that HTLV-1-specific CTLs have antiviral effects, these CTLs are likely to be one of the determinants of proviral loads.(26) However, proviral loads are also increased in HAM/TSP patients, and the correlations between proviral loads and HTLV-1-specific T-cell responses vary among studies,(27,28) suggesting the presence of additional factors for determining individual proviral loads.

Another curious finding in HTLV-1 infection is the scarcity of viral antigen expression in the peripheral blood, although the viral mRNA is barely expressed.(29) The transcription of HTLV-1 is mainly regulated by CRE-like repeats in the HTLV-1 LTR.(30) Involvement of inducible cAMP early repressor (ICER) and transducers of regulated CREB 2 (TORC2) in the inhibition of HTLV-1 transactivation has been suggested.(31,32) However, the mechanism involved in suppressing viral expression only in vivo has remained obscure. It is a paradox that HTLV-1 Tax contributes to the pathogenesis while Tax protein is undetectable in vivo. Expression of HBZ in the absence of Tax may partly explain the growth advantage of infected cells,(33) but not all of HTLV-1-mediated leukemogenesis. In addition, it does not make sense that Tax-specific T-cell responses are maintained if Tax is not expressed in vivo. The paradox will remain until the state of viral expression and the mechanisms for suppressing HTLV-1 expression in vivo are clarified.

We recently found that innate immune responses, especially type-I interferons (IFNs), suppress HTLV-1 expression.(34) This integrates the issue of viral expression and the host defense system against HTLV-1, which includes innate immunity as well as acquired immunity. The presence of double control systems explains some of the paradox in persistent HTLV-1 infection, and adds new aspects to the pathogenesis of HTLV-1-mediated diseases.

Control of HTLV-1 by HTLV-1-specific T-cell responses

  1. Top of page
  2. Abstract
  3. Control of HTLV-1 by HTLV-1-specific T-cell responses
  4. Control of HTLV-1 by innate immunity
  5. Double control of HTLV-1 by innate and acquire immunity
  6. Conclusions
  7. Acknowledgments
  8. References

Antitumor surveillance by HTLV-1-specific T-cells. 

CD8+ HTLV-1-specific CTL responses are found in many HAM/TSP patients and asymptomatic carriers (AC), but rarely in ATL patients.(17–19,35,36) These CTLs kill HTLV-1-infected cells in vitro, and mainly recognize HTLV-1 Tax.(18,37) The HTLV-1 envelope is also a popular target, especially for CD4+ CTLs.(38) Other viral antigens, including polymerase,(39) ROF (p12) and TOF (p30/p13),(40) and HBZ,(41) have also been shown to be targets of CTLs. Elimination of CD8+ cells among PBMCs from HAM/TSP patients induces HTLV-1 expression during subsequent cell culture,(42) clearly indicating that CD8+ HTLV-1-specific CTLs contribute to the control of HTLV-1-infected cells.

A series of animal model experiments indicated that HTLV-1-specific T-cell responses limit the expansion of HTLV-1-infected cells in vivo. Oral HTLV-1 infection induced insufficiency of HTLV-1-specific T-cell responses in rats, and the HTLV-1 proviral loads were inversely correlated with HTLV-1-specific T-cell responses.(21) Re-immunization of these rats with mitomycin C-treated HTLV-1-infected cells restored HTLV-1-specific T-cell responses and reduced the proviral loads(43) (Fig. 1). In another rat model of HTLV-1-induced tumors, the otherwise fatal HTLV-1-infected lymphomas in T-cell-deficient rats were eradicated by transfer of T-cells from syngeneic rats that had been vaccinated with a Tax-encoding DNA or peptides corresponding to a major epitope for Tax-specific CTLs.(44,45)

image

Figure 1.  Recovery of human T-cell leukemia virus type 1 (HTLV-1)-specific T-cell responses and reduction of proviral loads by re-immunization. Eight rats orally infected with HTLV-1 were divided into two groups. (A) One group was left untreated (Infect. alone) and the other was subcutaneously immunized with mitomycin C-treated HTLV-1-infected syngeneic rat T-cells (Infect. + Imm.) at 4 weeks. Spleen T-cells were harvested at 7 weeks after infection. (B,C) T-cells from the re-immunized rats (Infect. + Imm.) show elevated levels of Tax-specific T-cell proliferative responses (B) and lower proviral loads (C), compared with untreated rats (Infect. alone).(43)

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Recent clinical reports have indicated that HTLV-1-carrying recipients after liver transplantation developed ATL under the administration of immunosuppressants.(46,47) In contrast, Tax-specific CTL responses were strongly activated in some ATL patients who obtained complete remission after HSCT, but were not observed in the same patients before transplantation.(48) These findings suggest that HTLV-1-specific T-cells, including Tax-specific CTLs, play important roles in antitumor surveillance against HTLV-1 leukemogenesis.

Insufficient HTLV-1-specific T-cell responses as a potential risk for ATL. 

Most HTLV-1-infected individuals are asymptomatic, and only about 5% develop ATL and <1% develop HAM/TSP.(3,49) The epidemiological risk factors for ATL include vertical transmission and increases in the number of abnormal lymphocytes or HTLV-1 proviral loads.(3,50,51) HTLV-1 proviral loads are also elevated in HAM/TSP patients.(52)

Immunological studies have suggested that insufficiency in host T-cell responses against HTLV-1 might be another risk factor for ATL.(22) A small-scale survey measuring Tax protein-specific IFN-γ production revealed a wide variety in the strengths of HTLV-1-specific T-cell responses among HTLV-1 carriers.(53) The combinations of HTLV-1-specific T-cell responses and proviral loads categorize HTLV-1 carriers into the following four groups: (i) low proviral loads with HTLV-1-specific T-cell responses; (ii) elevated proviral loads with HTLV-1-specific T-cell responses; (iii) low proviral loads with low T-cell responses; and (iv) elevated proviral loads with low T-cell responses (Fig. 2).

image

Figure 2.  Diversities in Tax-specific T-cell responses and dissociation with proviral loads in human T-cell leukemia virus type 1 (HTLV-1)-infected individuals. (A) Diversity in CD8+ T-cell functions in two representative HTLV-1-infected individuals at the asymptomatic stage. Abundant amounts of HTLV-1 p19 were produced in PBMC cultures with or without CD8+ T-cells in subject 1, but only after CD8+ T-cell depletion in subject 2.(53) (B) A general image for the categories of HTLV-1-infected individuals at various stages according to the combinations of HTLV-1-specific T-cell responses (x-axis) and proviral loads (y-axis) is shown schematically. AC, asymptomatic carriers; ATL, adult T-cell leukemia; HAM/TSP, HTLV-1-associated myelopathy/tropical spastic paraparesis; HSCT, hematopoietic stem cell transplantation.

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Regarding these groups, ATL patients exhibit elevated proviral loads with low T-cell responses, while many, but not all, HAM/TSP patients show elevated proviral loads with high HTLV-1-specific T-cell responses. ACs are found in all four categories. It is noteworthy that small subgroups of ACs and smoldering ATL patients share a common feature with ATL patients. This indicates that the insufficiency of HTLV-1-specific T-cell responses is not merely the result of malignancy but is an underlying problem before the stage without apparent lymphoproliferation. Further follow-up studies are required to clarify whether the extent of the combination of elevated proviral loads with low T-cell responses could be a diagnostic indicator for risk of ATL.

Dissociation between proviral loads and T-cell responses.

Although HTLV-1-specific T-cells have the potential to control infected cells, there are no clear correlations between proviral loads and HTLV-1-specific T-cell responses among HTLV-1-infected individuals. This is not surprising because both the proviral loads and T-cell responses are high in HAM/TSP patients. The proviral loads may be negatively correlated with T-cell responses only within an individual but not among individuals. Several other reports have indicated various findings concerning this issue. For example, a study measuring IFN-γ-producing CD8+ HTLV-1-specific CTLs indicated a positive correlation with proviral loads in HAM/TSP patients but not in ACs,(28) while a study evaluating CD8+ CTL function by ex vivo clearance of infected cells showed negative correlations with low proviral loads within an AC or a HAM/TSP group,(42) and another study indicated an association of higher frequency of tetramer-binding Tax-specific CTLs with low proviral loads in ACs.(27) Such inconsistent results suggest the presence of certain other determinants of proviral loads in addition to HTLV-1-specific CTLs.

The HTLV-1 proviral loads reflect the number of infected cells in the peripheral blood. Expansion of HTLV-1-infected cells in vivo occurs through both de novo infection and proliferation of infected cells.(54) The number of CD4+ FoxP3+ cells,(55) the frequency of iNKT cells,(56) or MHC-I favorable for HBZ-specific T-cell responses(41) have been suggested to influence HTLV-1 proviral loads.

In HTLV-1-infected rats, however, the proviral loads are inversely correlated with HTLV-1-specific T-cell responses.(21) One reason for the discrepancy between humans and rats may be the genetic heterogeneity in humans. It appears that, under the homogeneous genetic background in the experimental rat system, the influence of insufficient HTLV-1-specific T-cell responses may appear more clearly than in humans, allowing de novo infection and proliferation of HTLV-1-infected cells in vivo. The dissociation of proviral loads and HTLV-1-specific T-cell responses in humans suggests that additional determinants of proviral loads may vary genetically among individuals. As described in the next section, we suppose that innate immunity could be a candidate for this effect.

Control of HTLV-1 by innate immunity

  1. Top of page
  2. Abstract
  3. Control of HTLV-1 by HTLV-1-specific T-cell responses
  4. Control of HTLV-1 by innate immunity
  5. Double control of HTLV-1 by innate and acquire immunity
  6. Conclusions
  7. Acknowledgments
  8. References

Status of HTLV-1 expression in vivo. 

Since HTLV-1-specific antibodies and T-cells are maintained in HTLV-1-infected individuals, viral expression must occur somewhere in vivo. This notion is further supported by the emergence of Tax-specific CTL responses in HTLV-1-uninfected donor-derived hematopoietic systems reconstituted in recipient ATL patients after HSCT.(48,57) However, HTLV-1 mRNA but not viral proteins are detectable in PBMCs freshly isolated from HTLV-1-infected individuals. The levels of HTLV-1 mRNA are higher in HAM/TSP patients than in ACs,(58) but viral proteins are still undetectable. Only a few reports have indicated HTLV-1 protein expression in situ.(59)

HTLV-1 expression in ATL cells immediately after isolation from the peripheral blood is very low, and becomes significantly induced after culture for some hours in vitro.(60,61) This phenomenon is observed in about one half of ATL patients regardless of the disease severity.(62) Viral induction after in vitro culture does not occur in the other one half of ATL patients, probably because of genetic and epigenetic changes in the viral genome.(63–65) Rapid induction of viral expression after in vitro culture has also been observed in PBMCs from HAM/TSP patients and ACs,(66) indicating that there must be a common mechanism for transiently suppressing HTLV-1 expression in vivo regardless of the diseases.

Suppression of HTLV-1 expression by type-I IFN responses.

Recently, we found that type-I IFN responses are involved in the suppression of HTLV-1 expression.(34) When HTLV-1-infected T-cell line cells were co-cultured with stromal cells such as epithelial cells and fibroblasts, HTLV-1 mRNA and proteins were markedly decreased in HTLV-1-infected cells. Similarly, induction of HTLV-1 expression in cultures of primary ATL cells was also suppressed by co-culture with stromal cells. Type-I IFNs were involved in the stromal cell-mediated suppression of HTLV-1 expression, because it was partly neutralized by anti-IFN-α/β receptor antibodies. Since efficient HTLV-1 expression is dependent on transactivation of its own LTR by Tax protein,(30,67) limitation of this protein below a certain level will lead to the maintenance of HTLV-1 expression at low levels. Stromal cells reduced viral expression via type-I IFNs, but did not reduce cell growth and even supported it by unknown mechanisms.(34,68)

It has been reported that plasmacytoid dendritic cells (pDCs), a major producer of type-I IFNs, are susceptible to HTLV-1 infection.(69,70) In ATL patients, pDCs are decreased in number and also lack the ability to produce IFN-α.(69) A recent report indicated that pDCs generate type-I IFNs mainly through TLR7 recognition of HTLV-1 RNA.(71) The precise mechanisms of the HTLV-1-mediated IFN responses remain to be clarified.

In addition to recombinant IFN-α and IFN-β, recombinant IFN-γ was also capable of reducing HTLV-1 expression to lesser extents in HTLV-1-infected cell lines.(34,72) Participation of type-II IFN-producing cells other than stromal cells in HTLV-1 suppression in vivo is also conceivable.

Potential involvement of type-I IFNs in HTLV-1 suppression in vivo. 

In in vitro experiments, co-cultured stromal cells suppressed viral expression in HTLV-1-infected cells. Interestingly, when infected cells were re-isolated from the co-cultures, viral expression was restored to the original level over the following 48 h (Fig. 3).(34) This observation shows a striking similarity to the rapid induction of HTLV-1 expression in freshly isolated ATL cells after culture in vitro.

image

Figure 3.  Reversible suppression of human T-cell leukemia virus type 1 (HTLV-1) expression by innate immunity. (A) When IL-2-dependent HTLV-1-infected cells are co-cultured with 293T cells, intracellular HTLV-1 Gag proteins in the infected cells are decreased within 48 h (left panel). When the infected cells are re-isolated and further cultured on their own, Gag expression is recovered within 48 h (right panel).(34) (B) Scheme of the presumed status of HTLV-1-infected cells in vivo. Viral expression (indicated as pink) would be suppressed in tissues with strong IFN responses (left) and increased in tissues with weak IFN responses (right). CTL function, if any, is only effective upon viral expression, resulting in an infected cell reservoir without viral expression (left) and a T-cell surveillance system with low efficiency (right).

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Involvement of type-I IFN responses in the suppression of HTLV-1 expression in vivo was confirmed using interferon regulatory factor-7-KO mice, which are deficient in most type-I IFN responses. Viral expression in HTLV-1-infected cells was significantly suppressed when the infected cells were intraperitoneally injected into WT mice but not into interferon regulatory factor-7-KO mice.(34)

It is speculated that the levels of viral expression in HTLV-1-infected lymphocytes may differ among various tissues depending upon the strength of IFN responses. Thus far, there is little information regarding HTLV-1 expression in various tissues. In transgenic mice with an HTLV-1 LTR-driven construct of the pX gene, expression of the transgene was only observed in limited organs including the central nervous system, eyes, salivary glands and joints.(73) It is intriguing that all of these tissues are involved in human inflammatory diseases related to HTLV-1 infection. Such coincidences suggest the involvement of HTLV-1 gene expression in the pathogenesis of these inflammatory diseases.

Double control of HTLV-1 by innate and acquire immunity

  1. Top of page
  2. Abstract
  3. Control of HTLV-1 by HTLV-1-specific T-cell responses
  4. Control of HTLV-1 by innate immunity
  5. Double control of HTLV-1 by innate and acquire immunity
  6. Conclusions
  7. Acknowledgments
  8. References

Relationship between acquired and innate immune control in HTLV-1 infection.

At the primary infection, type-I IFNs generally play a critical role in limiting viral replication, and have positive effects on antigen presentation by activating DCs, inducing type-II IFN, and upregulating MHC-I, which subsequently augments T-cell responses.(74) However, the role of type-I IFNs in the chronic phase of viral infection may not always be positive. In HIV-1 infection, type-I IFNs may be a progressive factor for the disease by accelerating T-cell exhaustion.(75)

Suppression of HTLV-1 expression by type-I IFNs may reduce the efficacy of T-cell-mediated surveillance against HTLV-1-infected cells, because T-cells require viral proteins for recognition. On the contrary, if the IFN-mediated suppressive system is insufficient, HTLV-1-specific T-cell responses will be activated in response to viral antigens.

The relationship between innate and acquired immunity may also differ among tissues. In tissues with strong IFN responses, viral expression in the infected cells would be suppressed and CTLs would ignore these cells. However, in tissues with weak IFN responses, infected cells would express viral antigens to be recognized by CTLs (Fig. 3). These presumptions can explain the status of HTLV-1-infected cells in vivo, which comprises a large reservoir of infected cells without viral expression and a low-efficiency surveillance system by CTLs that can only work on limited occasions.

Potential relationship between disease manifestation and innate and acquired host immunity in HTLV-1 infection.

Although suppression of HTLV-1 expression may partly interfere with the efficacy of T-cell immunity, it may contribute to a slowing down of the Tax-mediated pathogenesis, tumorigenesis and inflammation (Fig. 4). In a rat model, shRNA-mediated suppression of Tax in HTLV-1-transformed cells rendered these cells resistant to Tax-specific CTLs but also reduced their ability for tumorigenesis in vivo.(76) Continuous suppression of HTLV-1 expression in humans may have a similar decelerating effect against Tax-mediated tumorigenesis. This might be a reason why it takes so long for ATL to develop. So long as the viral expression is well controlled, the viral pathogenesis may not be apparent until malignant cell clones finally come through the process of clonal evolution in the infected cell reservoir. Without proper T-cell responses, the emergence of such clones may occur earlier, because they would have more chance to survive.

image

Figure 4.  Hypothetical relationships among the host immunity, status of human T-cell leukemia virus type 1 (HTLV-1)-infected cells and symptoms. HTLV-1-infected cells are controlled by at least two systems: type-I IFNs (innate immunity) and HTLV-1-specific T-cells (acquired immunity). The former suppress viral expression and the latter kill infected cells. An increase in viral expression would accelerate inflammation, increase the number of infected cells through de novo infection and activate HTLV-1-specific T-cells that determine an equilibrium level of proviral load within an individual. Viral expression may be a positive, but not absolute, factor for cell proliferation. When the viral expression is well controlled, the viral pathogenesis will proceed slowly, and may not be apparent until infected cell clones with a malignant phenotype finally emerge from the enlarged infected cell reservoir. Without proper T-cell responses, the emergence of such clones may occur earlier, because they would have more chance to survive.

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HAM/TSP patients show elevated levels of viral expression for an unknown reason. Increased levels of inflammatory cytokines could be either a cause or a result of this phenomenon. The involvement of HTLV-1 proviral integration sites in transcription units in elevated viral expression has also been suggested.(77) An experimental rat model of HAM/TSP using a certain WKAH strain exhibits increased Tax mRNA expression in the spinal cord without T-cell infiltration,(78) suggesting that viral expression is a primary event while T-cell responses are not. Further studies revealed that this particular rat strain contains mutations in the promoter region of the IL-12 receptor, which potentially lead to reduced IFN-γ production in the spinal cord.(72) The associations of genetic factors related to the IFN system with HAM/TSP patients have remained obscure. Very recently, a gene expression profiling study indicated that expression of suppressor of cytokine signaling 1 (SOCS1) is upregulated in HAM/TSP patients and ACs, and is positively correlated with high HTLV-1 mRNA loads.(79)

Conclusions

  1. Top of page
  2. Abstract
  3. Control of HTLV-1 by HTLV-1-specific T-cell responses
  4. Control of HTLV-1 by innate immunity
  5. Double control of HTLV-1 by innate and acquire immunity
  6. Conclusions
  7. Acknowledgments
  8. References

HTLV-1 is controlled by both acquired and innate immunity. HTLV-1-specific T-cells contribute to antitumor surveillance, and type-I IFNs contribute to silencing viral expression. The presence of the double control systems with partial conflicts would explain some of the puzzles in HTLV-1 infection, such as the transient suppression of viral expression in vivo, apparently reciprocal occurrence of ATL and HAM/TSP, inconsistent correlations of proviral loads with T-cell responses, and a long incubation period.

Insufficient T-cell responses are regarded as a risk factor for ATL, and vaccines that augment HTLV-1-specific T-cell responses would be beneficial in reducing the risk in a subpopulation of HTLV-1 carriers exhibiting insufficient T-cell responses and elevated proviral loads.

Innate immune responses in HTLV-1 infection should be further investigated, because they could be another important determinant of disease manifestation and represent therapeutic targets in HTLV-1-related diseases.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Control of HTLV-1 by HTLV-1-specific T-cell responses
  4. Control of HTLV-1 by innate immunity
  5. Double control of HTLV-1 by innate and acquire immunity
  6. Conclusions
  7. Acknowledgments
  8. References

We thank Dr Jun Okamura (National Kyushu Cancer Center) for his invaluable advices and enormous efforts to co-ordinate basic and clinical investigators on HTLV-1 research in Japan. The authors have no conflicting financial interests. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Ministry of Health, Labour, and Welfare of Japan.

References

  1. Top of page
  2. Abstract
  3. Control of HTLV-1 by HTLV-1-specific T-cell responses
  4. Control of HTLV-1 by innate immunity
  5. Double control of HTLV-1 by innate and acquire immunity
  6. Conclusions
  7. Acknowledgments
  8. References
  • 1
    Hinuma Y, Nagata K, Hanaoka M et al. Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci USA 1981; 78: 647680.
  • 2
    Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA 1980; 77: 74159.
  • 3
    Tajima K. The 4th nation-wide study of adult T-cell leukemia/lymphoma (ATL) in Japan: estimates of risk of ATL and its geographical and clinical features. The T- and B-cell Malignancy Study Group. Int J Cancer 1990; 45: 23743.
  • 4
    Uchiyama T. Human T cell leukemia virus type I (HTLV-I) and human diseases. Annu Rev Immunol 1997; 15: 1537.
  • 5
    Osame M, Usuku K, Izumo S et al. HTLV-I associated myelopathy, a new clinical entity. Lancet 1986; 1: 10312.
  • 6
    Gessain A, Barin F, Vernant JC et al. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet 1985; 2: 40710.
  • 7
    Mochizuki M, Watanabe T, Yamaguchi K et al. Uveitis associated with human T-cell lymphotropic virus type I. Am J Ophthalmol 1992; 114: 1239.
  • 8
    Nishioka K, Maruyama I, Sato K, Kitajima I, Nakajima Y, Osame M. Chronic inflammatory arthropathy associated with HTLV-I. Lancet 1989; 1: 441.
  • 9
    Utsunomiya A, Miyazaki Y, Takatsuka Y et al. Improved outcome of adult T cell leukemia/lymphoma with allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 27: 1520.
  • 10
    Okamura J, Utsunomiya A, Tanosaki R et al. Allogeneic stem-cell transplantation with reduced conditioning intensity as a novel immunotherapy and antiviral therapy for adult T-cell leukemia/lymphoma. Blood 2005; 105: 41435.
  • 11
    Yamamoto K, Utsunomiya A, Tobinai K et al. Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. J Clin Oncol 2010; 28: 15918.
  • 12
    Hermine O, Allard I, Levy V, Arnulf B, Gessain A, Bazarbachi A. A prospective phase II clinical trial with the use of zidovudine and interferon-alpha in the acute and lymphoma forms of adult T-cell leukemia/lymphoma. Hematol J 2002; 3: 27682.
  • 13
    Yoshida M. Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu Rev Immunol 2001; 19: 47596.
  • 14
    Grassmann R, Aboud M, Jeang KT. Molecular mechanisms of cellular transformation by HTLV-1 Tax. Oncogene 2005; 24: 597685.
  • 15
    Jeang KT, Giam CZ, Majone F, Aboud M. Life, death, and tax: role of HTLV-I oncoprotein in genetic instability and cellular transformation. J Biol Chem 2004; 279: 319914.
  • 16
    Matsuoka M, Jeang KT. Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer 2007; 7: 27080.
  • 17
    Kannagi M, Sugamura K, Kinoshita K, Uchino H, Hinuma Y. Specific cytolysis of fresh tumor cells by an autologous killer T cell line derived from an adult T cell leukemia/lymphoma patient. J Immunol 1984; 133: 103741.
  • 18
    Jacobson S, Shida H, McFarlin DE, Fauci AS, Koenig S. Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease. Nature 1990; 348: 2458.
  • 19
    Arnulf B, Thorel M, Poirot Y et al. Loss of the ex vivo but not the reinducible CD8+ T-cell response to Tax in human T-cell leukemia virus type 1-infected patients with adult T-cell leukemia/lymphoma. Leukemia 2004; 18: 12632.
  • 20
    Kato H, Koya Y, Ohashi T et al. Oral administration of human T-cell leukemia virus type 1 induces immune unresponsiveness with persistent infection in adult rats. J Virol 1998; 72: 728993.
  • 21
    Hasegawa A, Ohashi T, Hanabuchi S et al. Expansion of human T-cell leukemia virus type 1 (HTLV-1) reservoir in orally infected rats: inverse correlation with HTLV-1-specific cellular immune response. J Virol 2003; 77: 295663.
  • 22
    Kannagi M, Harashima N, Kurihara K et al. Tumor immunity against adult T-cell leukemia. Cancer Sci 2005; 96: 24955.
  • 23
    Jacobson S. Human T lymphotropic virus, type-I myelopathy: an immunopathologically mediated chronic progressive disease of the central nervous system. Curr Opin Neurol 1995; 8: 17983.
  • 24
    Osame M. Pathological mechanisms of human T-cell lymphotropic virus type I-associated myelopathy (HAM/TSP). J Neurovirol 2002; 8: 35964.
  • 25
    Jeffery KJ, Usuku K, Hall SE et al. HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy. Proc Natl Acad Sci USA 1999; 96: 384853.
  • 26
    Bangham CR, Osame M. Cellular immune response to HTLV-1. Oncogene 2005; 24: 603546.
  • 27
    Akimoto M, Kozako T, Sawada T et al. Anti-HTLV-1 tax antibody and tax-specific cytotoxic T lymphocyte are associated with a reduction in HTLV-1 proviral load in asymptomatic carriers. J Med Virol 2007; 79: 97786.
  • 28
    Kubota R, Kawanishi T, Matsubara H, Manns A, Jacobson S. HTLV-I specific IFN-gamma+ CD8+ lymphocytes correlate with the proviral load in peripheral blood of infected individuals. J Neuroimmunol 2000; 102: 20815.
  • 29
    Kinoshita T, Shimoyama M, Tobinai K et al. Detection of mRNA for the tax1/rex1 gene of human T-cell leukemia virus type I in fresh peripheral blood mononuclear cells of adult T-cell leukemia patients and viral carriers by using the polymerase chain reaction. Proc Natl Acad Sci USA 1989; 86: 56204.
  • 30
    Fujisawa J, Seiki M, Kiyokawa T, Yoshida M. Functional activation of the long terminal repeat of human T-cell leukemia virus type I by a trans-acting factor. Proc Natl Acad Sci USA 1985; 82: 227781.
  • 31
    Newbound GC, O’Rourke JP, Collins ND, Andrews JM, DeWille J, Lairmore MD. Repression of tax-mediated human t-lymphotropic virus type 1 transcription by inducible cAMP early repressor (ICER) protein in peripheral blood mononuclear cells. J Med Virol 2000; 62: 28692.
  • 32
    Jiang S, Inada T, Tanaka M, Furuta RA, Shingu K, Fujisawa J. Involvement of TORC2, a CREB co-activator, in the in vivo-specific transcriptional control of HTLV-1. Retrovirology 2009; 6: 73.
  • 33
    Satou Y, Yasunaga J, Yoshida M, Matsuoka M. HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. Proc Natl Acad Sci USA 2006; 103: 7205.
  • 34
    Kinpara S, Hasegawa A, Utsunomiya A et al. Stromal cell-mediated suppression of human T-cell leukemia virus type 1 expression in vitro and in vivo by type I interferon. J Virol 2009; 83: 51018.
  • 35
    Kannagi M, Sugamura K, Sato H, Okochi K, Uchino H, Hinuma Y. Establishment of human cytotoxic T cell lines specific for human adult T cell leukemia virus-bearing cells. J Immunol 1983; 130: 29426.
  • 36
    Parker CE, Daenke S, Nightingale S, Bangham CR. Activated, HTLV-1-specific cytotoxic T-lymphocytes are found in healthy seropositives as well as in patients with tropical spastic paraparesis. Virology 1992; 188: 62836.
  • 37
    Kannagi M, Harada S, Maruyama I et al. Predominant recognition of human T cell leukemia virus type I (HTLV-I) pX gene products by human CD8+ cytotoxic T cells directed against HTLV- I-infected cells. Int Immunol 1991; 3: 7617.
  • 38
    Goon PK, Igakura T, Hanon E et al. Human T cell lymphotropic virus type I (HTLV-I)-specific CD4+ T cells: immunodominance hierarchy and preferential infection with HTLV-I. J Immunol 2004; 172: 173543.
  • 39
    Elovaara I, Koenig S, Brewah AY, Woods RM, Lehky T, Jacobson S. High human T cell lymphotropic virus type 1 (HTLV-1)-specific precursor cytotoxic T lymphocyte frequencies in patients with HTLV-1-associated neurological disease. J Exp Med 1993; 177: 156773.
  • 40
    Pique C, Ureta-Vidal A, Gessain A et al. Evidence for the chronic in vivo production of human T cell leukemia virus type I Rof and Tof proteins from cytotoxic T lymphocytes directed against viral peptides. J Exp Med 2000; 191: 56772.
  • 41
    Macnamara A, Rowan A, Hilburn S et al. HLA class I binding of HBZ determines outcome in HTLV-1 infection. PLoS Pathog 2010; 6: e1001117.
  • 42
    Asquith B, Mosley AJ, Barfield A et al. A functional CD8+ cell assay reveals individual variation in CD8+ cell antiviral efficacy and explains differences in human T-lymphotropic virus type 1 proviral load. J Gen Virol 2005; 86: 151523.
  • 43
    Komori K, Hasegawa A, Kurihara K et al. Reduction of human T-cell leukemia virus type 1 (HTLV-1) proviral loads in rats orally infected with HTLV-1 by reimmunization with HTLV-1-infected cells. J Virol 2006; 80: 737581.
  • 44
    Ohashi T, Hanabuchi S, Kato H et al. Prevention of adult T-cell leukemia-like lymphoproliferative disease in rats by adoptively transferred T cells from a donor immunized with human T-cell leukemia virus type 1 Tax-coding DNA vaccine. J Virol 2000; 74: 96106.
  • 45
    Hanabuchi S, Ohashi T, Koya Y et al. Regression of human T-cell leukemia virus type I (HTLV-I)-associated lymphomas in a rat model: peptide-induced T-cell immunity. J Natl Cancer Inst 2001; 93: 177583.
  • 46
    Kawano N, Shimoda K, Ishikawa F et al. Adult T-cell leukemia development from a human T-cell leukemia virus type I carrier after a living-donor liver transplantation. Transplantation 2006; 82: 8403.
  • 47
    Suzuki S, Uozumi K, Maeda M et al. Adult T-cell leukemia in a liver transplant recipient that did not progress after onset of graft rejection. Int J Hematol 2006; 83: 42932.
  • 48
    Harashima N, Kurihara K, Utsunomiya A et al. Graft-versus-Tax response in adult T-cell leukemia patients after hematopoietic stem cell transplantation. Cancer Res 2004; 64: 3919.
  • 49
    Kaplan JE, Osame M, Kubota H et al. The risk of development of HTLV-I-associated myelopathy/tropical spastic paraparesis among persons infected with HTLV-I. J Acquir Immune Defic Syndr 1990; 3: 1096101.
  • 50
    Hisada M, Okayama A, Shioiri S, Spiegelman DL, Stuver SO, Mueller NE. Risk factors for adult T-cell leukemia among carriers of human T-lymphotropic virus type I. Blood 1998; 92: 355761.
  • 51
    Iwanaga M, Watanabe T, Utsunomiya A et al. Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan. Blood 2010; 116: 12119.
  • 52
    Nagai M, Usuku K, Matsumoto W et al. Analysis of HTLV-I proviral load in 202 HAM/TSP patients and 243 asymptomatic HTLV-I carriers: high proviral load strongly predisposes to HAM/TSP. J Neurovirol 1998; 4: 58693.
  • 53
    Shimizu Y, Takamori A, Utsunomiya A et al. Impaired Tax-specific T-cell responses with insufficient control of HTLV-1 in a subgroup of individuals at asymptomatic and smoldering stages. Cancer Sci 2009; 100: 4819.
  • 54
    Wodarz D, Nowak MA, Bangham CR. The dynamics of HTLV-I and the CTL response. Immunol Today 1999; 20: 2207.
  • 55
    Toulza F, Heaps A, Tanaka Y, Taylor GP, Bangham CR. High frequency of CD4+ FoxP3+ cells in HTLV-1 infection: inverse correlation with HTLV-1-specific CTL response. Blood 2008; 111: 504753.
  • 56
    Azakami K, Sato T, Araya N et al. Severe loss of invariant NKT cells exhibiting anti-HTLV-1 activity in patients with HTLV-1-associated disorders. Blood 2009; 114: 320815.
  • 57
    Harashima N, Tanosaki R, Shimizu Y et al. Identification of two new HLA-A*1101-restricted tax epitopes recognized by cytotoxic T lymphocytes in an adult T-cell leukemia patient after hematopoietic stem cell transplantation. J Virol 2005; 79: 1008892.
  • 58
    Yamano Y, Nagai M, Brennan M et al. Correlation of human T-cell lymphotropic virus type 1 (HTLV-1) mRNA with proviral DNA load, virus-specific CD8(+) T cells, and disease severity in HTLV-1-associated myelopathy (HAM/TSP). Blood 2002; 99: 8894.
  • 59
    Hasui K, Utsunomiya A, Izumo S et al. An immunohistochemical analysis of peripheral blood tissue specimens from leukemia cells: Leukemic cells of Adult T-cell leukemia/lymphoma express p40Tax protein of human T-cell lymphotropic virus type 1 when entering reproliferation. Acta Histochem Cytochem 2003; 36: 34552.
  • 60
    Hinuma Y, Gotoh Y, Sugamura K et al. A retrovirus associated with human adult T-cell leukemia: in vitro activation. Gann 1982; 73: 3414.
  • 61
    Umadome H, Uchiyama T, Hori T et al. Close association between interleukin 2 receptor mRNA expression and human T cell leukemia/lymphoma virus type I viral RNA expression in short-term cultured leukemic cells from adult T cell leukemia patients. J Clin Invest 1988; 81: 5261.
  • 62
    Kurihara K, Harashima N, Hanabuchi S et al. Potential immunogenicity of adult T cell leukemia cells in vivo. Int J Cancer 2005; 114: 25767.
  • 63
    Takeda S, Maeda M, Morikawa S et al. Genetic and epigenetic inactivation of tax gene in adult T-cell leukemia cells. Int J Cancer 2004; 109: 55967.
  • 64
    Tamiya S, Matsuoka M, Etoh K et al. Two types of defective human T-lymphotropic virus type I provirus in adult T-cell leukemia. Blood 1996; 88: 306573.
  • 65
    Koiwa T, Hamano-Usami A, Ishida T et al. 5′-long terminal repeat-selective CpG methylation of latent human T-cell leukemia virus type 1 provirus in vitro and in vivo. J Virol 2002; 76: 938997.
  • 66
    Hanon E, Hall S, Taylor GP et al. Abundant tax protein expression in CD4+ T cells infected with human T-cell lymphotropic virus type I (HTLV-I) is prevented by cytotoxic T lymphocytes. Blood 2000; 95: 138692.
  • 67
    Sodroski J, Rosen C, Goh WC, Haseltine W. A transcriptional activator protein encoded by the x-lor region of the human T-cell leukemia virus. Science 1985; 228: 14304.
  • 68
    Nagai K, Jinnai I, Hata T et al. Adhesion-dependent growth of primary adult T cell leukemia cells with down-regulation of HTLV-I p40Tax protein: a novel in vitro model of the growth of acute ATL cells. Int J Hematol 2008; 88: 55164.
  • 69
    Hishizawa M, Imada K, Kitawaki T, Ueda M, Kadowaki N, Uchiyama T. Depletion and impaired interferon-alpha-producing capacity of blood plasmacytoid dendritic cells in human T-cell leukaemia virus type I-infected individuals. Br J Haematol 2004; 125: 56875.
  • 70
    Jones KS, Petrow-Sadowski C, Huang YK, Bertolette DC, Ruscetti FW. Cell-free HTLV-1 infects dendritic cells leading to transmission and transformation of CD4(+) T cells. Nat Med 2008; 14: 42936.
  • 71
    Colisson R, Barblu L, Gras C et al. Free HTLV-1 induces TLR7-dependent innate immune response and TRAIL relocalization in killer plasmacytoid dendritic cells. Blood 2010; 115: 217785.
  • 72
    Miyatake Y, Ikeda H, Ishizu A et al. Role of neuronal interferon-gamma in the development of myelopathy in rats infected with human T-cell leukemia virus type 1. Am J Pathol 2006; 169: 18999.
  • 73
    Iwakura Y, Tosu M, Yoshida E et al. Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I. Science 1991; 253: 10268.
  • 74
    Medzhitov R, Janeway CA Jr. Innate immunity: impact on the adaptive immune response. Curr Opin Immunol 1997; 9: 49.
  • 75
    Boasso A, Shearer GM. Chronic innate immune activation as a cause of HIV-1 immunopathogenesis. Clin Immunol 2008; 126: 23542.
  • 76
    Nomura M, Ohashi T, Nishikawa K et al. Repression of tax expression is associated both with resistance of human T-cell leukemia virus type 1-infected T cells to killing by tax-specific cytotoxic T lymphocytes and with impaired tumorigenicity in a rat model. J Virol 2004; 78: 382736.
  • 77
    Meekings KN, Leipzig J, Bushman FD, Taylor GP, Bangham CR. HTLV-1 integration into transcriptionally active genomic regions is associated with proviral expression and with HAM/TSP. PLoS Pathog 2008; 4: e1000027.
  • 78
    Tomaru U, Ikeda H, Ohya O et al. Human T lymphocyte virus type I-induced myeloneuropathy in rats: implication of local activation of the pX and tumor necrosis factor-alpha genes in pathogenesis. J Infect Dis 1996; 174: 31823.
  • 79
    Oliere S, Hernandez E, Lezin A et al. HTLV-1 Evades Type I Interferon Antiviral Signaling by Inducing the Suppressor of Cytokine Signaling 1 (SOCS1). PLoS Pathog 2010; 6: e1001177.