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Journal of Virology, September 1998, p. 7289-7293, Vol. 72, No. 9
Department of Immunotherapeutics,
Received 12 January 1998/Accepted 3 June 1998
The major route of human T-cell leukemia virus type 1 (HTLV-1)
infection is mother-to-child transmission caused by breast-feeding. We
investigated the host immune responses to orally established persistent
HTLV-1 infection in adult rats. HTLV-1-producing MT-2 cells were
inoculated into immunocompetent adult rats either orally, intravenously, or intraperitoneally. HTLV-1 proviruses were detected in
the peripheral blood and several organs for at least 12 weeks. Transmission of HTLV-1 to these animals was confirmed by analysis of
HTLV-1 flanking regions. Despite persistent HTLV-1 presence, none of
the orally inoculated rats produced detectable levels of anti-HTLV-1
antibodies, whereas all intravenously or intraperitoneally inoculated
rats showed significant anti-HTLV-1 antibody responses. T-cell
proliferative responses against HTLV-1 were also absent in orally
inoculated rats. Our findings suggest that gastrointestinal exposure of
adult rats to HTLV-1-infected cells induces persistent HTLV-1 infection
in the absence of both humoral and cellular immune responses against
HTLV-1. This immune unresponsiveness at primary infection may
subsequently affect the host defense ability against HTLV-1.
Human T-cell leukemia virus type 1 (HTLV-1) is a human retrovirus associated with T-cell malignancies
(5, 26). Most HTLV-1-infected individuals remain
asymptomatic, and less than 5% develop adult T-cell leukemia,
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), or
other HTLV-1-associated diseases (11, 32). A number of
studies have shown that the variable clinical outcome of
HTLV-1 infection cannot be explained by different genetic forms of HTLV-1 strains (2, 16, 17). Instead, the
pathogenesis of HTLV-1 is more likely to be influenced by other
factors, such as oncogenic mutations and host factors.
One of the host factors that may determine the development of diseases
is the level of the immune response to HTLV-1 in individual subjects.
For example, the activity of HTLV-1-specific cytotoxic T lymphocytes in
peripheral blood is low in adult T-cell leukemia patients but high in
HAM/TSP patients (8-10). In the presence of a weak
cytotoxic-T-lymphocyte response, HTLV-1 can easily replicate and the
infected cells may have better chances to multiply and acquire an
autonomously proliferative character. Admittedly, the exact mechanisms
resulting in different immune responses to HTLV-1 are still unclear.
Involvement of the genetic background and immunological tolerance
in HTLV-1 carriers have been suggested (36). A number of
vertically HTLV-1-infected individuals lack antibody responses to
HTLV-1 during infancy (27), supporting the notion of
tolerance for HTLV-1 infection.
The transmission routes for HTLV-1 include mother-to-child
transmission, sexual contact, and parenteral transmission through blood
transfusion or intravenous drug use (4, 13, 25, 31). Among
these, mother-to-child transmission is the major natural transmission
pathway in Japan (4, 13, 23). HTLV-1 is detected in breast
milk from carrier mothers and sometimes in the cord blood
(28). The infants of these mothers are reported to be fed
about 108 HTLV-1-infected cells before weaning (14,
23). In contrast, bottle feeding prevents most infants from
acquiring HTLV-1 infection (1), indicating that postnatal
infection by breast-feeding is the major form of mother-to-child
transmission of HTLV-1, although prenatal infection also occurs, but at
a low frequency.
Oral administration of protein antigens is known to induce peripheral
tolerance for the fed antigens (3, 39). Since HTLV-1 is
transmitted to infants mainly via breast milk, gastrointestinal exposure to HTLV-1 could be one reason for immunological tolerance for
HTLV-1. A few studies showed that oral administration of
HTLV-1-producing cells transmitted HTLV-1 to common marmosets and
rabbits (15, 35, 41). However, no studies have fully
characterized the immunological responses in orally HTLV-1-infected
animals.
In the present study, we investigated the immune responses to HTLV-1 in
adult rats orally inoculated with HTLV-1-producing cells and found a
persistent HTLV-1 infection in the absence of humoral and cellular
immune responses. Our results indicate that the immune
unresponsiveness in oral HTLV-1 infection may be one of the
determinants affecting the host defense system against HTLV-1.
Animals and inoculation of HTLV-1.
Inbred female F344/N
Jcl-rnu/+ rats were purchased from Clea Japan, Inc. (Tokyo,
Japan). A human HTLV-1-infected T-cell line, MT-2, was used as the
viral source.
Detection of HTLV-1 provirus.
HTLV-1 provirus in peripheral
blood and tissues was detected by the nested PCR method. For this
purpose, 3 µl of each whole blood sample was lysed in a Gene trap
solution (single-tube PCR kit; Takara, Kyoto, Japan), precipitated, and
used as a template for PCR amplification. DNA samples from organ
tissues were prepared by sodium dodecyl sulfate and proteinase K
digestion, purification with phenol-chloroform, and ethanol
precipitation. A 0.5-µg quantity of each DNA sample was used as a PCR
template.
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Oral Administration of Human T-Cell Leukemia Virus
Type 1 Induces Immune Unresponsiveness with Persistent Infection in
Adult Rats
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
Analysis of HTLV-1 flanking regions. HTLV-1 flanking regions of MT-2 cells were obtained by the inverse PCR method as described by Takemoto et al. (33). Briefly, Sau3AI-digested cellular DNA of MT-2 cells was self-ligated and amplified with HTLV-1 long terminal repeat-specific primers. The fragments were cloned, and the sequence of one of the clones was determined by the dideoxy method with an Applied Biosystems DNA sequence kit. Primers MT2-1 (5'-TCCTCCAGTGACGCGCGCTG-3') and MT2-2' (5'-GTGTAGTCCTTCAGCCCAGT-3') were prepared based on the obtained HTLV-1 flanking sequence of MT-2 cells. The HTLV-1 long terminal repeat-specific primers used were U5-4 (5'-CCAGCGACAGCCCATTCTAT-3') and U5-5 (5'-CTCCAGGAGAGAAATTTAGTACAC-3'). Nested PCR amplifications were performed with outer primer set MT2-1 and U5-4 and inner primer set MT2-2' and U5-5 for 30 cycles with each set under conditions similar to those described above.
Detection of antibodies against HTLV-1 antigens. The titers of serum antibodies against HTLV-1 antigens were determined with a particle agglutination test kit (Serodia HTLV-I; Fuji Rebio Inc., Tokyo, Japan).
Proliferation assay. Spleen cells from naive and HTLV-1-inoculated rats were enriched for T cells with a nylon-wool column, suspended in interleukin 2 (IL-2)-free medium, and used as responder cells. To prepare stimulator cells, HTLV-1-infected FPM-1 cells established from a syngeneic rat (unpublished data) were treated with 1% formalin in phosphate-buffered saline for 5 min, washed, and resuspended in IL-2-free medium. Phytohemagglutinin (PHA) (Difco Laboratories, Detroit, Mich.) was used at a final 1% concentration as a positive control.
Responder cells (105 per well) were cultured in a 96-well round-bottom plate in the presence or absence of equal numbers of stimulator cells for 96 h in triplicate. Finally, [3H]thymidine (37 kBq/well) was added during the last 12 h, the cells were harvested on a glass filter, and thymidine incorporation into the cells was measured. The results were expressed as the mean counts per minute of triplicate cultures ± the standard deviation. Thymidine uptake into formalin-treated cells was less than 36 cpm.| |
RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Oral inoculation of HTLV-1 does not produce antibody responses. To compare the immune responses to HTLV-1 in animals infected through various routes, we inoculated HTLV-1-producing MT-2 cells orally, intravenously, or intraperitoneally into 4-week-old immunocompetent F344/N Jcl-rnu/+ rats. The serial changes in antibody titers to HTLV-1 in these animals are shown in Fig. 1. All intravenously or intraperitoneally inoculated rats produced anti-HTLV-1 antibodies as early as 2 to 4 weeks after inoculation, and the antibody titers gradually increased during the observation period of 12 weeks. In contrast, none of the four orally inoculated rats showed such an anti-HTLV-1 antibody response. Although some of these animals were monitored for up to 16 weeks after inoculation, the titers remained below the detection levels during that period.
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), intravenously (
), and intraperitoneally (
) into four, six,
and three F344/N Jcl-rnu/+ rats, respectively. The
anti-HTLV-1 antibody titers in the sera of these animals were
determined by the particle agglutination method. Data are the averages
of the titers ± standard deviations for each group.
2n, log2.
Presence of HTLV-1 provirus in inoculated rats. Although several inbred strains of adult rats are known to show persistent infection with HTLV-1 after intravenous inoculation with HTLV-1-producing cells (6, 30), little is known about orally inoculated rats. Accordingly, we used the PCR method to assess whether the rats inoculated with MT-2 cells were infected with HTLV-1. DNA extracted from 3 µl of each whole peripheral blood sample was used as a template for PCR amplification. At 6 to 8 weeks after inoculation, HTLV-1 provirus was detected in peripheral blood samples from four of the four orally, three of the three intraperitoneally, and five of the six intravenously inoculated rats (Table 1). After that, the presence of the provirus was confirmed in all animals during the period of observation or at autopsy. These findings indicate that HTLV-1 disseminates systemically in orally inoculated rats as well as intravenously or intraperitoneally inoculated ones. A similar seronegative HTLV-1 carrier state was induced in WKA/HKm rats by oral administration of MT-2 cells (data not shown).
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Tissue distribution of HTLV-1. The systemic dissemination of HTLV-1 in orally inoculated rats was also demonstrated by PCR analysis of DNA samples from various organs with primers specific for the pX and gag regions. HTLV-1 proviruses were present in tissues from two orally inoculated rats (E3 and E4) sacrificed at 3 months after inoculation (Fig. 2). HTLV-1 provirus was detected in various organs, including the submandibular gland, thymus, lungs, liver, spleen, lymph nodes, Peyer's patches, and peripheral blood mononuclear cells, in rat E3 (Fig. 2A). Although a small amount of HTLV-1 was present in animal E4 relative to the other animal, the provirus was detected in the lymphoid tissues and submandibular gland (Fig. 2A). However, HTLV-1 provirus was below the detection level in the brain and kidneys of both rats.
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Lack of long-term MT-2 survival in orally inoculated rats. To exclude the possible long-term survival of MT-2 cells in vivo in rats orally inoculated with HTLV-1, we analyzed the HTLV-1 flanking regions in infected cells of these animals. For this purpose, we cloned HTLV-1 flanking regions of MT-2 cells by using an inverse PCR method. Based on the nucleotide sequences of these regions, we prepared primers to specifically amplify the HTLV-1 flanking regions of MT-2 cells.
As shown in Fig. 3, by use of the nested PCR method, DNA fragments specific for pX and HTLV-1 flanking regions of MT-2 cells were amplified with a DNA template of MT-2 cells. In contrast, no fragment specific for the HTLV-1 flanking regions of MT-2 cells was amplified with a DNA template of the submandibular gland from an orally inoculated rat, whereas pX-specific fragments could be amplified with this template as well as the MT-2 template. These results suggested that HTLV-1-infected cells in orally inoculated rats differed from MT-2 cells but originated from host cells transmitted with HTLV-1 in vivo. Thus, oral administration of MT-2 cells transmitted HTLV-1 to the rats and induced a persistent HTLV-1 infection without an antibody response.
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Lack of T-cell proliferative responses against HTLV-1 after oral inoculation. In the next step, we examined T-cell proliferative responses against HTLV-1 antigens in HTLV-1-inoculated animals. A syngeneic rat HTLV-1-infected cell line, FPM-1, was used for HTLV-1 antigen-presenting cells. T-cell-enriched spleen cells from orally, intravenously, and intraperitoneally inoculated or naive rats were collected and incubated in the presence or absence of formalin-treated FPM-1 cells, and thymidine incorporation in these cells was measured.
Figure 4 shows the results for four representative animals. Spleen cells from orally inoculated rat E2 hardly proliferated in response to HTLV-1 antigens but proliferated with PHA stimulation. A similar pattern of T-cell proliferation was observed for another two orally inoculated rats and was indistinguishable from that of naive animals. In contrast, there was a significant proliferative response of T cells to HTLV-1 in intravenously or intraperitoneally inoculated rats. The pattern of T-cell proliferation in these animals was divided into two types, irrespective of the route of inoculation. The first pattern was observed for four animals and is represented by the results for rat D6 (Fig. 4), showing the proliferation of spleen T cells even in the absence of stimulation; this proliferation was hardly influenced by HTLV-1 stimulation. The second pattern was observed for four animals and is represented by the results for rat G4 (Fig. 4), showing a strong proliferative response of spleen T cells to HTLV-1 antigens. The response was confirmed to be specific for HTLV-1 by demonstrating that it was not induced by formalin-treated syngeneic rat simian virus 40-transformed cells (data not shown). Thus, orally HTLV-1-inoculated rats showed cellular as well as humoral immune unresponsiveness to HTLV-1 antigens.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The major finding of the present study was that oral administration of HTLV-1-infected cells induced both persistent HTLV-1 infection and immune unresponsiveness to HTLV-1. Orally inoculated rats completely lacked both antibody and T-cell responses to HTLV-1 antigens. In contrast, these responses were detected in intravenously or intraperitoneally inoculated rats. HTLV-1 provirus was detected in peripheral blood from orally inoculated rats as frequently as in that from intravenously or intraperitoneally inoculated rats, indicating that the quality of the anti-HTLV-1 immune responses but not viral persistence was affected by the route of HTLV-1 transmission.
Since the major cause of HTLV-1 infection is breast-feeding of infants by carrier mothers, it is possible that oral tolerance may occur in humans. It should be noted, however, that there are certain differences between our experimental design and natural milk-borne infection of children. For example, milk-borne HTLV-1 transmission in humans occurs after multiple low doses provided over a period of a few months, whereas we inoculated HTLV-1-infected cells into rats orally in a single dose. In addition, we used adult rats, while HTLV-1 infection occurs in neonates in humans. Therefore, neonatal tolerance and maternal antibodies may modify host immunity in humans.
Various animal models of HTLV-1 infection have been described. A seronegative HTLV-1 carrier state is produced in rabbits and rats by intraperitoneal inoculation with HTLV-1-producing cells during the neonatal period (6, 29). The development of the seronegative carrier state in these animals is thought to be due to immaturity of the immune system. Other investigators demonstrated that HTLV-1 could be orally transmitted to common marmosets and rabbits (15, 35, 41). In these reports, low levels of antibodies to HTLV-1 were present in a small proportion of inoculated animals, and this finding was regarded as evidence for HTLV-1 transmission. In our study, however, all orally infected rats lacked antibody responses. The discrepancy between our findings and those of previous studies may be due to differences in the species or experimental procedures. In such experiments, a minor injury during oral administration might cause a positive reaction. Further studies are required to clarify species differences.
Friedman and Weiner reported that the mechanism of oral tolerance
induced by hen egg white lysozyme or myelin basic protein is determined
by the dose of the antigen (3). A high dose induces anergy
of antigen-specific Th1 cells, whereas a low dose induces active
suppression mediated by regulatory T cells secreting suppressive cytokines (20-22, 40). In the present study, the exact dose
of the antigen was difficult to evaluate, because the animals were persistently exposed to infecting HTLV-1 in addition to the initial dose of 5 × 107 MT-2 cells. In the case of natural
mother-to-child infection, the extent of exposure to HTLV-1 antigens
may vary widely from one case to another. Moreover, HTLV-1-infected
cells potentially produce cytokines affecting immune responses
(12, 24, 34, 37, 38). Therefore, the HTLV-1 system may not
be as simple as the hen egg white lysozyme or myelin basic protein
system. Involvement of suppressive cytokines, such as transforming
growth factor 
or IL-10, and induction of certain active suppression mechanisms in the immune unresponsiveness against HTLV-1 remain to be
clarified.
Interestingly, a number of intravenously or intraperitoneally inoculated rats demonstrated T-cell proliferation even without stimulation, as represented by the data for rat D6 (Fig. 4). A similar spontaneous lymphocyte proliferation has been reported for HTLV-1-infected individuals, particularly HAM/TSP patients (7, 19). This finding has been partly explained by the presence of an already activated HTLV-1-specific immune response in vivo and by HTLV-1-induced activation of growth factors and costimulatory molecules (18, 34). The absence of such spontaneous responses in orally inoculated animals in the present study suggested that host immune responses to HTLV-1 play a pivotal role in this phenomenon.
Many vertically HTLV-1-infected individuals lack antibody responses to HTLV-1 during infancy, suggesting that these subjects have, to a certain extent, immunological tolerance. Even among seroconverted individuals, the level of cellular immune responses to HTLV-1 varies and weak cellular immune responses are known to be associated with lymphoproliferative diseases. Our data for immune unresponsiveness against HTLV-1 not only in humoral but also in cellular immune responses emphasize the potential role of breast-feeding in early tolerance and weak cellular immune responses in some HTLV-1 carriers, which might be related to disease development. This possibility should be taken into consideration, particularly with prophylaxis of HTLV-1 infection.
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ACKNOWLEDGMENTS |
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We thank Masao Matsuoka (Kumamoto University, Kumamoto, Japan) for technical advice on the inverse PCR method. We also thank F. G. Issa (University of Sydney, Sydney, New South Wales, Australia) for careful reading and editing of the manuscript.
This work was supported in part by grants from the Agency of Science and Technology of Japan and from Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Immunotherapeutics, Medical Research Division, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan. Phone: 81 (3) 5803-5798. Fax: 81 (3) 5803-0235. E-mail: kann.impt{at}med.tmd.ac.jp.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Journal of Virology, September 1998, p. 7289-7293, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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