Development of Adult T-Cell Leukemia-Like Disease in African Green Monkey Associated with Clonal Integration of Simian T-Cell Leukemia Virus Type I1

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[CANCER RESEARCH 47, 269-274, January 1, 1987] Development of Adult T-Cell Leukemia-like Disease in African Green Monkey Associated with Clonal Integration of Simian T-Cell Leukemia Virus Type I1

Hajime Tsujimoto,2 Yoshihiro Noda, Koh-ichi Ishikawa, Hideo Nakamura, Masashi Fukasawa, Ippei Sakakibara, Akira Sasagawa, Shigeo Honjo, and Masanori Hayami Department of Animal Pathology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108 [H. T., Y. N., K. I., H. N., M. F., M. H.], and Tsukuba Primate Center for Medical Science, National Institute of Health, Tsukuba, Â¡baragi305 [l. S., A. S., S. H., M. H.], Japan

ABSTRACT (24, 25). Furthermore, STLV-I was shown to be able to im mortalize cultured T-cells (20, 21, 26). These structural and Proviral integration of a simian retrovirus highly homologous to human biological similarities between STLV-I and HTLV-I suggest T-cell leukemia virus type I was examined in cellular DNAs extracted the usefulness of STLV-I infection in monkeys as an animal from primary peripheral blood lymphocytes of 31 adult African green monkeys (Cercopithecus aethiops) that were seropositive for simian T- model of HTLV-I infection in man. cell leukemia virus type I (STLV-I). Among these monkeys, one case Recently, a high proportion of the macaques that developed with overt leukemia, showing pleomorphic leukemia cells similar to those spontaneous lymphoma were found to have antibodies cross- in human adult T-cell leukemia (ATL), and five cases in a preleukemic reacting with HTLV-I antigens (27). However, there is no state of ATL-like disease were found. Judging from the integration site distinct evidence for the leukemogenic potential of STLV-I. of the provirus genome, primary lymphocytes of these leukemic or Hematological abnormalities have been examined in several preleukemic cases contained monoclonally proliferated STLV-I-infected monkey species, and a typical ATL-like disease (28) and its cells, whereas lymphocytes of other seropositive monkeys without he- preleukemic state were found in African green monkeys natu matological abnormalities were polyclonal, and those of seronegative rally infected with STLV-I. This communication demonstrates monkeys did not contain the provirus. The restriction patterns with Pstl and .S'.vrlofmost STLV-I proviruses were identical to those of the previous the close association of the development of ATL-like disease with clonal integration of the STLV-I provirus genome, and isolate from this species, but in three monkeys there was a deletion of one I'stl site. From the correlation of the development of simian ATL- indicates the possible leukemogenic potential of STLV-I. like disease with the monoclonal integration of the STLV-I provirus genome, it should be indicated that STLV-I has similar leukemogenicity MATERIALS AND METHODS to human T-cell leukemia virus type I, and so STLV-I infection in African green monkeys will be useful as an animal model of human ATL. Monkeys. Forty-three adult African green monkeys, which had been imported from several countries in Africa and kept in Tsukuba Primate Center for Medical Science for 4-6 years were examined. They were INTRODUCTION kept under suitable conditions in individual cages and fed appropriately HTLV-I3 is an exogenous retrovirus isolated from mature T- for breeding. cell malignancies (1-4), and the virus is known to be the Examination of STLV-I Infection. Serum antibodies against S 11 V etiological agent of ATL (5-8). HTLV-I does not contain any I, which cross-react with HTLV-I, were examined by indirect immu nofluorescence with MT-1 cells (29). Expression of STLV-I antigens known typical oncogenes (9) and is not integrated into a specific was examined in primary uncultured and short-term cultured lymphoid site in chromosomal DNA (10). Therefore, the mechanism of leukemogenesis by HTLV-I infection is unknown, although it cells by immunofluorescence procedures as described previously (21). has been suggested that it is due to a virus-coded frans-acting Hematological Examination. Fresh primary peripheral blood samples collected from African green monkeys were taken for examination of factor (11, 12). Establishment of an animal model system morphology of the blood cells in Giemsa-stained preparations, and should be helpful in studies on leukemogenesis by HTLV-I erythrocyte and leukocyte counts. Counts of atypical cells were made infection. of lymphocytes with an incised or lobulate nucleus among more than After the discovery of HTLV-I in humans, Old World mon 400 lymphoid cells in each case. keys and apes were found to have antibodies cross-reacting with Detection and Analysis of Provirus DNA. Southern blotting (20-23) HTLV-I antigens (13-18), and several strains of HTLV-I- and nucleotide sequence (24, 25) analyses have shown the availability related simian retroviruses, STLV-I, were isolated from sÃ©ro of cloned HTLV-I DNAs for detection of the proviral genome of STLV- I. Therefore, HTLV-I probes were used in this hybridization assay. positive primates such as the chimpanzee (Pan troglodytes), Primary lymphoid cell preparations were isolated from fresh heparin- African green monkey (Cercopithecus aethiops), and several ized peripheral blood taken from African green monkeys. High molec macaque species (19-21). STLV-I has the same genomic ar ular weight cellular DNAs extracted from these cells were analyzed by rangement as HTLV-I, LTR-gag-pol-env-pX-LTR, and each Southern blot hybridization (30). Samples of cellular DNAs (3 Â¿ig/lane corresponding region is highly homologous to that of HTLV-I in Case 1 and 8 Â¿tg/laneinall other cases) were digested with restriction (20-23). However, restriction mapping indicated that STLV-I endonuclease, EcoRl, Sstl, or Pstl, and subjected to 0.8 or 1.0% agarose could be distinguished from HTLV-I and that there were several gel electrophoresis. The DNAs were then transferred to a nylon mem subtypes of STLV-I (22, 23). Sequence analysis of the STLV-I brane filter and hybridized with 32P-labeled cloned DNA fragments of genomes revealed 90-95% sequence homology with HTLV-I the HTLV-I genome under relatively stringent conditions in buffer containing 900 HIMsodium chloride, 90 HIMtrisodium citrate, 0.1% sodium dodecyl sulfate, and 10 HIM EDTA at 65Â°Cfor 24-48 h. As Received 6/10/86; revised 9/3/86; accepted 9/10/86. The costs of publication of this article were defrayed in part by the payment shown in Fig. 1, pATK-32 (gag-poi) (kindly provided by Dr. M. of page charges. This article must therefore be hereby marked advertisement in Yoshida, Cancer Institute, Tokyo, Japan), pHT-39.1 (env-pX), and accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Supported by a Grant-in-Aid for Cancer Research from the Ministry of pHT-39.2 (LTR) (kindly supplied by Dr. K. Shimotohno, National Education, Science, and Culture of Japan. Cancer Center Research Institute, Tokyo, Japan) were used as probes. 2To whom requests for reprints should be addressed. 3The abbreviations used are: HTLV-I, human T-cell leukemia virus type 1; After hybridization, the filter was washed three times in a solution containing 75 HIMsodium chloride, 7.5 mM triosodium citrate, 0.1% STLV-I, simian T-cell leukemia virus type I; ATL, adult T-cell leukemia; AG- sodium dodecyl sulfate, and 1 mM EDTA at 55"C and then exposed to STLV-I, simian T-cell leukemia virus type I of African green monkey origin; X-ray film at -70"C. LTR, long terminal repeat (sequence). 269

Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1987 American Association for Cancer Research. Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1987 American Association for Cancer Research. ATL-LIKE DISEASE IN MONKEY

A. 1 23456 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

kb â€¢ ^K. A "" â€¢" 3 Â»â€¢* 9.4-T

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B. 1 23456 7 8 9 10 11 12 13 14

Fig. 3. Integration of the provirus genome of STLV-I in the primary lymphocytes of Af 8.5- rican green monkeys. Cellular DNAs extracted from the primary lymphocytes of African green monkeys were digested with EcoRl (A), Ssll (B), or Pstl (Q and subjected to Southern blot analysis with a representative mixture probe. Numbers of lanes, case numbers of African green monkeys, i.e.. Lane 1, DNA of the STLV-I-infected monkey with overt ATL-like leukemia (Case 1); Lanes 2-6, DNAs of the STLV-I-infected monkeys in the preleukemic state of ATL-like disease (Cases 2-6); Lanes 7-19, DNAs of the STLV-I-infected healthy carrier monkeys (Cases 7-19); Lanes 20 and 21, DNAs of STLV-I-free monkeys, kb, kilobase. c. 23456 7 8 9 10 11 12 13 14

cells were polyclonal, but that a few clonally expanded cells of 8.5 kilobases was detected as in a previous isolate (23) were also present in some cases. Positive results were not indicating the presence of a common Sstl site in the LTR of obtained by this hybridization assay in the DNA samples from the proviral genome of AG-STLV-I and of the intact provirus 8 of 25 seropositive monkeys (Cases 24-31) indicating that genome in all of the infected lymphocytes (Fig. 3B). there were too few cells with integrated provirus DNA for For examination of the detailed restriction patterns and the detection in their peripheral blood. No hybridization was ob clonalities of the infected cells by viral cellular junction bands, served with the DNAs of 12 seronegative monkeys, which these DNAs of monkey lymphocytes were digested with Pstl, confirmed that STLV-I is exogenous in African green monkeys. which cuts the provirus genome of the previous isolate of AG- For characterization of the proviral DNA, the restriction STLV-I at several sites (23) (Fig. 1), and the digests were pattern with Sstl was examined in these African green monkey hybridized with a representative mixture probe. In the monkey lymphocytes. The DNA samples were digested with Sstl which with ATL-like disease (Case 1), 4 small fragments of 1.0, 1.2, cuts only in the 5' and 3' LTRs of one isolate of STLV-I of 1.3, and 1.6 kilobases corresponding to internal fragments of African green monkey origin, AG-STLV-I, in a cultured cell the previous AG-STLV-I isolate, and 2 larger fragments of 2.5 line reported previously (23), and the digests were analyzed by and 2.8 kilobases were found in the Pstl digest (Fig. 3C). DNA blot hybridization with the representative mixture probe. In all samples from 5 preleukemic monkeys also contained the 4 14 seropositive monkeys examined, which were in leukemic, small internal frgments and several faint bands of more than preleukemic, and hematologically normal states, a strong band 1.6 kilobases. In most of the leukemic, preleukemic, and he- 271 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1987 American Association for Cancer Research. ATL-LIKE DISEASE IN MONKEY

matologically normal monkeys, the 4 internal fragments iden other preleukemic monkeys (Cases 3-6) also hybridized with tical to those of the previous AG-STLV-I isolate (23) were the LTR probe. These data indicating the clonality of cells were commonly detected in the proviral genome by this assay, but in consistent with the results obtained by EcoRl digestion assay. 3 monkeys (Cases 8, 13, and 14), no 1.3-kilobase band was The different restriction pattern with Pstl detected with the detectable, and a discrete band of 2.2 kilobases was found representative probe in 3 cases (Cases 8, 13, and 14) was instead. analyzed with each probe. In Case 13, the newly detected 2.2- For identification of the fragments other than the common kilobase band hybridized with both pATK-32 and pHT-39.1, internal fragments in the leukemic and preleukemic monkeys and the 1.0- and 1.3-kilobase internal bands usually detected and for analysis of the restriction maps of the 3 provirus with pATK-32 and pHT-39.1, respectively, were not detectable genomes showing different restriction patterns with Pstl, these (Fig. 4). The same results were obtained in Cases 8 and 14. Pstl digests were hybridized with the probes of pATK-32, pHT- These findings indicated deletion of one Pstl site at the pol and 39.1, and pHT-39.2, respectively. In the DNA sample from a env junction in these proviruses, suggesting that they were typical ATL-like case, 2 discrete bands of 2.5 and 2.8 kilobases variants of AG-STLV-I. hybridized strongly with the LTR probe, pHT-39.2 (Fig. 4). As internal fragments, 3 bands of 1.0, 1.2, and 1.6 kilobases and 2 bands of 1.0 and 1.3 kilobases were detected with pATK-32 DISCUSSION and pHT-39.1, respectively (Fig. 4). The pHT-39.1 probe, In the present study, provirus integration of STLV-I was which covers env-pX and a small part of LTR, also hybridized investigated in primary lymphocytes of African green monkeys with 2 cellular viral junction bands, and the 2.8-kilobase band, infected with STLV-I. The primary lymphocytes obtained from which was more intense than the 2.5-kilobases band, probably seropositive monkeys did not express detectable viral antigens, represented the 3' flanking sequence. These data on Case 1 but most of them contained the proviral genome in their chro clearly indicated that the tumor cells were monoclonal with mosomal DNA. Therefore, the expression of viral antigens is respect to the integration site of the provirus and that the considered to be suppressed in vivo by serum antibodies or some restriction map of the internal sequences of the provirus was inhibitory factors, as is known to be the case in HTLV-I and the same as that of the previous AG-STLV-I isolate. bovine leukosis virus infections (31, 32). When the lymphocytes The proviral genome of Case 2 in the preleukemic state was are transferred to culture, they express viral antigens and release also analyzed with each probe (Fig. 4). The restriction map of extracellular virus particles which infect uninfected cells (19- Pst\ in this case, deduced from the small-sized internal frag 21). Lymphoid cell lines producing STLV-I are known to have ments that hybridized with each probe, was identical to that in multiple copies of the integrated provirus (23). Therefore, it Case 1 and the previous isolate. Two bands of 2.9 and 3.4 was necessary to examine the fresh uncultured lymphocytes to kilobases detected with the representative probe, which were determine the correlation of the development of leukemia with less intense than the viral cellular junction bands in Case 1, the manner of provirus integration. also hybridized with the LTR probe, indicating the presence of HTLV-I was shown to interact directly with target cells which monoclonally expanded cells infected with STLV-I. Further later grew as malignant transformed cells, because the primary more, the faint bands that were larger than the internal ones leukemic cells of all ATL cases tested were found to be mono detected by the representative probe in the Pstl digests from clonal with respect to the integration site of HTLV-I (5-8).

1 13

Fig. 4. Analysis with each probe of the provirus genome of STLV-I in primary lympho cytes of African green monkeys. Cellular DNAs were extracted from the primary lym phocytes of Case 1 with overt ATL-like leu kemia (Lane I, a-d). Case 2 in the preleukemic state of ATL-like disease (Lane 2, a-d), and Case 13 in which the provirus genome gave a different restriction pattern with Pstl (Lane 13, a-d). The Pstl digests were subjected to South ern blot analysis with a representative mixture probe (a), LTR probe (pHT-39.2) (*), gag-pot probe (pATK-32) (c), or env-pX probe (pHT- 39. !)(

Furthermore, preleukemic ATL cases showing no typical clin in African green monkeys were positive for Leu 2a and negative ical symptoms were found that had abnormal lymphocytes with for Leu 3a (28),4 although those in human ATL patients are an incised or lobulata! nucleus in the peripheral blood (33, 34), known to have helper/inducer T-cell markers (35). Recently, and monoclonal integration of the provirus genome was also we found that this AG-STLV-I could immortalize cultured detected in these cases (34). Lymphocytes from healthy carriers normal lymphocytes collected from Afican green monkeys that of HTLV-I had multiple integration sites (6). In the present expressed Leu 2a antigen.5 Thus, the Leu 2a-positive lympho study on the development of ATL-like disease in the African cytes may be the target of AG-STLV-I in this monkey species. green monkey, one case of typical ATL-like disease and 5 cases Previously an STLV-I-producing cell line, GM0650 (21), was of the preleukemic state were found among the STLV-I-infected established from a seropositive African green monkey and the monkeys. Southern blot analysis showed that leukemic cells provirus genome in this cell line was analyzed (21, 23). To derived from the typical leukemia case were monoclonally determine whether this isolate in GM0650 was a prototype of expanded cells in which the provirus genome was integrated species-specific STLV-I in African green monkeys, the restric into one site and that the lymphoid cells of the preleukemic tion sites of Sstl and Pstl in the provirus genome were examined monkeys also contained clonally provirus-integrated cells. in primary lymphocytes of 14 infected African green monkeys However, the STLV-I-infected lymphocytes derived from in this study. In 11 of these monkeys the provirus genome gave healthy virus carrier monkeys that had no abnormal lympho the same restriction pattern as that of the previous isolate in cytes were polyclonal with respect to the integration site of the GM0650. However, 3 monkeys were infected with a variant provirus genome, and the lymphocytes of seronegative monkeys virus with the minor difference that one Pstl site was not did not contain the STLV-I provirus genome. From these present. From these observations, the virus in GM0650 cells observations, successive events are considered to occur as fol can be regarded as the species-specific STLV-I that is com lows: (a) the proviral genome is randomly integrated into virus- monly transmitted among African green monkeys. The African sensitive lymphocytes; (b) then some infected lymphocyte green monkeys kept in Tsukuba Primate Center seemed to have clones proliferate among the infected cells; (c) one selected been infected with STLV-I in their native countries in Africa, clone transformed by STLV-I begins to grow; and (

4 Y. Noda, K. Ishikawa, A. Sasagawa, S. Honjo, S. Mori, H. Tsujimoto, and *H. Tsujimoto, M. Fukasawa, H. Nakamura, and M. Hayami. Immortaliza- M. Hayami. HÃ©matologieabnormalities in African green monkeys naturally lion of human and simian lymphocytes by simian T-cell leukemia virus type-I, infected with simian T-cell leukemia virus, manuscript in preparation. manuscript in preparation. 273

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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1987 American Association for Cancer Research. Development of Adult T-Cell Leukemia-like Disease in African Green Monkey Associated with Clonal Integration of Simian T-Cell Leukemia Virus Type I

Hajime Tsujimoto, Yoshihiro Noda, Koh-ichi Ishikawa, et al.

Cancer Res 1987;47:269-274.

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