![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
Previous Article | Next Article 
J Virol, January 1998, p. 841-846, Vol. 72, No. 1
Department of Pediatrics,
Received 19 February 1997/Accepted 28 September 1997
Human T-cell lymphotrophic virus type 2 (HTLV-2), a common
infection of intravenous drug users and subpopulations of Native Americans, is uncommon in the general population. In contrast with the
closely related HTLV-1, which is associated with both leukemia and
neurologic disorders, HTLV-2 lacks a strong etiologic association with
disease. HTLV-2 does shares many properties with HTLV-1, including in
vitro lymphocyte transformation capability. To better assess the
ability of HTLV-2 to transform lymphocytes, a limiting dilution assay
was used to generate clonal, transformed lymphocyte lines. As with
HTLV-1, the transformation efficiency of HTLV-2 producer cells was
proportionately related to the number of lethally irradiated input
cells and was comparable to HTLV-1-mediated transformation efficiency.
HTLV-2-infected cells were reproducibly isolated and had markedly
increased growth potential compared to uninfected cells; HTLV-2
transformants required the continued presence of exogenous interleukin
2 for growth for several months and were maintained for over 2 years in
culture. All HTLV-2-transformed populations were CD2 and/or CD3
positive and B1 negative and were either CD4+ or
CD8+ populations or a mixture of CD4+ and
CD8+ lymphocytes. Clonality of the HTLV-2 transformants was
confirmed by Southern blot analysis of T-cell receptor The first identified human
retroviruses, the human T-cell lymphotropic virus types 1 and 2 (HTLV-1
and -2), have the ability to transform lymphocytes in vitro
(10, 11, 51, 62). T lymphocytes infected with HTLV
demonstrate enhanced growth potential, marked by seemingly unlimited
entry into the cell cycle. The two HTLV serotypes are approximately
65% homologous on the nucleotide level (56, 59) and
demonstrate a correspondingly high serologic cross-reactivity
(37). Nevertheless, they have distinct seroepidemiologic and
clinical profiles. HTLV-1 is associated etiologically with adult T-cell
leukemia (16, 26, 63) as well as with a peripheral neuropathy known as tropical spastic paraparesis or HTLV-associated myelopathy (1, 20, 31, 48). HTLV-1 is endemic to southern Japan, the Caribbean basin, central Africa, northeastern South America,
and regions of the southeastern United States (3-6, 8, 25, 38,
43, 54). HTLV-2 is occasionally found in Native American Indians
(12-15, 28, 34, 39, 41) as well as in a significant
proportion of intravenous drug users (IVDUs) (2, 33, 35,
53). Recently, Hall et al. defined two subtypes of HTLV-2,
HTLV-2a and HTLV-2b, isolated from peripheral blood lymphocytes (PBLs)
of IVDUs (23). HTLV-2 has not been associated with any
disease to date, though there have been isolated reports of
HTLV-2-associated neuropathy mostly from south Florida and the
Caribbean (24, 27, 30, 42, 58).
Persaud et al. (50) reported a limiting dilution
infectivity assay for HTLV-1 which allowed early detection of infected cultures and interleukin 2 (IL-2)-driven expansion of clonal
populations. The present study extends this method to HTLV-2
and characterizes the resultant transformants. Clonal HTLV-2
populations were routinely and reproducibly generated with the HTLV-2a
laboratory strain LAMP/MO. Furthermore, Southern blot analysis was used
to characterize both the number and size of proviral integrations in
the transformants derived from the in vitro system. These results
are compared with those previously noted for HTLV-1. Additionally,
chromosomal in situ hybridization was used to localize both HTLV-1 and
HTLV-2 proviral integrations.
Infection-transformation efficiency and assay reproducibility.
The HTLV-2 transformation assay was performed as described by Persaud
for HTLV-1 (50). Briefly, LAMP/MO cells (gift of Robert Gallo, National Cancer Institute, Bethesda, Md.) were exposed on ice to
11,700 rads (390 rads/min for 30 min) from a gamma source. Various
numbers of irradiated cells (10, 100, and 1,000) were cocultivated with
104 activated peripheral blood mononuclear cells (PBMCs) in
round-bottom 96-well plates in the presence of IL-2 (10 U/ml)
(Boehringer-Mannheim Corp., Indianapolis, Ind.). HTLV-2-transformed
cell populations were identified as cells that continued to proliferate
beyond 6 weeks, the point at which most of the activated PBMCs not
exposed to the HTLV-2-producing cells no longer proliferate in medium containing IL-2, and also by the continued production of HTLV p24
antigen (determined by enzyme-linked immunosorbent assay; (Coulter
Immunology, Hialeah, Fl) >1,000 pg/ml) in the culture supernatant.
Control wells containing only activated PBMCs or only irradiated
LAMP/MO (104 cells/well) were maintained in parallel. After
6 to 9 weeks of culture, cocultures which continued to grow were
expanded in growth medium supplemented with 10 U of IL-2/ml.
HTLV-2-transformed clones were defined as cells exposed to HTLV-2 that
continued to proliferate in the presence of IL-2 and that continuously
produced p24 antigen (>1,000 pg/ml) by 12 weeks after the initial
coculture. Control wells, which contained 104
phytohemagglutinin-activated PBMCs in the absence of HTLV-2-infected cells, proliferated for approximately 4 weeks and were never
p24+; wells which contained only HTLV-2-irradiated cells
never exhibited growth and remained positive for p24 at low levels for
approximately 3 to 6 weeks after the assay set-up.
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Human T-Lymphocyte Transformation with Human T-Cell
Lymphotropic Virus Type 2
ABSTRACT
Top
Abstract
Text
References
chain
rearrangement. Southern blot analysis revealed a range of integrated
full-length genomes from one to multiple. In situ hybridization
analysis of HTLV-2 integration revealed no obvious chromosomal
integration pattern.
TEXT
Top
Abstract
Text
References
TABLE 1.
HTLV-2 transformation efficiency and reproducibility
Time course of HTLV-2-mediated T-cell transformation. In one representative experiment (Table 1, experiment C), at 9 weeks after coculture with 104 PBMCs (the earliest time point tested, to allow residual p24 to reach undetectable levels), 67% of the wells with 100 LAMP/MO cells/well were p24+, indicating infection. By week 10, 70% of the wells with 103 LAMP/MO cells/well were p24 positive. By week 12, all cultures which demonstrated growth had detectable p24, and no additional positive cultures were noted. Supernatant from cells in control wells containing only irradiated LAMP/MO cells were p24 negative at the earliest time point tested. Most of the wells that continued to proliferate could be readily expanded and continued to produce p24. These cultures have been maintained in culture for over 2 years with the addition of IL-2. Abrupt removal of IL-2 results in cessation of cell growth, but it is possible to generate IL-2 independence of HTLV-2-transformed cells (data not shown). We conclude that these HTLV-2 lymphocyte lines are IL-2 dependent in the initial phases of transformation.
Cell surface phenotypes of HTLV-2 transformants. The cell surface phenotypes of 41 cultures from experiment C (Table 1) were determined at the earliest time possible after coculture (approximately 12 weeks). As shown in Table 2, all HTLV-2-transformed cultures were positive for the T-lymphocyte markers CD2 and/or CD3 and negative for the B1 cell surface antigen. Forty-four percent of the HTLV-2 transformants generated consisted of pure (>95%) populations of CD4+ or CD8+ T lymphocytes, and the remainder consisted of mixtures of the two subsets. A greater percentage of the transformants (39 versus 5%) were CD4+ than CD8+ in this system. In contrast, analyses of lymphocytes in vivo indicate that HTLV-1 is detected primarily in the CD4+ subset (52) and HTLV-2 is found in the CD8+ population (29). The findings reported here indicate that in vitro, the CD4+ cell is at least as susceptible to infection and transformation with HTLV-2 as the CD8+ T cell. One possible explanation for the difference between the in vitro and in vivo observations is that HTLV-2-infected CD4+ T lymphocytes may be eliminated in vivo (45) or suppressed by the host immune system.
|
T-cell receptor rearrangement of HTLV-2 transformants.
The
cell surface analyses indicated that several of the HTLV-2
transformants were homogenous T-lymphocyte populations. Southern blot
analysis for T-cell receptor beta chain (TCR) gene rearrangement was
performed to confirm lineage and to establish clonality (44, 60). A representative blot is shown in Fig.
1. All 15 cultures analyzed were
confirmed to be T cells by virtue of rearrangement. Ten were determined
to be clonal populations, and 5 were oligoclonal. Notably, the TCR
gene pattern demonstrated by LAMP/MO (Fig. 1, lane MO) was distinct
from that of the other samples analyzed, indicating that the cultures
generated in the infectivity assay were in fact new transformants and
not the result of outgrowth of insufficiently irradiated LAMP/MO.
|
Proviral copy number in HTLV-2-transformed cell lines.
LAMP/MO and the 15 HTLV-2 transformants studied above were next
analyzed for viral copy number by Southern blot analysis. Digestion of
DNA from the HTLV-2 transformants with the enzyme HindIII, which does not cut in the proviral sequence,
was utilized to determine the number of integrated proviruses. Each
band generated by HindIII digest on Southern blot
analysis thus represents a distinct proviral integration site. A
representative blot is shown in Fig. 2.
LAMP/MO contained a single major band and several (at least three)
other, much fainter appearing bands. Of the 10 cultures determined to
be clonal by TCR rearrangement, 5 had single integration sites, 3 had a single strong band and several faint bands, and 2 had multiple
bands. The five samples which were oligoclonal by TCR rearrangement
all had multiple integration sites. No difference in growth properties
in cells with single or multiple integration sites was noted (with
regard to IL-2 requirements and generation time).
|
Defective proviral forms associated with HTLV-2. Clonal populations of HTLV-1-infected lymphocytes have been shown to contain both full-length and subgenomic, or defective, proviruses. The presence of three proviral forms (full-length, 8.8 kb; defective, 6.5 and 3.5 kb) in LAMP/MO has been described previously (9). However, the transmissibility of these forms has not been investigated qualitatively in vitro. The HTLV-2 transformants derived from this transformation assay provided the opportunity to determine whether defective proviral forms are associated with T lymphocytes transformed in vitro with HTLV-2. For these analyses, a combination of the enzymes AseI and EcoRV, which each cut once in the 5' (bp 1032) and 3' (bp 8035) long terminal repeat, respectively, were used. A full-length provirus digested with the combination EcoRV/AseI would be visualized at 7.0 kb; a defective with internal deletions would be detected as a smaller band.
LAMP/MO and a total of 18 HTLV-2 transformants were analyzed for proviral structure. As demonstrated in Fig. 3, all transformants contained a full-length proviral copy and no transformant contained only a subgenomic fragment. LAMP/MO (Fig. 3, lane 2) contains, in addition to the full-length provirus (visualized here as a band of 7.0 kb) one major defective form of approximately 6.0 kb. One sample (Fig. 3, lane 5) contained, in addition to the full-length form, a band slightly larger than the full-length form. Two other HTLV-2 transformants harbored a smaller HTLV-2 proviral form in addition to the full-length provirus (Fig. 3, lane 3, and data not shown). With these three exceptions, all of the other 15 samples examined contained exclusively a full-length provirus.
|
Chromosomal localization of HTLV integration. Several studies have addressed the site specificity of HTLV-1 proviral chromosomal integration (40, 55, 65). No obvious clustering of proviral integration has been observed, indicating that HTLV-1 probably integrates randomly into chromosomal DNA. The localization of HTLV-2 proviral integration has not been previously addressed. In this series of experiments, chromosomal in situ hybridization of several HTLV-1 and HTLV-2 transformants was used to determine the proviral chromosomal localization. If there were a preferential site(s) of proviral integration, the transformants derived from this assay could facilitate its localization because multiple transformants from a single donor can be analyzed. Figure 4 shows an example of in situ hybridization of metaphase spreads of two HTLV-2-transformed cell lines with probe pMO4: proviral integration at 2p24 was noted for cell line 7MO3-27, and proviral integration at 1q21-22 was noted for cell line 7MO2-7. A minimum of 20 cells were analyzed for each cell line. Signals detected more than three times at the same chromosome locations were scored as specific proviral integration sites. Eight HTLV-2 transformants were examined, and a total of 17 integration locations were detected; 10 HTLV-1 transformants were also examined, and a total of 25 integration locations were noted (data not shown). No specific chromosomal integration site or pattern was identified with transformants from either virus.
|
,
CD4+, or CD8+ T lymphocytes demonstrating
IL-2-dependent long-term growth and continuous p24 production. The time
course of transformation and transformation efficiency, as well as the
phenotypic profile of the resultant HTLV-2 clones, are comparable
to the results obtained when HTLV-1 is used to transform PBMCs
(50). One notable difference is the frequent detection of
defective proviral formation with HTLV-1 transformants and the
rarity of defective proviruses noted with HTLV-2 transformants.
The present results do not illuminate one of the more intriguing
biologic questions about HTLV-1 and HTLV-2, namely,
the viral properties that account for the markedly different ecologic
niches. In recent years, the HTLV seroprevalence among IVDUs has been attributed predominantly to HTLV-2, indicating a possible
quantitative or qualitative difference in infectivity between the two
viruses. Since in vitro transformation with HTLV-1 and
HTLV-2 are apparently equivalent, perhaps other factors are
important determinants of transmission and explain the seeming
differences in the niches occupied by these closely related
retroviruses. Particularly puzzling from a seroepidemiologic
perspective is the relative absence of HTLV-2 in the general
population and, in spite of a low level of HTLV-1 in the general
population, the relative absence of HTLV-1 in IVDUs (2, 33,
35, 53). It is clear that HTLV-1 is etiologically associated
with clinical disease; it seems possible that HTLV-2 may be as
virulent as HTLV-1 but the high mortality of infected patients from
other causes (49) may obscure HTLV-2-specific disease.
Alternatively, HTLV-2 may produce only subclinical
infections in the vast majority of HTLV-2-infected patients and
differ qualitatively from HTLV-1 in disease potential.
The present studies are the first qualitative analyses of the
HTLV-2 proviral structure in transformed T lymphocytes. Clonal T-cell populations were shown to contain either single or multiple integration sites. HTLV-1 proviral integration has been
characterized by numerous studies: adult T-cell leukemia cells contain
oligo- or monoclonal viral integration (64), while in cells
from patients with tropical spastic paraparesis/HTLV-associated
myelopathy, there is a notably polyclonal pattern (21, 22).
Though the demonstration of immortalization with a single proviral
integration in both HTLV-1 and HTLV-2 suggests that one
integration site, or virus by itself, is sufficient for transformation,
additional cellular events are most likely involved as well in
HTLV-mediated T-cell transformation. Transformation
associated with multiple integrants could be due to successive
integration cycles until one favorable integration event occurs;
alternatively, the transformed phenotype may represent the cumulative
effect of multiple integrations. The in vitro data presented above
provide support for the former hypothesis.
HTLV transformation confers enhanced growth potential on the infected
lymphocyte. This transforming capacity has been exploited in the
laboratory as a method of immortalizing lymphocytes for further study,
in a manner similar to Epstein-Barr virus transformation of B
lymphocytes. PBLs from patients with adenosine deaminase deficiency
(32) and paroxysmal nocturnal hemoglobinura (46) have been immortalized with HTLV-1, and a series of papers have examined hormone responsiveness in Pygmy and normal
HTLV-2-transformed T-cell lines (17-19). The
transforming ability of HTLV-2, the relative frequency of
monoclonal integrants, and the absence of disease association render
HTLV-2 a suitable candidate for the immortalization of T
lymphocytes from patients for multiple purposes.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Department of Pediatrics, New York University School of Medicine, 550 First Ave., Rm. TH-501A, New York, NY 10016. Phone: (212) 263-6425. Fax: (212) 263-8172. E-mail: PARKSW01{at}mcrcr.med.nyu.edu.
| |
REFERENCES |
|---|
|
Top
Abstract
Text
References
|
|---|
| 1. | Bhagavati, S., G. Ehrlich, R. W. Kula, S. Kwok, J. Sninsky, V. Udani, and B. J. Poiesz. 1988. Detection of human T-cell lymphoma/leukemia virus type I DNA and antigen in spinal fluid and blood of patients with chronic progressive myelopathy. N. Engl. J. Med. 318:1141-1147[Abstract]. |
| 2. | Biggar, R. J., Z. Buskell-Bales, P. N. Yakshe, D. Caussy, G. Gridley, and L. Seeff. 1991. Antibody to human retroviruses among drug users in three east coast American cities, 1972-1976. J. Infect. Dis. 163:57-63[Medline]. |
| 3. | Biggar, R. J., B. K. Johnson, C. Oster, P. S. Sarin, D. Ocheng, P. Tukei, H. Nsanze, S. Alexander, A. J. Bodner, T. A. Siongok, et al. 1985. Regional variation in prevalence of antibody against human T-lymphotropic virus types I and III in Kenya, East Africa. Int. J. Cancer 35:763-767[Medline]. |
| 4. | Biggar, R. J., C. Saxinger, C. Gardiner, W. E. Collins, P. H. Levine, J. W. Clark, F. K. Nkrumah, and W. A. Blattner. 1984. Type-I HTLV antibody in urban and rural Ghana, West Africa. Int. J. Cancer 34:215-219[Medline]. |
| 5. | Blattner, W. A., V. S. Kalyanaraman, M. Robert-Guroff, T. A. Lister, D. A. Galton, P. S. Sarin, M. H. Crawford, D. Catovsky, M. Greaves, and R. C. Gallo. 1982. The human type-C retrovirus, HTLV, in blacks from the Caribbean region, and relationship to adult T-cell leukemia/lymphoma. Int. J. Cancer 30:257-264[Medline]. |
| 6. | Blayney, D. W., W. A. Blattner, M. Robert-Guroff, E. S. Jaffe, R. I. Fisher, P. Bunn, Jr., M. G. Patton, H. R. Rarick, and R. C. Gallo. 1983. The human T-cell leukemia-lymphoma virus in the southeastern United States. JAMA 250:1048-1052[Abstract]. |
| 7. |
Burns, J.,
V. Chan,
J. Jonasson,
K. Fleming,
S. Taylor, and J. McGee.
1985.
Sensitive system for visualising biotinylated DNA probes hybridised in situ: rapid sex determination of intact cells.
J. Clin. Pathol.
38:1085-1092 |
| 8. | Catovsky, D., M. F. Greaves, M. Rose, D. A. Galton, A. W. Goolden, D. R. McCluskey, J. M. White, I. Lampert, G. Bourikas, R. Ireland, A. I. Brownell, J. M. Bridges, W. A. Blattner, and R. C. Gallo. 1982. Adult T-cell lymphoma-leukaemia in blacks from the West Indies. Lancet 1:639-643[Medline]. |
| 9. | Chen, I. S., J. McLaughlin, J. C. Gasson, S. C. Clark, and D. W. Golde. 1983. Molecular characterization of genome of a novel human T-cell leukaemia virus. Nature 305:502-505[Medline]. |
| 10. |
Chen, I. S.,
S. G. Quan, and D. W. Golde.
1983.
Human T-cell leukemia virus type II transforms normal human lymphocytes.
Proc. Natl. Acad. Sci. USA
80:7006-7009 |
| 11. | Chosa, T., N. Yamamoto, Y. Tanaka, Y. Koyanagi, and Y. Hinuma. 1982. Infectivity dissociated from transforming activity in a human retrovirus, adult T-cell leukemia virus. Gann 73:844-847[Medline]. |
| 12. | Duenas-Barajas, E., J. E. Bernal, D. R. Vaught, V. R. Nerurkar, P. Sarmiento, R. Yanagihara, and D. C. Gajdusek. 1993. Human retroviruses in Amerindians of Colombia: high prevalence of human T cell lymphotropic virus type II infection among the Tunebo Indians. Am. J. Trop. Med. Hyg. 49:657-663. |
| 13. | Echeverria de Perez, G., M. Leon-Ponte, O. Noya, C. Botto, D. Gallo, and N. Bianco. 1993. First description of endemic HTLV-II infection among Venezuelan Amerindians. J. Acquired Immune Defic. Syndr. 6:1368-1372. |
| 14. | Feigenbaum, F., C. Fang, and S. G. Sandler. 1994. Human T-lymphotropic virus type II in Panamanian Guaymi Indians. Transfusion 34:158-161[Medline]. |
| 15. | Ferrer, J. F., N. Del Pino, E. Esteban, M. P. Sherman, S. Dube, D. K. Dube, M. A. Basombrio, E. Pimentel, A. Segovia, S. Quirulas, et al. 1993. High rate of infection with the human T-cell leukemia retrovirus type II in four Indian populations of Argentina. Virology 197:576-584[Medline]. |
| 16. |
Gallo, R. C.,
V. S. Kalyanaraman,
M. G. Sarngadharan,
A. Sliski,
E. C. Vonderheid,
M. Maeda,
Y. Nakao,
K. Yamada,
Y. Ito,
N. Gutensohn,
S. Murphy,
P. Bunn, Jr.,
D. Catovsky,
M. F. Greaves,
D. W. Blayney,
W. Blattner,
W. F. Jarrett,
H. zur Hausen,
M. Seligmann,
J. C. Brouet,
B. F. Haynes,
B. V. Jegasothy,
E. Jaffe,
J. Cossman,
S. Broder,
R. I. Fisher,
D. W. Golde, and M. Robert-Guroff.
1983.
Association of the human type C retrovirus with a subset of adult T-cell cancers.
Cancer Res.
43:3892-3899 |
| 17. | Geffner, M. E., R. C. Bailey, N. Bersch, J. C. Vera, and D. W. Golde. 1993. Insulin-like growth factor-I unresponsiveness in an Efe Pygmy. Biochem. Biophys. Res. Commun. 193:1216-1223[Medline]. |
| 18. | Geffner, M. E., N. Bersch, R. C. Bailey, and D. W. Golde. 1994. Growth hormone induces resistance to the mitogenic action of insulin through local IGF-I. Studies in normal and Pygmy T-cell lines. Diabetes 43:68-72[Abstract]. |
| 19. | Geffner, M. E., N. Bersch, and D. W. Golde. 1992. Insulin and IGF-I stimulate normal and virally transformed T-lymphocyte cell growth in vitro. Brain Behav. Immun. 6:377-386[Medline]. |
| 20. | Gessain, A., F. Barin, J. C. Vernant, O. Gout, L. Maurs, A. Calender, and G. de The. 1985. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet 2:407-410[Medline]. |
| 21. |
Gessain, A.,
F. Saal,
O. Gout,
M. T. Daniel,
G. Flandrin,
G. de The,
J. Peries, and F. Sigaux.
1990.
High human T-cell lymphotropic virus type I proviral DNA load with polyclonal integration in peripheral blood mononuclear cells of French West Indian, Guianese, and African patients with tropical spastic paraparesis.
Blood
75:428-433 |
| 22. | Greenberg, S. J., S. Jacobson, T. A. Waldmann, and D. E. McFarlin. 1989. Molecular analysis of HTLV-I proviral integration and T cell receptor arrangement indicates that T cells in tropical spastic paraparesis are polyclonal. J. Infect. Dis. 159:741-744[Medline]. |
| 23. |
Hall, W. W.,
H. Takahashi,
C. Liu,
M. H. Kaplan,
O. Scheewind,
S. Ijichi,
K. Nagashima, and R. C. Gallo.
1992.
Multiple isolates and characteristics of human T-cell leukemia virus type II.
J. Virol.
66:2456-2463 |
| 24. | Harrington, W., Jr., W. Sheremata, B. Hjelle, D. K. Dube, P. Bradshaw, S. K. Foung, S. Snodgrass, G. Toedter, L. Cabral, and B. Poiesz. 1993. Spastic ataxia associated with human T-cell lymphotropic virus type II infection. Ann. Neurol. 33:411-414[Medline]. |
| 25. | Hinuma, Y., H. Komoda, T. Chosa, T. Kondo, M. Kohakura, T. Takenaka, M. Kikuchi, M. Ichimaru, K. Yunoki, I. Sato, R. Matsuo, Y. Takiuchi, H. Uchino, and M. Hanaoka. 1982. Antibodies to adult T-cell leukemia-virus-associated antigen (ATLA) in sera from patients with ATL and controls in Japan: a nation-wide sero-epidemiologic study. Int. J. Cancer 29:631-635[Medline]. |
| 26. |
Hinuma, Y.,
K. Nagata,
M. Hanaoka,
M. Nakai,
T. Matsumoto,
K. I. Kinoshita,
S. Shirakawa, and I. Miyoshi.
1981.
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
78:6476-6480 |
| 27. | Hjelle, B., O. Appenzeller, R. Mills, S. Alexander, N. Torrez-Martinez, R. Jahnke, and G. Ross. 1992. Chronic neurodegenerative disease associated with HTLV-II infection. Lancet 339:645-646[Medline]. |
| 28. |
Hjelle, B.,
R. Scalf, and S. Swenson.
1990.
High frequency of human T-cell leukemia-lymphoma virus type II infection in New Mexico blood donors: determination by sequence-specific oligonucleotide hybridization.
Blood
76:450-454 |
| 29. |
Ijichi, S.,
M. B. Ramundo,
H. Takahashi, and W. W. Hall.
1992.
In vivo cellular tropism of human T cell leukemia virus type II (HTLV-II).
J. Exp. Med.
176:293-296 |
| 30. | Jacobson, S., T. Lehky, M. Nishimura, S. Robinson, D. E. McFarlin, and S. Dhib-Jalbut. 1993. Isolation of HTLV-II from a patient with chronic, progressive neurological disease clinically indistinguishable from HTLV-I-associated myelopathy/tropical spastic paraparesis. Ann. Neurol. 33:392-396[Medline]. |
| 31. | Jacobson, S., C. S. Raine, E. S. Mingioli, and D. E. McFarlin. 1988. Isolation of an HTLV-1-like retrovirus from patients with tropical spastic paraparesis. Nature 331:540-543[Medline]. |
| 32. | Kohn, D. B., H. Mitsuya, M. Ballow, J. E. Selegue, J. Barankiewicz, A. Cohen, E. Gelfand, W. F. Anderson, and R. M. Blaese. 1989. Establishment and characterization of adenosine deaminase-deficient human T cell lines. J. Immunol. 142:3971-3977[Abstract]. |
| 33. | Kwok, S., D. Gallo, C. Hanson, N. McKinney, B. Poiesz, and J. J. Sninsky. 1990. High prevalence of HTLV-II among intravenous drug abusers: PCR confirmation and typing. Aids Res. Hum. Retroviruses 6:561-565[Medline]. |
| 34. |
Lairmore, M. D.,
S. Jacobson,
F. Gracia,
B. K. De,
L. Castillo,
M. Larreategui,
B. D. Roberts,
P. H. Levine,
W. A. Blattner, and J. E. Kaplan.
1990.
Isolation of human T-cell lymphotropic virus type 2 from Guaymi Indians in Panama.
Proc. Natl. Acad. Sci. USA
87:8840-8844 |
| 35. |
Lee, H.,
P. Swanson,
V. S. Shorty,
J. A. Zack,
J. D. Rosenblatt, and I. S. Chen.
1989.
High rate of HTLV-II infection in seropositive I.V. drug abusers in New Orleans.
Science
244:471-475 |
| 36. | Lee, J. J., D. Warburton, and E. J. Robertson. 1990. Cytogenetic methods in the mouse: preparation of chromosomes, karyotyping, and in situ hybridization. Anal. Biochem. 189:1-17[Medline]. |
| 37. |
Lee, T. H.,
J. E. Coligan,
M. F. McLane,
J. G. Sodroski,
M. Popovic,
F. Wong-Staal,
R. C. Gallo,
W. Haseltine, and M. Essex.
1984.
Serological cross-reactivity between envelope gene products of type I and type II human T-cell leukemia virus.
Proc. Natl. Acad. Sci. USA
81:7579-7583 |
| 38. | Levine, P. H., W. A. Blattner, J. Clark, R. Tarone, E. M. Maloney, E. M. Murphy, R. C. Gallo, M. Robert-Guroff, and W. C. Saxinger. 1988. Geographic distribution of HTLV-I and identification of a new high-risk population. Int. J. Cancer 42:7-12[Medline]. |
| 39. | Levine, P. H., S. Jacobson, R. Elliott, A. Cavallero, G. Colclough, C. Dorry, C. Stephenson, R. M. Knigge, J. Drummond, M. Nishimura, et al. 1993. HTLV-II infection in Florida Indians. Aids Res. Hum. Retroviruses 9:123-127[Medline]. |
| 40. | Macera, M. J., P. Szabo, and R. S. Verma. 1992. Chromosomal localization of HTLV-1 viral integration sites using in situ hybridization: detection of a novel IL2R fragment. Mol. Gen. Genet. 234:466-474[Medline]. |
| 41. | Maloney, E. M., R. J. Biggar, J. V. Neel, M. E. Taylor, B. H. Hahn, G. M. Shaw, and W. A. Blattner. 1992. Endemic human T cell lymphotropic virus type II infection among isolated Brazilian Amerindians. J. Infect. Dis. 166:100-107[Medline]. |
| 42. | McFarlin, D. E. 1993. Neurological disorders related to HTLV-I and HTLV-II. J. Acquired Immune Defic. Syndr. 6:640-644. |
| 43. | Merino, F., M. Robert-Guroff, J. Clark, M. Biondo-Bracho, W. A. Blattner, and R. C. Gallo. 1984. Natural antibodies to human T-cell leukemia/lymphoma virus in healthy Venezuelan populations. Int. J. Cancer 34:501-506[Medline]. |
| 44. |
Minden, M. D.,
B. Toyonaga,
K. Ha,
B. Yanagi,
B. Chin,
E. Gelfand, and T. Mak.
1985.
Somatic rearrangement of T-cell antigen receptor gene in human T-cell malignancies.
Proc. Natl. Acad. Sci. USA
82:1224-1227 |
| 45. | Miyamoto, K., T. Kamiya, J. Minowada, N. Tomita, and K. Kitajima. 1991. Transformation of CD8+ T-cells producing a strong cytopathic effect on CD4+ T-cells through syncytium formation by HTLV-II. Jpn. J. Cancer Res. 82:1178-1183[Medline]. |
| 46. |
Nakakuma, H.,
S. Nagakura,
K. Horikawa,
M. Hidaka,
T. Kawaguchi,
N. Iwamoto,
I. Sanada,
T. Kagimoto, and K. Takatsuki.
1994.
Interleukin-2-dependent T-cell lines established from paroxysmal nocturnal hemoglobinuria patients.
Blood
84:309-314 |
| 47. |
Ohshima, K.,
M. Kikuchi,
Y. Masuda,
S. Kobari,
Y. Sumiyoshi,
F. Eguchi,
H. Mohtai,
T. Yoshida,
M. Takeshita, and N. Kimura.
1991.
Defective provirus form of human T-cell leukemia virus type I in adult T-cell leukemia/lymphoma: clinicopathological features.
Cancer Res.
51:4639-4642 |
| 48. | Osame, M., M. Matsumoto, K. Usuku, S. Izumo, N. Ijichi, H. Amitani, M. Tara, and A. Igata. 1987. Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemia-like cells. Ann. Neurol. 21:117-122[Medline]. |
| 49. | Page, J. B., S. H. Lai, D. D. Chitwood, N. G. Klimas, P. C. Smith, and M. A. Fletcher. 1990. HTLV-I/II seropositivity and death from AIDS among HIV-1 seropositive intravenous drug users. Lancet 335:1439-1441[Medline]. (Comments.) |
| 50. | Persaud, D., J. Munoz, S. Tarsis, E. Parks, and W. Parks. 1995. Time course and cytokine dependence of human T-cell lymphotropic virus type 1 T-lymphocyte transformation as revealed by a microtiter infectivity assay. J. Virol. 69:6297-6303[Abstract]. |
| 51. |
Popovic, M.,
G. Lange-Wantzin,
P. S. Sarin,
D. Mann, and R. C. Gallo.
1983.
Transformation of human umbilical cord blood T cells by human T-cell leukemia/lymphoma virus.
Proc. Natl. Acad. Sci. USA
80:5402-5406 |
| 52. |
Richardson, J. H.,
A. J. Edwards,
J. K. Cruickshank,
P. Rudge, and A. G. Dalgleish.
1990.
In vivo cellular tropism of human T-cell leukemia virus type 1.
J. Virol.
64:5682-5687 |
| 53. | Robert-Guroff, M., S. H. Weiss, J. A. Giron, A. M. Jennings, H. M. Ginzburg, I. B. Margolis, W. A. Blattner, and R. C. Gallo. 1986. Prevalence of antibodies to HTLV-I, -II, and -III in intravenous drug abusers from an AIDS endemic region. JAMA 255:3133-3137[Abstract]. |
| 54. |
Saxinger, W.,
W. A. Blattner,
P. H. Levine,
J. Clark,
R. Biggar,
M. Hoh,
J. Moghissi,
P. Jacobs,
L. Wilson,
R. Jacobson, et al.
1984.
Human T-cell leukemia virus (HTLV-I) antibodies in Africa.
Science
225:1473-1476 |
| 55. | Seiki, M., R. Eddy, T. B. Shows, and M. Yoshida. 1984. Nonspecific integration of the HTLV provirus genome into adult T-cell leukaemia cells. Nature 309:640-642[Medline]. |
| 56. |
Seiki, M.,
S. Hattori,
Y. Hirayama, and M. Yoshida.
1983.
Human adult T-cell leukemia virus: complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA.
Proc. Natl. Acad. Sci. USA
80:3618-3622 |
| 57. | Shaw, G. M., S. Broder, M. Essex, and R. C. Gallo. 1984. Human T-cell leukemia virus: its discovery and role in leukemogenesis and immunosuppression. Adv. Intern. Med. 30:1-27[Medline]. |
| 58. | Sheremata, W. A., W. Harrington, Jr., P. A. Bradshaw, S. K. Foung, S. P. Raffanti, J. R. Berger, S. Snodgrass, L. Resnick, and B. J. Poiesz. 1993. Association of `(tropical) ataxic neuropathy' with HTLV-II. Virus Res. 29:71-77[Medline]. |
| 59. |
Shimotohno, K.,
Y. Takahashi,
N. Shimizu,
T. Gojobori,
D. W. Golde,
I. S. Chen,
M. Miwa, and T. Sugimura.
1985.
Complete nucleotide sequence of an infectious clone of human T-cell leukemia virus type II: an open reading frame for the protease gene.
Proc. Natl. Acad. Sci. USA
82:3101-3105 |
| 60. | Siu, G., S. P. Clark, Y. Yoshikai, M. Malissen, Y. Yanagi, E. Strauss, T. W. Mak, and L. Hood. 1984. The human T cell antigen receptor is encoded by variable, diversity joining gene segments that rearrange to generate a complete V gene. Cell 37:393-401[Medline]. |
| 61. | Warburton, D., M. T. Yu, U. Tantravahi, C. Lee, E. Cayanis, J. Russo, and S. Fischer. 1993. Regional localization of 32 NotI-HindIII fragments from a human chromosome 13 library by a somatic cell hybrid panel and in situ hybridization. Genomics 16:355-360[Medline]. |
| 62. |
Yamamoto, N.,
M. Okada,
Y. Koyanagi,
M. Kannagi, and Y. Hinuma.
1982.
Transformation of human leukocytes by cocultivation with an adult T cell leukemia virus producer cell line.
Science
217:737-739 |
| 63. |
Yoshida, M.,
I. Miyoshi, and Y. Hinuma.
1982.
Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease.
Proc. Natl. Acad. Sci. USA
79:2031-2035 |
| 64. |
Yoshida, M.,
M. Seiki,
K. Yamaguchi, and K. Takatsuki.
1984.
Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease.
Proc. Natl. Acad. Sci. USA
81:2534-2537 |
| 65. | Zoubak, S., J. H. Richardson, A. Rynditch, P. Hollsberg, D. A. Hafler, E. Boeri, A. M. Lever, and G. Bernardi. 1994. Regional specificity of HTLV-I proviral integration in the human genome. Gene 143:155-163[Medline]. |
This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| J. Bacteriol. | Mol. Cell. Biol. | Microbiol. Mol. Biol. Rev. |
|---|
| Clin. Vaccine Immunol. | ALL ASM JOURNALS |
|---|
