Human T-cell Lymphotrophic Virus Type I Research Articles

CADM1 Expression and Stepwise Downregulation of CD7 Are Closely Associated with Clonal Expansion of HTLV-I–Infected Cells in Adult T-cell Leukemia/Lymphoma

Cell adhesion molecule 1 (CADM1), initially identified as a tumor suppressor gene, has recently been reported to be ectopically expressed in primary adult T-cell leukemia-lymphoma (ATL) cells. We incorporated CADM1 into flow-cytometric analysis to reveal oncogenic mechanisms in human T-cell lymphotrophic virus type I (HTLV-I) infection by purifying cells from the intermediate stages of ATL development. We isolated CADM1- and CD7-expressing peripheral blood mononuclear cells of asymptomatic carriers and ATLs using multicolor flow cytometry. Fluorescence-activated cell sorted (FACS) subpopulations were subjected to clonal expansion and gene expression analysis. HTLV-I-infected cells were efficiently enriched in CADM1(+) subpopulations (D, CADM1(pos)CD7(dim) and N, CADM1(pos)CD7(neg)). Clonally expanding cells were detected exclusively in these subpopulations in asymptomatic carriers with high proviral load, suggesting that the appearance of D and N could be a surrogate marker of progression from asymptomatic carrier to early ATL. Further disease progression was accompanied by an increase in N with a reciprocal decrease in D, indicating clonal evolution from D to N. The gene expression profiles of D and N in asymptomatic carriers showed similarities to those of indolent ATLs, suggesting that these subpopulations represent premalignant cells. This is further supported by the molecular hallmarks of ATL, that is, drastic downregulation of miR-31 and upregulation of abnormal Helios transcripts. The CADM1 versus CD7 plot accurately reflects disease progression in HTLV-I infection, and CADM1(+) cells with downregulated CD7 in asymptomatic carriers have common properties with those in indolent ATLs.

Cutaneous Manifestations in HTLV-I Positive Blood Donors.

Infection with the human T-cell lymphotrophic virus type-I (HTLV-I) is endemic in Mashhad, Iran. In our research we evaluated the relation between exposure to this infection and the occurrence of dermatologic manifestations. 100 blood donors, who were seropositive but asymptomatic for infection with HTLV-I, were selected as case group. They were identified by the Blood Transfusion Organization Mashhad via the ELISA test and documented by PCR. Another 100 blood donors, that were seronegative for HTLV-I via the ELISA test and who were matched to the case group for age, gender, and existence of systemic diseases, were considered as the controls. Dermatologic evaluations and skin biopsies were performed if deemed necessary, and the results were statistically analyzed. 73% of the case and control groups were male, while 27% in each of these groups were female. The mean age in both groups was 40.96±11.94 years. The examination indicated that 58% of the case group and 37% of the control group had cutaneous manifestations (P<0.01). The most common diseases found in the case group were aphthous stomatitis, herpes labialis, and non-genital warts, while common diseases found in the control group were herpes labialis, aphthous stomatitis, and skin tag. The frequency of aphthous stomatitis, eczema, and non-genital warts in the case group were significantly more than the control group (P<0.05). Conclusion : Cutaneous diseases can be found more frequent in asymptomatic carriers of HTLV-I than those who are HTLV-I seronegative. The aphthous stomatitis, eczema, and non-genital warts are more prevalent in those infected by HTLV-I.

Adult T-cell leukemia/lymphoma: report of two cases

Adult T-cell leukemia/lymphoma is a lymphoproliferative disorder of mature T lymphocytes associated with infection with human T-cell lymphotrophic virus type I (HTLV-I). Adult T-cell leukemia/lymphoma is characterized by clinical and laboratory polymorphism that allows it to be classified into four distinct subgroups: smoldering, chronic, acute and lymphomatous types. We present here two cases of adult T-cell leukemia/lymphoma, respectively in the acute and lymphomatous forms of the disease. Case 1 was a 35-year-old woman who presented abdominal distension accompanied by hepatosplenomegaly, adenomegaly, skin lesions, positivity for anti-HTLV-I antibodies and leukocytosis with the presence of flower cells. Case 2 was a 38-year-old man who was admitted with generalized lymphadenomegaly, positivity for anti-HTLV-I antibodies, hypercalcemia and osteolytic lesions. In this paper, we correlate the clinical-laboratory findings of these two cases with data in the literature.

Adult T-Cell Leukemia/Lymphoma with Terminal Ileal Involvement

Introduction: Adult T-cell leukemia/lymphoma (ATLL) is an uncommon highly aggressive non-hodgkins lymphoma. Secondary gastrointestional involvement has been documented in literature, predominately the gastrum. This rare case describes a pt with ATLL involving the terminal ileum with endoscopy findings. Case Presentation: The patient is a 64 yo old male from Ghana who was admitted with symptoms of fatigue, weight loss and skin rash × 1 month. He initially presented 2 wks ago as outpatient with diarrhea and vague abd pain which resolved at the time of admission and denied any acute GI complaints upon presentation. Pt had tender right supraclavicular and b/l nontender cervical lymphadenopathy measured 2×2 cm. Abd exam was nontender, nondistended with active bowel sounds. Liver span measured 40 cm and no splenomegaly. On skin exam, there was pruritic scaly hyperkeratotic papules involving the palms, soles, chest, abdomen, back with hyperpigmentation. On laboratory examination he had hypercalcemia and renal insufficiency. Western blot was positive for HTLV1. Skin, bone marrow and lymph node biopsy revealed ATLL. Endoscopy Findings: EGD showed a diffuse congested mucosa with ulcerative lesions in the proximal gastric and fundus. Colonoscopy revealed diffuse mucosal erythema in the sigmoid and descending colon; terminal ileum evaluation demonstrated polypoid mucosa with cobblestone appearance. Biopsies of the colon, terminal ileum and gastric mucosa were all diagnostic of ATLL. Discussion: ATLL is associated with human T-cell lymphotrophic virus type I (HTLV-I). HTLV-1 affects 10–20 million people worldwide and carries a life time risk of 2–5% of developing ATLL. GI infiltration with gastrum is more commonly involved with the frequency much lower for large and small intestine. Conclusion: This is a rare case of ATLL involving the terminal ileum. Only two cases of terminal ileal involvement have been described in Japan. It can be suggested that routine endoscopic surveillance of the upper and lower GI tract in all newly diagnosed patients with ATLL is recommended for prognostic purposes and in evaluating response to chemotherapy.[figure1]Figure

ATYPICAL CLINICAL PRESENTATION OF STRONGYLOIDIASIS IN A PATIENT CO-INFECTED WITH HUMAN T CELL LYMPHOTROPHIC VIRUS TYPE I

Alterations in the immunologic response induced by human T cell lymphotrophic virus type I (HTLV-I) predispose the development of disseminated strongyloidiasis. We report a case of an atypical clinical presentation of strongyloidiasis in a patient co-infected with HTLV-I causing scrotal and perineal pain and infertility. Strongyloides stercoralis was found in the analysis of the sperm and specific therapy for strongyloidiasis was associated with disappearance of the symptoms.

HTLV-I Tax induces a novel interaction between p65/RelA and p53 that results in inhibition of p53 transcriptional activity

AbstractNuclear factor κB (NF-κB) activation plays a critical role in oncogenesis by human T-cell lymphotrophic virus type I (HTLV-I), the etiologic agent of adult T-cell leukemia (ATL), and is indispensable for maintenance of the malignant phenotype. In T lymphocytes, Tax-mediated p53 inhibition is dependent on Tax activation of the NF-κB pathway and is linked to p53 phosphorylation. We now report that blocking NF-κB transcriptional activation in HTLV-I–transformed cells restores p53 activity. Further, using mouse embryo fibroblast (MEF) null cells and antisense oligonucleotides to inhibit expression of NF-κB family members, we demonstrate that the p65 subunit of NF-κB is uniquely involved in p53 inhibition. Coimmunoprecipitation assays demonstrate an interaction between p65 and p53 in HTLV-I–transformed cells. In transient transfection assays, we demonstrate that Tax induces the p53-p65 interaction. Phosphorylation of p53 at serines 15 and 392 is critical for complex formation. Importantly, Tax-mediated p53 inhibition correlates with p65 and p53 interaction. By using chromatin immunoprecipitation (ChIP) assays, we find that in HTLV-I–transformed cells p53 and p65 form a complex on the inactive, p53-responsive murine double minute 2 (MDM2) promoter. Consistent with reduced transcriptional activity, transcription factor IID (TFIID) binding is not observed. These studies identify a unique mechanism for p53 regulation by the p65/RelA subunit of NF-κB.

A case-control study of risk factors associated with human T-cell lymphotrophic virus type-I seropositivity in blood donors from Guadeloupe, French West Indies.

An age- and gender-specific distribution characterizes human T-cell lymphotrophic virus type-I (HTLV-I) seropositivity in Guadeloupe (French West Indies). Further epidemiological studies are required to identify other possible risk factors associated with this retroviral infection. A nested case-control study was conducted between 1997 and 1999 among blood donors. A total of 102 HTLV-I-positive subjects were matched (at a ratio of 1 : 3) by gender, age (+/-5 years) and donor status (new or regular) to 306 HTLV-I-negative controls. Information was obtained through a questionnaire assessing both environmental and behavioural variables. Factors independently associated with HTLV-I infection included a low level of education [odds ratio (OR) 6.61, confidence interval (CI) 2.89-15.15], black ethnicity (OR 3.28, CI 1.01-10.65), two or more sex partners in the previous 3 years (OR 2.43, CI 1.16-5.10), early age at first sexual intercourse (0.84 risk reduction per additional year, CI 0.76-0.93), a history of sexually transmitted diseases (OR 2.29, CI 1.0-5.34) and positive Chlamydia serology (OR 1.95, CI 1.03-3.68). These data provide a wide spectrum of features associated with HTLV-I seropositivity, especially sexual risk factors. It strongly suggests that heterosexual intercourse is an important route of HTLV-I transmission in Guadeloupe, even among low-risk populations such as blood donors.

Late diagnosis of HIV infection in women seeking counseling and testing services in São Paulo, Brazil.

We investigated whether women positive for human immunodeficiency virus (HIV) infection were late in seeking an anonymous HIV counseling and testing service, and the factors associated with a low CD4 count, in São Paulo, Brazil. Seventy-one consecutive HIV-1-seropositive women were interviewed by means of a structured questionnaire. Blood samples were collected for CD4+ T-lymphocytes count and determination of HIV-1 subtypes. Hepatitis C, syphilis, human T-cell lymphotrophic virus type I (HTLV-I), and HTLV-II infections were assessed by serologic tests. More than 70% of the women had less than 500 CD4+ cells/mm3 (20% below 200). Low CD4 count was significantly associated with sex work history, condom use in the last 6 months, and seropositivity to HTLV-I and syphilis. There was no relation between low CD4 count and HIV-1 subtypes. These results indicate that in Sao Paulo many women are seeking an anonymous testing service late in the course of HIV infection. The main purposes of anonymous HIV testing services - early diagnosis of infection, and counseling to prevent infection - are not being achieved. Another strategy for reducing the interval between infection and diagnosis in women must be addressed.

An inverse correlation of HTLV-I viral load in CSF and intrathecal synthesis of HTLV-I antibodies in TSP/HAM.

The authors measured human T-cell lymphotrophic virus type I (HTLV-I) proviral load and intrathecal synthesis of antibodies to HTLV-I in CSF of 13 Brazilian patients with tropical spastic paraparesis/ HTLV-I-associated myelopathy (HAM). The authors also measured HTLV-I proviral load in peripheral blood mononuclear cells of five of these patients and found that it was 10- to 100-fold higher than that in CSF cells. The combination of HTLV-I proviral load and intrathecal synthesis of antibodies to HTLV-I appears to be a useful marker of disease progression. Patients with high viral load and no intrathecal synthesis of antibodies to HTLV-I had more rapidly progressing, serious clinical disease.

Clinical Course of HTLV-I–Associated Uveitis

Purpose: To define the long-term clinical course and visual outcome of human T-cell lymphotrophic virus type I (HTLV-I)-associated uveitis (HAU). Methods: We reviewed the clinical data on 96 eyes of 70 patients, 26 men and 44 women, with HAU, with specific reference to recurrence of the disease and long-term visual outcome. The mean follow-up period was 83 months (range, 12–276 months). Results: The mean age of onset was 42.8 years (range, 7–78 years of age), with men presenting at a significantly younger age. Forty-seven patients had isolated HAU; in 10 patients, HTLV-I–associated myelopathy occurred before or after the onset of HAU; in 14 patients, hyperthyroidism had preceded HAU. A single episode of mild to moderate acute uveal inflammation with resolution in a few weeks or more occurred in 44 (62.9%) patients, and multiple episodes in 26 (37.1%), with a mean interval of 16 months (range, 1–250 months), which affected the same eye, fellow eye, or both. The majority of patients had favorable visual outcome at the last examination, whereas only a few patients suffered poor vision resulting from steroid cataract and retinochoroidal degeneration. Conclusions: The clinical course of HAU is virtually benign and its visual outcome is favorable, although its recurrence is common. The uveitis is usually isolated and affects a portion of otherwise unremarkable HTLV-I carriers, but it may sometimes be manifest as a symptom of syndromic diseases such as HTLV-I–associated myelopathy or hyperthyroidism. This study describes for the first time cases of HAU that occurred many years before manifestation of HTLV-I–associated myelopathy.

Quantitative assessment of subclinical spasticity in human T-cell lymphotropic virus type I infection.

To compare human T-cell lymphotrophic virus type I (HTLV-I) seropositive and seronegative women for symptoms and signs of spasticity. Infection with HTLV-I causes tropical spastic paraparesis/ HTLV-I-associated myelopathy (TSP/HAM). Certain populations, including female commercial sex workers (FSW), are at increased risk of developing this infection. Fewer than 5% of HTLV-I-seropositive persons develop TSP/HAM, which is typically associated with spasticity. Cross-sectional study of 255 registered FSW in Callao, Perú, involving a questionnaire detailing demographics and neurologic symptoms, standard neurologic examination, quantitative assessment of spasticity (QSA) of muscle tone, and serologic testing for HTLV-I. Participants and examiners were blinded to serology results. On the questionnaire and neurologic examination, none of the 32 HTLV-I-seropositive or 223 seronegative women had signs or symptoms of spasticity. However, mean values on QSA were significantly higher among seropositive women (27.1 Newton-meters/radian [N-m/r]) than among seronegative women (21.6 N-m/r, p = 0.01), indicating a subclinical increase in lower extremity tone. With values of QSA divided into tertiles, and the first tertile serving as the comparison group, the odds ratio for seropositivity was 1.4 (95% confidence interval [CI] 1.0 to 2.0) in the second and 3.1 (95% CI 2.2 to 4.3) in the third tertile, after adjusting for age and place of birth. Although a standard neurologic evaluation could not distinguish between women with and without HTLV-I infection, QSA indicated significantly increased lower extremity tone in those with infection. Long-term follow-up will determine whether these subclinical findings in asymptomatic women progress to overt TSP/HAM.

The Coactivator CBP Stimulates Human T-cell Lymphotrophic Virus Type I Tax Transactivation in Vitro

Tax interacts with the cellular cyclic AMP-responsive element binding protein (CREB) and facilitates the binding of the coactivator CREB binding protein (CBP), forming a multimeric complex on the cyclic AMP-responsive element (CRE)-like sites in the human T-cell lymphotrophic virus type I (HTLV-I) promoter. The trimeric complex is believed to recruit additional regulatory proteins to the HTLV-I long terminal repeat, but there has been no direct evidence that CBP is required for Tax-mediated transactivation. We present evidence that Tax and CBP activate transcription from the HTLV-I 21 base pair repeats on naked DNA templates. Transcriptional activation of the HTLV-I sequences required both Tax and CBP and could be mediated by either the N-terminal activation domain of CBP or the full-length protein. Fluorescence polarization binding assays indicated that CBP does not markedly enhance the affinity of Tax for the trimeric complex. Transcription analyses suggest that CBP activates Tax-dependent transcription by promoting transcriptional initiation and reinitiation. The ability of CBP to activate the HTLV-I promoter does not involve the stabilization of Tax binding, but rather depends upon gene activation properties of the co-activator that function in the context of a naked DNA template.

Rheumatologic manifestations of HIV-1 and HTLV-1 infections.

HIV infection is the new "great mimic." Although its more common signs and symptoms are well known, HIV infection sometimes presents with rheumatologic manifestations, as does human T-cell lymphotrophic virus type I (HTLV-I), the causative agent of adult T-cell leukemia. This review briefly describes these manifestations and presents a logical clinical approach to their diagnosis and treatment.

Lupus erythematosus‐like features in patients with cutaneous T‐cell lymphoma

The development of lupus erythematosus-like (LE-like) features in patients with cutaneous T-cell lymphoma (CTCL) has not been reported previously in the literature. Both diseases, however, have been etiologically linked to retroviruses. Our purpose was to report four cases of patients with CTCL who developed LE-like features during the course of their disease, and to evaluate for evidence of antibodies to retroviruses in the sera of these patients. Four patients with biopsy-proven CTCL with clinical or histologic features of systemic lupus erythematosus (SLE) were evaluated for clinical and laboratory criteria for SLE. Only one patient demonstrated four American Rheumatism Association (ARA) criteria sufficient for the diagnosis of SLE. The remaining three patients demonstrated one or two criteria for SLE. In addition, the sera of these patients were examined by Western blot analysis for evidence of human immunodeficiency virus type I (HIV-I), human T-cell lymphotrophic virus type I (HTLV-I), or human intracisternal A-type particle type I (HIAP-I) retroviral proteins. Each patient demonstrated antibodies to some of the retroviral proteins examined. The sera of two patients reacted to proteins for HIAP-I, and the sera of two patients reacted to p24 gag proteins of HIV-I. No patient reacted to HTLV-I proteins. Our report identifies four patients with CTCL who developed LE-like features during the course of their disease. Although the etiology of CTCL and SLE has not been well established, each has been linked to retroviruses. Evidence of antibodies to retroviral proteins was identified in each of our patients by Western blot analysis. Although the clinical and laboratory findings in these cases do not resolve the etiologic role of retroviruses in CTCL or SLE, they suggest that retroviruses may have a role in the pathogenesis of the clinical phenomenon reported in these four patients.

A human suppressor of c-Jun N-terminal kinase 1 activation by tumor necrosis factor alpha.

Tumor necrosis factor alpha (TNFalpha) has pleiotropic effects on cellular metabolism. One of the signaling paths from the TNFalpha receptor induces a stress-activated protein kinase cascade. Components within this TNFalpha kinase cascade include mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1) and stress-activated protein kinase/extracellular signal-regulated kinase kinase (SEK), which regulate the activity of c-Jun N-terminal kinase 1 (JNK1). Currently, molecules upstream of MEKK1 that link TNFalpha receptor to downstream kinases are not well understood. Besides TNFalpha, many other stimuli including several oncoproteins can activate JNK1. In most cases, the signaling cascade(s) leading from oncoproteins to JNK1 is poorly elucidated. We report here that the human T-cell lymphotrophic virus, type I (HTLV-I) oncoprotein, Tax, can activate JNK1. We isolated a novel human cell factor, G-protein pathway suppressor 2 (GPS2), by its ability to bind the HTLV-I oncoprotein, and we show that this factor can potently suppress Tax activation of JNK1. In trying to understand the mechanism of GPS2 activity, we found that it also suppressed TNFalpha activation of JNK1 but not TNFalpha activation of p38 kinase nor phorbol activation of extracellular signal-regulated kinase 2. Because GPS2 has minimal effect on MEKK1- or SEK-regulated JNK1 activity, it could act at a point between the TNFalpha receptor and MEKK1 in the initial step(s) of this kinase cascade. Alternatively, it is not excluded that GPS2 could work in a parallel pathway that leads from TNFalpha to JNK1. GPS2 represents a new molecule that could contribute important insights toward how cytokine- and oncoprotein-mediated signal transduction might converge.

Screening for Human T-cell Lymphotrophic Virus type-I (HTLV-I) infection in high risk schizophrenic patients

The Mashhadi-Jewish community originating in Iran is a closed and ethnically segregated population with a unique history and a high rate of intra-familial marriage among its members. High infection rate (23%) by Human T-Lymphotrophic Virus type-I (HTLV-I) was found in this population. The known modes of HTLV-I transmission are by sexual intercourse, from mother to child in breast milk, via blood transfusion, and by sharing of needles by parenteral drug users. In the present study we examined the presence of HTLV-I infection in high-risk psychiatric patients of Iranian origin in order to evaluate the infection rate in socially isolated subjects. We screened and examined all (N=42) Iranian-born schizophrenic patients in our center, of whom 17 were Mashhadi subjects (7 females, 10 males, mean age 48.7±13.2 years), and 25 were born in Iran in other cities than Mashhad (12 females, 13 males, mean age 43.2±11.9). Blood samples were tested for HTLV-I antibodies by particle agglutination test. The polymerase chain reaction (PCR) was used to detect HTLV-I proviral DNA sequences from peripheral blood mononuclear cells. One Mashhadi-born Jew (5.9%) was seropositive and PCR-positive for HTLV-I. None of the schizophrenic non-Mashhadi Iranian subjects was positive for HTLV-I by either method. This infection rate in schizophrenic patients of Mashhadi origin is significantly lower than rates reported for the normal Mashhadi community. We suggest that the relative isolation imposed by the stigma associated with mental illness and recurrent psychiatric hospitalizations serve to protect this sub-group from HTLV-I infection.

Induction of anergy in CD8 T cells by B cell presentation of antigen.

Induction of T cell anergy is thought to occur during activation in the absence of adequate costimulation. Here we demonstrate induction of anergy in a CD8 T cell clone by its cognate Ag in the presence of B7-1 and B7-2 costimulation. Primary activation of a CD28+CD8+ T cell clone by either human T cell lymphotrophic virus type I (HTLV-I) Tax11-19 peptide-pulsed EBV-transformed B cells, CD40L-stimulated B cells, or T cells was sufficient to induce complete unresponsiveness to a secondary Ag challenge. This was not caused by lack of B7 costimulation since the APCs expressed B7-1 and B7-2 and failed to induce anergy in an MBP peptide 84-102-reactive CD4 T cell clone. While anergic CD8 T cells did not proliferate, they retained their ability to lyse peptide-pulsed target cells. However, Ag stimulation failed to induce IL-2 mRNA transcription and IL-2 secretion, although immediate early tyrosine phosphorylation was normal and anti-CD3 cross-linking induced identical levels of CD40L expression in anergized and non-anergized CD8 T cells. Secondary Ag stimulation in the presence of exogenous IL-2, however, resulted in normal proliferative response. Moreover, while stimulation of CD8 T cells with PHA and B cells induced anergy, CD8 T cell stimulation with PHA and mononuclear cells failed to do so. In addition, the presence of mononuclear cells during the exposure of CD8 T cells to peptide-pulsed B cells prevented the induction of anergy. Together, our observations demonstrate that at least a subpopulation of CD8 T cells are anergized when costimulation is provided by B cells or T cells.

Evidence Against a Role for Human T-Cell Lymphotrophic Virus Type I (HTLV-I) in the Pathogenesis of American Cutaneous T-Cell Lymphoma

We used a standard polymerase chain reaction (PCR)/Southern blot assay (sensitivity > 10(-5)) to detect human T-cell lymphotrophic virus type I (HTLV-I) proviral pX, pol, and env genes in the lesional skin of 42 American patients with cutaneous T-cell lymphoma (CTCL). As in some prior reports using similar methods, a variable proportion of PCR tests were positive (seven of 42 for pX, three of 42 for pol, and two of 37 for env), resulting in an overall positive test rate of 12 of 121 (10%). To determine the significance of these positive test results, we performed several additional studies. D1S80 polymorphism analysis of CTCL cases and HTLV-I PCR analysis of non-CTCL dermatosis controls showed no evidence that positive PCR tests resulted from sample mislabeling, gross HTLV-I contamination, or human endogenous retroviruses. We then modified the standard PCR assay to incorporate ultraviolet (UV) light to destroy low-level PCR contamination. With this modified assay (sensitivity > 10(-5)), only three of 12 previously positive cases were still positive, suggesting that the earlier positives were due to trace contamination of PCR reagents or trace contamination of sample DNA. This interpretation was also supported by: (i) a match between pX and pol sequences cloned from one PCR-positive specimen and the MT4-positive control, (ii) our inability to confirm HTLV-I in any PCR-positive case using genomic dot blotting (sensitivity > 10(-2)), and (iii) negative PCR results when new samples from two of the remaining positive cases were analyzed. Finally, we used our modified UV/ PCR/Southern blot assay to test an additional 28 cases of American CTCL for pX. All of them were negative. Although these studies of 70 cases of American CTCL do not exclude the possibility that another virus is involved in the pathogenesis of this disease, they provide strong evidence against a role for HTLV-I. Furthermore, they emphasize the need for special strategies to control for false-positive PCR tests that can result from even trace levels of contamination with viral DNA. As a consequence, associations between diseases and viruses should be viewed skeptically if they are based primarily on conventional PCR data.

Interleukin (IL) 15/IL-T production by the adult T-cell leukemia cell line HuT-102 is associated with a human T-cell lymphotrophic virus type I region /IL-15 fusion message that lacks many upstream AUGs that normally attenuates IL-15 mRNA translation.

We reported previously that the human T-cell lymphotrophic virus type I (HTLV-I)-associated adult T-cell leukemia line HuT-102 produces a cytokine designated interleukin (IL) T that requires interleukin (IL) 2 receptor beta-subunit expression for its action. Using anti-cytokine antibodies, we demonstrated that IL-T is identical to the simultaneously described IL-15. When compared to activated monocytes, IL-15 mRNA expression was 6- to 10-fold greater in HuT-102 cells. The predominant IL-15 message from HuT-102 is a chimeric mRNA joining a segment of the R region of the long terminal repeat of HTLV-I and the 5'-untranslated region (UTR) of IL-15. Normally, by alternative splicing, this 118-nucleotide R element represents the most 5' region of several HTLV-I transcripts including tax, rex, and env. The introduction of the R element eliminated over 200 nucleotides of the IL-15 5'-UTR, including 8 of 10 upstream AUGs that are present in normal IL-15 messages. On analysis of the 5'-UTR of normal IL-15, we demonstrated that the presence of these 10 upstream AUGs interferes with IL-15 mRNA translation. Thus, IL-15 synthesis by the adult T-cell leukemia line HuT- 102 involves an increase in IL-15 mRNA transcription and translation secondary to the production of an HTLV-I R element fusion message that lacks many upstream AUGs.

Stimulation of the CD2 receptor pathway induces apoptosis in human T lymphotropic virus type I-infected cell lines.

We demonstrate that CD2 receptor engagement, but not CD3 crosslinking, induces apoptosis in lymphocytes transformed by human T-cell lymphotrophic virus type I (HTLV-I). Mitogenic pairs of anti-CD2 monoclonal antibodies inhibited [3H]thymidine incorporation from 25 to 62% in CD2+ HTLV-I-infected lymphocytes. This inhibition was associated with a 20-40% reduction in cell number and viability over a 3-day period, morphologic evidence of apoptosis, and irreversible DNA fragmentation. While cyclosporin A abrogated CD2-mediated proliferation in peripheral blood mononuclear cells, it had no effect on CD2-induced apoptosis in the HTLV-I-infected cell lines. Since HTLV-I is mitogenic to resting lymphocytes through CD2 activation pathways, these results suggest that HTLV-I-infected lymphocytes are primed for apoptosis following additional CD2 stimulation. This CD2-mediated apoptosis might be a factor in immune regulation of HTLV-I-associated diseases or might offer a novel adjunctive approach to treatment.