Human T-cell Leukemia-lymphoma Virus Research Articles

Human pathogenic virus-associated pseudolymphomas and lymphomas with primary cutaneous manifestation in humans and animals.

The etiologic role of viruses in cutaneous lymphoproliferative disorders is still controversial. In benign cutaneous pseudolymphomas of the human skin, human T-cell leukemia/lymphoma virus (HTLV) type I (HTLV-I), varicella zoster virus, Epstein-Barr virus (EBV), and human herpesvirus (HHV) 6 (HHV-6) are the viruses most often identified, whereas in malignant lymphoproliferation human immunodeficiency virus type 1 (HIV-1), HTLV-I/II, and EBV are more common. Coinfections with more than one virus species have occurred in a number of cases. HHV-8 in association with a lymphoproliferative lesion appears to be indicative of a malignant cutaneous lymphoma rather than of pseudolymphoma. Negative results are of no diagnostic value because of the relatively low number of virus-positive cases: a considerable proportion of studies (with a large number of subjects) have documented virus-negative findings. Perhaps with the exception of HIV-1, findings of viral infections seem to indicate secondary rather than primary infections. Reports on animal models associated with human pathogenic viruses are scarce.

Epitope mapping of HTLV envelope seroreactivity in LGL leukaemia.

Sera from approximately 50% of patients with large granular lymphocyte (LGL) leukaemia react with a recombinant human T-cell leukaemia/lymphoma virus (HTLV) transmembrane envelope protein, p21e. Two immunodominant epitopes within env p21e have been defined by reactivity against recombinant proteins GD21 and BA21. In this study sera from 41 patients with LGL leukaemia were examined for reactivity against these recombinant HTLV env proteins. Overall, 21/41 (51%) sera reacted to p21e. Only two sera reacted to GD21. The predominant immunoreactivity against p21e was directed against the BA21 epitope, with 19/41 (46%) sera being BA21 positive. Seroconversion to BA21 protein was also documented. PCR analyses confirmed the low incidence of protypical HTLV sequences (2/41, 5%). These data document an association between BA21 seroreactivity and LGL leukaemia. This finding raises the possibility that such BA21 seroreactivity could be due to cross-reactivity to a cellular or retroviral antigen sharing some amino acid homology with the transmembrane glycoprotein of HTLV.

Seroreactivity to an Envelope Protein of Human T-Cell Leukemia/Lymphoma Virus in Patients With CD3− (Natural Killer) Lymphoproliferative Disease of Granular Lymphocytes

AbstractNatural killer (NK) cells are CD3− large granular lymphocytes (LGL) responsible for immunity against viral infections. A chronic lymphoproliferative disorder of NK cells has been described in which the expanded NK cells display a restricted phenotype and cytotoxic activity. These data raise the hypothesis that proliferating LGL in these patients result from discrete expansions of NK cells responding to an unknown, perhaps viral, antigen. Recently, it was found that mice transgenic for the tax gene of human T-cell leukemia/lymphoma virus (HTLV) develop NK leukemia. Therefore, we studied 15 patients with chronic NK lymphoproliferative disorder for evidence of HTLV infection. Sera were tested using an HTLV-I/II-enzyme linked immunosorbent assay and a modified Western blot assay containing recombinant envproteins. None of the sera met conventional criteria for HTLV seroreactivity. However, sera from 11 patients (73%) reacted with the recombinant HTLV env protein p21E. The anti-p21E reactivity of these sera was then mapped employing the recombinant proteins GD21 and BA21. No reactivity to the immunodominant HTLV epitope GD21 was observed, suggesting that prototypical HTLV infection is unlikely in these patients. This was confirmed by finding no evidence for HTLV nucleic acids by PCR analyses employing primers specific for conserved regions in the env, pol, and pX genes. In contrast, 10 of the 15 sera reacted with the epitope BA21, documenting for the first time an association between a unique seroreactivity and disease. The high incidence of BA21 seroreactivity in these patients suggests that exposure to a protein containing homology to BA21 may be important in the pathogenesis of this lymphoproliferative disorder.

Epstein–Barr Virus Permissively Infects Human Syncytiotrophoblastsin Vitroand Induces Replication of Human T Cell Leukemia-Lymphoma Virus Type I in Dually Infected Cells

Epstein–Barr virus (EBV) and human immunodeficiency virus type 1 (HIV-1), as well as human T-cell leukemia-lymphoma virus type I (HTLV-I), may interact in the pathogenesis of human retroviral infections. The placental syncytiotrophoblast layer represents a barrier protecting the fetal compartment from exposure to retroviruses. We studied the interactions of EBV with HIV-1 and HTLV-I in human term syncytiotrophoblast cells to investigate the significance of double infections in transplacental transmission of human retroviruses. We found that syncytiotrophoblast cells could be productively infected with EBV. Dual infection of the cells with EBV and HTLV-I resulted in full replication cycle of otherwise latent HTLV-I. In contrast, the restricted permissiveness of syncytiotrophoblasts for HIV-1 was not influenced by coinfection of the cells with EBV. Infection of syncytiotrophoblast cells with EBV, but not HTLV-I, induced interleukin-2 and interleukin-6 secretion, and augmented secretion occurred on coinfection with both viruses. Coinfection of syncytiotrophoblast cells with EBV and HTLV-I induced tumor necrosis factor-β and transforming growth factor-β1 secretion, but infection with either virus alone did not lead to secretion of these cytokines. Permissive replication cycle of HTLV-I was induced by the EBV immediate-early gene product Zta. Pseudotype formation between EBV and HTLV-I in coinfected syncytiotrophoblast cells was not found. Our data suggest that activation of HTLV-I gene expression by EBV in coinfected syncytiotrophoblast cells may be a mechanism for transplacental transmission of HTLV-I.

Infectious agents associated with myopathies.

Several infectious agents can cause chronic or acute myopathy. Most current investigations into possible infectious causes of the idiopathic inflammatory myopathies have focused on retroviruses, including HIV and human T-cell leukemia-lymphoma virus type I. In both cases, viruses likely do not directly infect muscle fibers but instead induce an immunologically mediated myositis. Other interest has focused on enteroviruses as potential etiologic agents of idiopathic inflammatory myopathy, but their relationship to human myositis is less clear. In addition to chronic muscle disease, several infectious agents can cause acute myositis, including pyomyositis, which is being recognized in temperate climates with increasing frequency, and rhabdomyolysis.

High occurrence of primary malignant neoplasms in patients with adult T-cell leukemia/lymphoma, their siblings, and their mothers.

Attempts were made to clarify the correlation between human T-cell leukemia/lymphoma virus (HTLV)-1 infection and malignant oncogenicity other than adult T-cell leukemia/lymphoma (ATL) in a case-control study. The occurrence of primary malignant neoplasms (MN) in 110 ATL patients, their parents, and 430 siblings was compared with HTLV-1 seronegative non-Hodgkin's lymphoma (NHL) patients, their parents and 867 siblings. The chi-square test, odds ratio (OR), and 95% confidence intervals (CI) were used to determine the statistical significance of differences in the occurrence of the primary MN among ATL patients, HTLV-1 seronegative NHL patients, their siblings, and their parents. The occurrence of primary MN in the ATL patients was higher than the occurrence in HTLV-1 seronegative NHL patients (P = 0.0036; OR = 2.91; 95% CI: 1.42, 6.02). In siblings of the ATL patients, there was a higher occurrence of primary MN than in siblings of the HTLV-1 seronegative NHL patients (P < 0.0001; OR = 3.35; 95% CI: 2.01, 5.58). In mothers of the ATL patients, there was a higher occurrence of primary MN than in mothers of the HTLV-1 seronegative NHL patients (P = 0.0063; OR = 2.55; 95% CI: 1.30, 5.00), but not in fathers (P = 0.1602; OR = 1.68; 95% CI: 0.81, 3.47). There is an increased risk of primary MN in ATL patients, their siblings, and their mothers.

High Rate of Infection with the Human T-Cell Leukemia Retrovirus Type II in Four Indian Populations of Argentina

Sera from 215 non-drug-injecting Toba and Mataco-Mataguayo pure Indians belonging to four communities in northern Argentina were examined using assays that allow differentiation between reactivities due to type-specific antigens of the human T-cell leukemia/lymphoma virus (HTLV). Three of these populations have very little contact with non-Indian groups and reside in remote, isolated areas. HTLV-II type-specific seroreactivity was present in 24 (13.7%) of the 175 Indians older than 13 years of age and in none of the 40 who were of younger ages. None of the Indians had antibodies reacting with HTLV-I type-specific antigen. Seroreactivity was more prevalent and appeared at younger ages in females than in males. The majority of the HTL-II-seropositive Indians belonged to the mcca isolated communities. The seroprevalences among the Tobas and Mataco-Mataguayo Indians were comparable. With the exception of a Toba who was positive in a test for Treponema pallidum, no serological evidence of sexually transmitted infections with this spirochete, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus was found among the Indians tested. None of the 55 non-Indian people tested in the region showed HTLV-II type-specific seroreactivity. PCR analysis of DNA isolated from peripheral blood lymphocytes of seropositive Indians confirmed that the virus present in these populations is HTLV-II. Sequence analysis of PCR-amplified genomic segments showed that the virus belongs to the HTLV-II subtype which has been found to be endemic in other Paleo-American Indians.

Viral risks associated with blood transfusion

The presence of viruses in blood cells or plasma from asymptomatic donors is the major risk of transmitting an infectious agent through blood transfusion. The main viruses involved are hepatitis viruses and retroviruses. The risk of transmitting hepatitis B virus (HBV) and hepatitis C virus (HCV) has been progressively and efficiently reduced in the last years by the successive introduction of hepatitis B surface antigen (HBsAg) screening, elevated serum alanine aminotransferase (ALT), antibody to hepatitis B core (HBc Ab), and more recently antibody to hepatitis C virus (HCV Ab). The risk of transmitting human retroviruses like human immunodeficiency virus (HIV) and human T-cell leukemia/lymphoma virus (HTLV) has also been reduced drastically thanks to screening for corresponding antibodies. However, except for HBs Ag screening, the immunoassays used for HCV, HIV, or HTLV only detect antibodies. Therefore, although they are infectious, a few blood units may be not discarded. The efficacy of preventive measures depends on the incubation time, the infectivity during this silent phase, and the sensitivity of screening procedures. Human cytomegalovirus (HCMV) and parvovirus B 19 are responsible for common infections. Consequently, 30% to more than 50% adults have serologic evidence of past infection. However, both viruses may cause severe primo-infections in some circumstances, especially in pregnant women or immunodeficient individuals.

T-cell leukemia-lymphoma and mycosis fungoides

Notable efforts have been made to relate aspects of the cell biology of T cells to the pathology, diagnosis, and treatment T-cell neoplasms. In particular, the application of molecular biologic tools to these areas has already allowed the generation of patient-specific markers for disease. A case can be made that a knowledge of the distinctive natural history of T-cell neoplasms should influence choices of treatment. Additional insights into the relevance of the human T-cell leukemia-lymphoma virus family to human disease have been recorded, and an important association of cutaneous T-cell lymphoproliferative disorders with human immunodeficiency virus infection has been documented.

Detection of human T-cell leukemia/lymphoma virus, type II, in a patient with large granular lymphocyte leukemia

We studied a patient with large granular lymphocyte (LGL) leukemia for evidence of human T-cell leukemia/lymphoma virus (HTLV) infection. Serum from this patient was positive for HTLV-I/II antibodies by enzyme- linked immunosorbent assay (ELISA) and was confirmed positive in Western blot and radioimmunoprecipitation assays. Results of a synthetic peptide-based ELISA showed that the seropositivity was caused by HTLV-II and not HTLV-I infection. Analyses of enzymatic amplification of DNA from bone marrow sections using the polymerase chain reaction (PCR) were positive for HTLV-II specific gag, pol, env, and pX gene sequences. Cloning and sequencing of amplified products showed that the HTLV-II pol and pX sequences in patient DNA differed from the sequences of 17 other HTLV-II isolates examined in our laboratory. HTLV infection may have a role in some patients in the pathogenesis of LGL leukemia.

Detection of Human T-Cell Leukemia/Lymphoma Virus, Type II, in a Patient With Large Granular Lymphocyte Leukemia

We studied a patient with large granular lymphocyte (LGL) leukemia for evidence of human T-cell leukemia/lymphoma virus (HTLV) infection. Serum from this patient was positive for HTLV-I/II antibodies by enzyme-linked immunosorbent assay (ELISA) and was confirmed positive in Western blot and radioimmunoprecipitation assays. Results of a synthetic peptide-based ELISA showed that the seropositivity was caused by HTLV-II and not HTLV-I infection. Analyses of enzymatic amplification of DNA from bone marrow sections using the polymerase chain reaction (PCR) were positive for HTLV-II specific gag, pol, env, and pX gene sequences. Cloning and sequencing of amplified products showed that the HTLV-II pol and pX sequences in patient DNA differed from the sequences of 17 other HTLV-II isolates examined in our laboratory. HTLV infection may have a role in some patients in the pathogenesis of LGL leukemia.

Primary isolation of human T-cell leukemia-lymphoma virus types I and II: use for confirming infection in seroindeterminate blood donors

We describe the use of an immunofluorescence assay and coculture to confirm human T-cell leukemia-lymphoma virus (HTLV) infection. Peripheral blood mononuclear cells from 32 of 32 seropositive donors were positive in the immunofluorescence assay, and 63% of their cocultures produced p24 antigen. Specific antibodies distinguished HTLV type I (HTLV-I) from HTLV-II. HTLV-I or HTLV-II was isolated from donors with indeterminate serologic test results.

Sequence variation of functional HTLV-II tax alleles among isolates from an endemic population: lack of evidence for oncogenic determinant in tax.

Human T-cell leukemia-lymphoma virus type II (HTLV-II) has been isolated from patients with hairy cell leukemia (HCL). We previously described a population with longstanding endemic HTLV-II infection, and showed that there is no increased risk for HCL in the affected groups. We thus have direct evidence that the endemic form(s) of HTLV-II cause HCL infrequently, if at all. By comparison, there is reason to suspect that the viruses isolated from patients with HCL had an etiologic role in the disease in those patients. One way to reconcile these conflicting observations is to consider that isolates of HTLV-II might differ in oncogenic potential. To determine whether the structure of the putative oncogenic determinant of HTLV-II, tax2, might differ in the new isolates compared to the tax of the prototype HCL isolate, MO, four new functional tax cDNAs were cloned from new isolates. Sequence analysis showed only minor (0.9-2.0%) amino acid variation compared to the published sequence of MO tax2. Some codons were consistently different from published sequences of the MO virus, but in most cases, such variations were also found in each of two tax2 clones we isolated from the MO T-cell line. These variations rendered the new clones more similar to the tax1 of the pathogenic virus HTLV-I. Thus we find no evidence that pathologic determinants of HTLV-II can be assigned to the tax gene.

Human T-cell leukemia-lymphoma virus type I (HTLV-I) expression in fresh peripheral blood mononuclear cells from patients with tropical spastic paraparesis/HTLV-I-associated myelopathy

Tropical spastic paraparesis/human T-cell leukemia-lymphoma virus type I (HTLV-I)-associated myelopathy (TSP/HAM) is a chronic neurological illness epidemiologically associated with HTLV-I infection. We investigated the role of HTLV-I in the pathogenesis of this disease by studying viral expression in fresh uncultured peripheral blood mononuclear cells (PBMCs) of six patients of Caribbean origin with TSP/HAM. The PBMC genomic DNA of all the patients studied carried HTLV-I provirus, but viral expression was not detected by Northern (RNA) blot analysis of total cellular PBMC RNA. When the reverse transcriptase polymerase chain reaction technique was used with primers specific for the tax-rex mRNA, all of the samples were positive for this viral mRNA species, regardless of the duration of the illness (range, 2 to 13 years). The splice junctions for the tax-rex mRNA described in cases of HTLV-I-induced adult T-cell leukemia (position 5183 of the envelope and position 7302 of the pX region) were identical in three TSP/HAM cases studied. To ascertain whether viral expression occurred at a low level in many cells or at a high level in a few permissive cells, we performed in situ hybridization on fresh PBMCs from two patients (2 and 7 years after clinical diagnosis), seeking HTLV-I RNA sequences. Our finding indicated that in vivo HTLV-I expression occurred at a high level in a few cells (1 of every 5,000 PBMCs) in both cases studied. The fact that cells of all six patients with TSP/HAM were positive for viral expression, regardless of the time lag from diagnosis, suggests that persistent expression of a viral product(s) may be pivotal in the pathogenesis of TSP/HAM.

High frequency of human T-cell leukemia-lymphoma virus type II infection in New Mexico blood donors: determination by sequence- specific oligonucleotide hybridization

The Albuquerque branch of the United Blood Services system was found to have an unusually high blood donor human T-cell leukemia/lymphoma virus (HTLV) seroprevalence (0.72 per 1,000). Many studies investigating HTLV seroprevalence and transmission have assumed that all seropositivity is due to HTLV type I (HTLV-I); recent data dispute this conclusion. We investigated the high prevalence of HTLV seropositivity in New Mexico by determining whether HTLV-I or HTLV-II is predominant in our donors. Using polymerase chain reaction (PCR) amplification of proviral DNA from peripheral blood, followed by sequence-specific hybridization with oligonucleotide probes to distinguish the two viruses, we demonstrate that 9 of 10 Western blot-confirmed HTLV-seropositive blood donors from New Mexico are infected with HTLV-II. Implications of this finding for donors and the safety of the blood supply are discussed.

High Frequency of Human T-Cell Leukemia-Lymphoma Virus Type II Infection in New Mexico Blood Donors: Determination by Sequence-Specific Oligonucleotide Hybridization

The Albuquerque branch of the United Blood Services system was found to have an unusually high blood donor human T-cell leukemia/lymphoma virus (HTLV) seroprevalence (0.72 per 1,000). Many studies investigating HTLV seroprevalence and transmission have assumed that all seropositivity is due to HTLV type I (HTLV-I); recent data dispute this conclusion. We investigated the high prevalence of HTLV seropositivity in New Mexico by determining whether HTLV-I or HTLV-II is predominant in our donors. Using polymerase chain reaction (PCR) amplification of proviral DNA from peripheral blood, followed by sequence-specific hybridization with oligonucleotide probes to distinguish the two viruses, we demonstrate that 9 of 10 Western blot-confirmed HTLV-seropositive blood donors from New Mexico are infected with HTLV-II. Implications of this finding for donors and the safety of the blood supply are discussed.

Prevalence of human T-cell leukemia/lymphoma virus (HTLV) type II infection among high-risk individuals: type-specific identification of HTLVs by polymerase chain reaction

The extent of human T-cell leukemia/lymphoma virus type II (HTLV-II) infection and its rate of spread have been difficult to determine owing to the serological cross-reactivity between HTLV-I and HTLV-II. The present study overcame this problem by directly detecting type-specific proviral sequences by means of the polymerase chain reaction (PCR) and liquid hybridization. Screening was performed on a cohort of primarily white intravenous drug abusers (IVDAs), and individuals of other behaviorally defined risk groups from the New York City area. Eleven percent (19 of 169) of the individuals in these high-risk groups were determined by PCR to have HTLV-II proviral infections. One of these patients displayed an exfoliative erythrodermatitis. Thirteen of the 19 subjects were positive in an HTLV-II enzyme-linked immunosorbent assay (ELISA). The remaining six individuals, although negative in the HTLV- II ELISA, were confirmed as HTLV-II positive by analyzing their DNA with a second HTLV-II-specific primer detector system. Four additional individuals were reactive in the HTLV-II ELISA but were PCR-negative for HTLV-II. PCR analysis for HTLV-I revealed that all four were positive for that virus. Thirty-seven percent (seven of 19) of the HTLV- II PCR-positive subjects were also PCR-positive for HTLV-I, and 84% (16 of 19) of the HTLV-II positive individuals were infected with human immunodeficiency virus (HIV-1). Six individuals were triply infected with HTLV-I, HTLV-II, and HIV-1.

Human retroviruses

After many unsuccessful years of searching, the first pathogenic human retrovirus, the human T-cell leukaemia lymphoma virus (HTLV-I), was reported as recently as 1980 and since that time has been causally linked to the adult T-cell leukaemia lymphoma syndrome. A second HTLV (HTLV-II) isolated shortly afterwards is less clearly linked to some leukaemic and chronic lymphoid malignancies. The second major family of human retroviruses are the human immunodeficiency viruses (HIV) the first group of isolates (HIV-I) of which cause the acquired deficiency syndrome (AIDS). A second group of these viruses (HIV-II), have recently been identified in West Africa. They appear to be less clearly associated with disease and more similar in molecular structure to the Simian immunodeficiency viruses. AIDS has now become a major global pandemic, and vaccine and therapeutic strategies are urgently being investigated in an effort to control the disease. Unfortunately, current results are not very encouraging. In the meantime, preventative and educational measures are of utmost priority in order to prevent further spread. It is not unlikely that new human retroviruses will be discovered over the next few years.

The effects of tumor promoters on HTLV-1 expression in a low-virus producer and a non-virus producer cell line

Chemical agents including 5-iodo-2′-deoxyuridine (IUdR), 4- O-methyl 12- O-tetradecanoyl phorbol-13-acetate (TPA), phorbol, and the tumor promoters teleocidin and TPA were tested for their ability to induce Human T-cell leukemia-lymphoma virus Type I (HTLV-I) expression in the low-virus producer MT-1 cell line and in the non-virus producer C63/CR II-2 cell line, which contains at least one integrated HTLV-I genome equivalent per cell [26]. Viral antigen expression increased from 0.3% to 8.7% in the MT-1 cell line after treatment with IUdR, while TPA and teleocidin were marginally or non-effective as inducers. Chemicals did not induce HTLV-I antigen expression in the C63/CI II-2 cell line. No enhancement of reverse transcriptase activity or alteration of proviral organization was observed after chemical treatment of MT-1 cells.

Establishment of an interleukin 2-dependent human T cell line from a patient with T cell chronic lymphocytic leukemia who is not infected with human T cell leukemia/lymphoma virus

We established an interleukin 2 (IL-2)-dependent human T cell line, Kit 225, from a patient with T cell chronic lymphocytic leukemia (T-CLL) with OKT3+, -T4+, -T8- phenotype. Southern blot analysis showed that Kit 225 is not infected with human T cell leukemia/lymphoma virus (HTLV) type I or II, and is probably derived from the major clone in the fresh leukemic cells. Kit 225 cells express a large amount of IL 2 receptors constitutively and their growth is absolutely dependent on IL 2. No other stimuli, such as lectins or antigens, are required for maintaining the responsiveness to IL 2. As abnormal IL 2 receptor expression was also seen originally in the fresh leukemic cells, the establishment of this cell line with IL 2 suggests that IL 2-mediated T cell proliferation is involved in the leukemogenesis of some cases of HTLV-negative T-CLL.