T-Cell Control by Human T-Cell Leukemia/Lymphoma Virus Type 1

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) causes neoplastic transformation of human T-cells in a small number of infected individuals several years from infection. Collective evidence from in vitro studies indicates that several viral proteins act in concert to increase the responsiveness of T-cells to extracellular stimulation, modulate proapoptotic and antiapoptotic gene signals, enhance T-cell survival, and avoid immune recognition of the infected T-cells. The virus promotes T-cell proliferation by usurping several signaling pathways central to immune T-cell function, such as antigen stimulation and receptor-ligand interaction, suggesting that extracellular signals are important for HTLV-1 oncogenesis. Environmental factors such as chronic antigen stimulation may therefore be of importance, as also suggested by epidemiological data. Thus genetic and environmental factors together with the virus contribute to disease development. This review focuses on current knowledge of the mechanisms regulating HTLV-1 replication and the T-cell pathways that are usurped by viral proteins to induce and maintain clonal proliferation of infected T-cells. The relevance of these laboratory findings is related to clonal T-cell proliferation and adult T-cell leukemia/lymphoma development in vivo.     

Immunologic Control of Human T-Cell Leukemia Virus Type I and Adult T-Cell Leukemia

Host T-cell responses to human T-cell leukemia virus type I (HTLV-I) control the expansion of HTLV-I-infected cells and are determinants of the equilibrium proviral load in vivo. Insufficient T-cell responses are regarded as an immunologic risk factor for adult T-cell leukemia (ATL) because they allow increased proviral loads, which represent an epidemiologic risk factor for ATL. ATL cells from approximately half of ATL cases retain the ability to express HTLV-I Tax, a major target antigen of HTLV-I-specific cytotoxic T-lymphocytes (CTL), whereas Tax-specific CTL in ATL patients are inactive. Tax-specific CTL responses are strongly activated after hematopoietic stem cell transplantation in some ATL patients in long-term remission, indicating that HTLV-I Tax is expressed in vivo rather than being silent, and that the donor-derived T-cell system can recognize it. These findings strongly suggest that reactivation of Tax-specific CTL by vaccines may be promising for prophylaxis of ATL in the high-risk group of HTLV-I carriers and for therapy of ATL in patients whose tumor cells are capable of expressing Tax.     

Antibodies to the Human T-Cell Lymphoma/Leukemia Virus Type I in Dutch Haemophiliacs

95 Dutch haemophiliacs were tested for antibodies to membrane antigens on cells infected with human T-cell leukemia virus type I (HTLV-I-MA) by indirect immunofluorescence and to purified HTLV-I by enzyme-linked immunosorbent assay. Antibodies to HTLV-I-MA were present in 8 of 95 (8%) haemophiliacs, but only 3 (3%) had antibodies to purified HTLV-I. No clinical disease was related to HTLV-I seropositivity. The importance of iatrogenic HTLV-I transmission to haemophiliacs is discussed.     

Risk Factors for Adult T-Cell Leukemia Among Carriers of Human T-Lymphotropic Virus Type I

The presence of circulating "flower cells" and a lowprevalence of antibody to Tax regulatory protein of humanT-lymphotropic virus type I (HTLV-I) are characteristics of adultT-cell leukemia (ATL). To examine the predictability of levels ofHTLV-I antibodies and of flower cell-like abnormal lymphocytes (Ably)for the risk of ATL among asymptomatic HTLV-I carriers, weprospectively evaluated the levels of viral markers of five HTLV-Icarriers who developed ATL and 38 age-, sex-, and screen-matchedHTLV-I-positive controls in the Miyazaki Cohort Study. Afteraccounting for matching factors, Ably level was slightly, but notsignificantly, higher among cases than among controls (P = .13). Anti-HTLV-I (odds ratio [OR] = 1.6 per twofold dilution;95% confidence interval [CI] 0.94, 3.8) was associated with ATLdiagnosis, but antibody to Tax regulatory protein (anti-Tax) was not(OR = 0.78; 95% CI 0.26, 1.7). Anti-Tax level was low for all ATLcases for up to 10 years preceding their diagnosis, independent of thelevel of anti-HTLV-I titer. HTLV-I carriers with a higher anti-HTLV-Ititer and a lower anti-Tax reactivity may be at greatest risk of ATL.     

Revisiting Keratoconjunctivitis sicca associated with Human T-Cell Lymphotropic Virus Type 1: prevalence,clinical aspects and proviral load

BackgroundThe prevalence of keratoconjunctivitis sicca (KCS) associated with Human T-Cell Lymphotropic Virus Type 1 (HTLV-1) (HTLV-1/KCS) has been estimated at around 37%, but its clinical manifestations are poorly described.PurposeTo determine the prevalence and associated factors of HTLV-1/KCS in a large cohort of HTLV-1-infected individuals living in Salvador, Brazil.MethodsA cross-sectional study was conducted between June 2004 and September 2017 at the Integrative and Multidisciplinary Center for HTLV in Salvador, Bahia-Brazil. Data from 758 HTLV-1-infected patients was collected. A complete ophthalmologic examination was performed in both eyes. Lacrimal function was evaluated by breakup time, Rose Bengal and Schirmer I Tests. KCS diagnosis was considered in the presence of at least two out of three positive tests. HTLV-1 proviral load Crude and Adjusted Prevalence Rates (PR) with 95% Confidence Intervals (95% CI) were estimated using multivariate Poisson Regression with robust error variance.ResultsThe overall prevalence of KCS was 31.7%, with higher rates observed in HTLV-1-associated myelopathy/tropical spastic paraparesis patients (crude PR: 1.84; CI95%: 1.50–2.26) even after adjusting for age, sex, time of HTLV-1 diagnosis and schooling (adjusted PR: 1.63; CI95%: 1.31–2.02). Proviral load, low corrected visual acuity, burning and/or pain and itching were all significantly higher in patients with KCS.ConclusionBurning and/or pain and itching and low corrected visual acuity were the most common alterations of HTLV-1/KCS. High Proviral load was found to be associated with the presence of KCS. It is strongly recommended that HTLV-1 patients undergo periodic ophthalmologic examination to promote the early diagnosis of KCS and prevent the consequences associated with dry eye disease.     

Prognosis of Indolent Adult T-Cell Leukemia/Lymphoma

A retrospective chart survey of the clinical features of indolent adult T-cell leukemia/lymphoma (ATL) was conducted in the Miyazaki Prefecture, Japan. This study enrolled 24 smoldering-type ATLs, 10 favorable chronic-type ATLs, and 20 unfavorable chronic-type ATLs diagnosed between 2010 and 2018. Among them, 4, 3, and 10 progressed to acute-type ATLs during their clinical course. The median survival time (MST) in smoldering-type ATL and favorable chronic-type ATL was not reached, and their 4-year overall survival (OS) was 73% and 79%, respectively. Compared with this, the prognosis of unfavorable chronic-type ATL was poor. Its MST was 3.32 years, and the 4-year OS was 46% (p = 0.0095). In addition to the three features that determine the unfavorable characteristics of chronic-type ATL, namely, increased lactate dehydrogenase, increased blood urea nitrogen, and decreased albumin, the high-risk category by the indolent ATL-Prognostic Index, which was defined by an increment of soluble interleukin-2 receptor (sIL2-R) of >6000 U/mL, could explain the poor prognosis in indolent ATL patients. The level of sIL-2R might be an indicator of the initiation of therapy for indolent ATL.     

Expression of Human Tumor-Associated Antigen RCAS1 in Adult T-Cell Leukemia/Lymphoma

In human cancer, RCAS1 (the receptor-binding cancer antigen expressed on SiSo cells) on the surface of various kinds of tumor cells reportedly induces the apoptosis of T-cells and natural killer cells, resulting in evasion of the immune system. In the present study, an immunohistochemical analysis of RCAS1 expression was performed with lymph node specimens obtained from patients with adult T-cell leukemia/lymphoma (ATLL). Positive staining was seen in 15 (75%) of 20 cases and in all cases of patients with short survival times. In the cases of B-cell lymphomas, positive staining was seen in only 1 (13%) of 8 cases. These findings indicate that expression of RCAS1 may be associated with the evasion from immune surveillance of cells infected with human T-lymphotropic virus type I, resulting in the development of overt leukemia/lymphoma. Determination of RCAS1 expression may be useful for predicting the prognosis of patients with ATLL.     

Allogeneic Stem Cell Transplantation for Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATLL) develops in elderly individuals who have been infected with human T-cell leukemia virus type 1 (HTLV-1), and the prognosis for patients with ATLL has been extremely poor. Retrospective studies of allogeneic stem cell transplantation (alloSCT) for selected populations of patients have achieved several encouraging results; however, the reported incidence of transplantation-related mortality (TRM) have been high, even though more than 80% of patients received stem cells from related donors and the patients were relatively young for ATLL. This report documents a prospective feasibility study of alloSCT with reduced-intensity conditioning (RIST) for elderly ATLL patients (>50 years). Regimen-related toxicities and nonhematologic toxicities were acceptable. Fourteen of 15 evaluable patients achieved complete donor chimerism within 90 days, and 1 patient had early TRM after RIST. The HTLV-1 proviral load became undetectable in 8 of 15 patients, suggesting that RIST has potential as an antiviral treatment. The results of alloSCT are promising, and 30% to 40% of patients who achieve remission and have suitable donors can now become long-term survivors with either conventional alloSCT or RIST. It is clear that a graft-versus-ATLL effect is present after alloSCT, regardless of the conditioning regimen or the stem cell source.     

NK/T-Cell Lymphoma Associated with Epstein-Barr Virus in a Patient Infected with Human Immunodeficiency Virus: An Autopsy Case

Natural killer (NK)/T-cell lymphoma associated with Epstein-Barr virus (EBV) in a patient infected with human immunodeficiency virus (HIV) is very rare. The authors encountered a case of NK/T-cell lymphoma in a 36-year-old man who presented with an ulcerative mass on both tonsils. During assessment, HIV positivity was noted. The EBV was detected by EBV-encoded RNA 1 messenger RNA in situ hybridization and polymerase chain reaction for EBV-encoded nuclear antigen 1. On immunohistochemical staining, the infiltrated lymphoid cells of the tonsils demonstrated positvity for CD3, CD56, UCHL1, and granzyme, a finding compatible with NK/T-cell lymphoma. The patient received radiation therapy and chemotherapy, but died as a result of opportunistic infection of invasive aspergillosis after tumor recurrence. An autopsy was done with the consent of the patient's family. To our knowledge, this is the first case in an HIV patient of NK/T-cell lymphoma of the tonsils associated with EBV, confirmed by autopsy. NK/T-cell lymphoma should be considered in the HIV-positive patients with an ulcerating tonsillar mass.     

Human T-Cell Leukemia Virus Type 1 Tax and Cellular Transformation

Infection of T-cells by human T-cell leukemia virus type 1 (HTLV-1) causes a lymphoproliferative malignancy known as adult T-cell leukemia (ATL). ATL is characterized by abnormal lymphocytes, called flower cells, which have cleaved and convoluted nuclei. Tax, encoded by the HTLV-1 pX region, is a critical nonstructural protein that plays a central role in leukemogenesis; however, the mechanisms of HTLV-1 oncogenesis have not been clarified fully. In this review, we summarize current thinking on how Tax may affect ATL leukemogenesis.     

Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis

Human T lymphotropic viruses (HTLVs) are complex deltaretroviruses that do not contain a proto-oncogene in their genome, yet are capable of transforming primary T lymphocytes both in vitro and in vivo. There are four known strains of HTLV including HTLV type 1 (HTLV-1), HTLV-2, HTLV-3 and HTLV-4. HTLV-1 is primarily associated with adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 is rarely pathogenic and is sporadically associated with neurological disorders. There have been no diseases associated with HTLV-3 or HTLV-4 to date. Due to the difference in the disease manifestation between HTLV-1 and HTLV-2, a clear understanding of their individual pathobiologies and the role of various viral proteins in transformation should provide insights into better prognosis and prevention strategies. In this review, we aim to summarize the data accumulated so far in the transformation and pathogenesis of HTLV-1, focusing on the viral Tax and HBZ and citing appropriate comparisons to HTLV-2.     

Nationwide Hospital-Based Survey of Adult T-Cell Leukemia/Lymphoma in Japan

Nationwide surveys of adult T-cell leukemia/lymphoma (ATL) have played an important role in helping us to understand the pathophysiology of this disease and analyze its prognosis in Japan. Classifications of clinical subtypes have been proposed based on the results of nationwide surveys of patients with ATL diagnosed in the 1980s. This article highlighted the classification and prognosis of ATL based on different surveys and focused on the comparison of data derived from the available surveys. The 11th nationwide hospital-based survey was conducted in patients with ATL diagnosed in 2010–2011 using the same method as that used in the 1980s survey. The median age of disease onset was 68 years, which was increased compared with previous surveys. While median survival of patients with the acute and lymphoma types had not improved much since the 1980s, the 4-year survival rate was higher. Little improvement in the prognosis was observed for the chronic and smoldering types. The 12th nationwide survey of patients with ATL diagnosed in 2012–2013 also showed an increase in age at onset. Further epidemiological research that includes more cases is needed to deepen our understanding of the actual state of treatment and prognosis of this disease.     

Low Proviral Load is Associated with Indeterminate Western Blot Patterns in Human T-Cell Lymphotropic Virus Type 1 Infected Individuals: Could Punctual Mutations be Related?

Background: indeterminate Western blot (WB) patterns are a major concern for diagnosis of human T-cell lymphotropic virus type 1 (HTLV-1) infection, even in non-endemic areas. Objectives: (a) to define the prevalence of indeterminate WB among different populations from Argentina; (b) to evaluate if low proviral load (PVL) is associated with indeterminate WB profiles; and (c) to describe mutations in LTR and tax sequence of these cases. Results: Among 2031 samples, 294 were reactive by screening. Of them, 48 (16.3%) were WB indeterminate and of those 15 (31.3%) were PCR+. Quantitative real-time PCR (qPCR) was performed to 52 HTLV-1+ samples, classified as Group 1 (G1): 25 WB+ samples from individuals with pathologies; Group 2 (G2): 18 WB+ samples from asymptomatic carriers (AC); and Group 3 (G3): 9 seroindeterminate samples from AC. Median PVL was 4.78, 2.38, and 0.15 HTLV-1 copies/100 PBMCs, respectively; a significant difference (p=0.003) was observed. Age and sex were associated with PVL in G1 and G2, respectively. Mutations in the distal and central regions of Tax Responsive Elements (TRE) 1 and 2 of G3 were observed, though not associated with PVL.The 8403A>G mutation of the distal region, previously related to high PVL, was absent in G3 but present in 50% of WB+ samples (p = 0.03). Conclusions: indeterminate WB results confirmed later as HTLV-1 positive may be associated with low PVL levels. Mutations in LTR and tax are described;  their functional relevance remains to be determined.