Human T-Lymphotropic Virus Type 1 (HTLV-1): Persistence and Immune Control

The human retrovirus human T-lymphotropic virus type 1 (HTLV-1) is associated with two distinct types of disease: the malignancy known as adult T-cell leukemia and a range of chronic inflammatory conditions including the central nervous system disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Until recently, it was believed that HTLV-1 was largely latent in vivo. However, evidence from a number of types of experiments shows that HTLV-1 persistently expresses its genes, and that the "set point" of an individual's proviral load of HTLV-1 is mainly determined by the efficiency of that individual's cellular immune response to the virus. These conclusions have two main consequences. First, HTLV-1 may be vulnerable to antiretroviral drug therapy or immunotherapy. Second, HTLV-1 infection has become a useful system to analyze the determinants of the efficiency of the antiviral immune response.     

Mixed connective tissue disease with interstitial pneumonia in HTLV-1 carrier: case report and review of the literature

We report on a carrier of human T-lymphotropic virus type 1 (HTLV-1) who developed mixed connective tissue disease (MCTD). This patient suddenly manifested clinical symptoms and interstitial pneumonia ascribable to MCTD following long-term infection with HTLV-1. After initiation of oral prednisolone all manifestations quickly improved in parallel with a decrease in inflammatory reactions. In this patient HTLV-1 infection might have played an important role in the pathogenesis of MCTD. Since HTLV-1 can cause adult T-cell leukemia and HTLV-1-associated myelopathy, and also collagen diseases including MCTD, careful observation is necessary even in a carrier, particularly when autoantibodies are detectable in serum.     

Molecular determinants of human T-lymphotropic virus type 1 transmission and spread

Human T-lymphotrophic virus type-1 (HTLV-1) infects approximately 15 to 20 million people worldwide, with endemic areas in Japan, the Caribbean, and Africa. The virus is spread through contact with bodily fluids containing infected cells, most often from mother to child through breast milk or via blood transfusion. After prolonged latency periods, approximately 3 to 5% of HTLV-1 infected individuals will develop either adult T-cell leukemia/lymphoma (ATL), or other lymphocyte-mediated disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The genome of this complex retrovirus contains typical gag, pol, and env genes, but also unique nonstructural proteins encoded from the pX region. These nonstructural genes encode the Tax and Rex regulatory proteins, as well as novel proteins essential for viral spread in vivo such as, p30, p12, p13 and the antisense encoded HBZ. While progress has been made in the understanding of viral determinants of cell transformation and host immune responses, host and viral determinants of HTLV-1 transmission and spread during the early phases of infection are unclear. Improvements in the molecular tools to test these viral determinants in cellular and animal models have provided new insights into the early events of HTLV-1 infection. This review will focus on studies that test HTLV-1 determinants in context to full length infectious clones of the virus providing insights into the mechanisms of transmission and spread of HTLV-1.     

Factors associated with pain in individuals infected by human T-cell lymphotropic virus type 1 (HTLV-1)

Introduction

Despite the high prevalence of chronic pain in individuals infected with HTLV-1, predictive and protective factors for its development are still unclear.

Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P)

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were −13.8% (95% CI: −20.1–−7.1; p < 0.001) and −6.0% (95% CI: −12.8–1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085)     

Updates on HTLV-1 Uveitis

HTLV-1 uveitis (HU) is the third clinical entity to be designated as an HTLV-1-associated disease. Although HU is considered to be the second-most frequent HTLV-1-associated disease in Japan, information on HU is limited compared to that on adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). Recent studies have addressed several long-standing uncertainties about HU. HTLV-1-related diseases are known to be caused mainly through vertical transmission (mother-to-child transmission), but emerging HTLV-1 infection by horizontal transmission (such as sexual transmission) has become a major problem in metropolitan areas, such as Tokyo, Japan. Investigation in Tokyo showed that horizontal transmission of HTLV-1 was responsible for HU with severe and persistent ocular inflammation. The development of ATL and HAM is known to be related to a high provirus load and hence involves a long latency period. On the other hand, factors contributing to the development of HU are poorly understood. Recent investigations revealed that severe HU occurs against a background of Graves’ disease despite a low provirus load and short latency period. This review highlights the recent knowledge on HU and provides an update on the topic of HU in consideration of a recent nationwide survey.     

An Epitope Platform for Safe and Effective HTLV-1-Immunization: Potential Applications for mRNA and Peptide-Based Vaccines

Human T-cell lymphotropic virus type 1 (HTLV-1) infection affects millions of individuals worldwide and can lead to severe leukemia, myelopathy/tropical spastic paraparesis, and numerous other disorders. Pursuing a safe and effective immunotherapeutic approach, we compared the viral polyprotein and the human proteome with a sliding window approach in order to identify oligopeptide sequences unique to the virus. The immunological relevance of the viral unique oligopeptides was assessed by searching them in the immune epitope database (IEDB). We found that HTLV-1 has 15 peptide stretches each consisting of uniquely viral non-human pentapeptides which are ideal candidate for a safe and effective anti-HTLV-1 vaccine. Indeed, experimentally validated HTLV-1 epitopes, as retrieved from the IEDB, contain peptide sequences also present in a vast number of human proteins, thus potentially instituting the basis for cross-reactions. We found a potential for cross-reactivity between the virus and the human proteome and described an epitope platform to be used in order to avoid it, thus obtaining effective, specific, and safe immunization. Potential advantages for mRNA and peptide-based vaccine formulations are discussed.     

Seroindeterminate HTLV-1 Prevalence and Characteristics in Blood Donors in Taiwan

Human T-cell leukemia virus type 1 (HTLV-1) is commonly accepted as the cause of adult T-cell leukemia and tropical spastic paraparesis/HTLV-1-associated myelopathy. Screening of blood donors for HTLV-1 and HTLV-2 was implemented in Taiwan in February 1996. From February 1996 to December 1998, we investigated the seroprevalence of HTLV-1 in all unpaid blood donors in Taiwan. Of 2,578,238 donors in all 6 blood centers, 1793 (0.06%) were seropositive for HTLV-1, and 605 (0.023%) were indeterminate for HTLV-1. Among these indeterminate donors, 359 (59.3%) were male. The most common HTLV-1-indeterminate pattern by Western blot in our study was GD21 alone (34.6%) followed by p24 alone (7.8%), p53 alone (6.5%), and gp46 + GD21 (6.0%). That GD21 pattern was found in 59.6% of indeterminate results in this study suggested that the majority of nonspecific enzyme immunoassay reactions were probably precipitated by viral envelop glycoprotein GD21.     

Multiple tiny granulomatous lesions with eosinophils in a patient with smoldering-type adult T-cell leukaemia: The possibility of a new type of bronchioloalveolopathy

We herein describe the first case, to our knowledge, of pulmonary lesions characterized by necrotizing granuloma formation with eosinophils, in a patient with smoldering-type adult T-cell leukaemia. A 74-year-old man, diagnosed with smoldering-type adult T-cell leukaemia 1 year previously, was admitted due to repeated pyrexia and concurrent identification of diffuse small pulmonary nodules. A surgical lung biopsy specimen revealed inflammatory nodular lesions measuring up to 3 mm in size, which contained necrotizing and non-necrotizing granulomas, intraluminar organization and eosinophils, and were of unknown aetiology. The patient's condition, including the radiological findings, improved gradually without any treatment. This case suggests the possibility of a new type of human T-lymphotropic virus type-1 associated bronchioloalveolar disorder.     

The HTLV-1 Virological Synapse

Human T-lymphotropic virus-1 (HTLV-1) spreads efficiently between T-cells via a tight and highly organized cell-cell contact known as the virological synapse. It is now thought that many retroviruses and other viruses spread via a virological synapse, which may be defined as a virus-induced, specialized area of cell-to-cell contact that promotes the directed transmission of the virus between cells. We summarize here the mechanisms leading to the formation of the HTLV-1 virological synapse and the role played by HTLV-1 Tax protein. We propose a model of HTLV-1 transmission between T-cells based on the three-dimensional ultrastructure of the virological synapse. Finally, in the light of recent advances, we discuss the possible routes of HTLV-1 spread across the virological synapse.     

HTLV-1 associated myelopathy in an HTLV-1 and HBV double carrier family: Report of a case and the mode of vertical transmission of both viruses

Osame et al. first described human T cell lymphotropic virus type 1 (HTLV-1) associated myelopathy (HAM) as a new clinical entity in 1986. A 23 year old female diagnosed as having HAM whose family had a high frequency of double virus infection with HTLV-1 and hepatitis B virus (HBV) gave reason to suspect mother-to-child transmission of both viruses. No clear coincidence in the mode of transmission of HTLV-1 and HBV was found. It is presumed that the mechanism of infection with HTLV-1 and HBV differ slightly.     

ORIGIN AND PREVALENCE OF HUMAN T-LYMPHOTROPIC VIRUS TYPE 1 (HTLV-1) AND TYPE 2 (HTLV-2) AMONG INDIGENOUS POPULATIONS IN THE AMERICAS

Human T-lymphotropic virus type 1 (HTLV-1) is found in indigenous peoplesof the Pacific Islands and the Americas, whereas type 2 (HTLV-2) is widelydistributed among the indigenous peoples of the Americas, where it appears to be moreprevalent than HTLV-1, and in some tribes of Central Africa. HTLV-2 is consideredancestral in the Americas and is transmitted to the general population and injectiondrug users from the indigenous population. In the Americas, HTLV-1 has more than oneorigin, being brought by immigrants in the Paleolithic period through the BeringStrait, through slave trade during the colonial period, and through Japaneseimmigration from the early 20^th century, whereas HTLV-2 was only broughtby immigrants through the Bering Strait. The endemicity of HTLV-2 among theindigenous people of Brazil makes the Brazilian Amazon the largest endemic area inthe world for its occurrence. A review of HTLV-1 in all Brazilian tribes supports theAfrican origin of HTLV-1 in Brazil. The risk of hyperendemicity in theseepidemiologically closed populations and transmission to other populations reinforcesthe importance of public health interventions for HTLV control, including therecognition of the infection among reportable diseases and events.     

HTLV-1 and innate immunity

Innate immunity plays a critical role in the host response to a viral infection. The innate response has two main functions. First, it triggers effector mechanisms that restrict the infection. Second, it primes development of the adaptive response, which completes the elimination of the pathogen or of infected cells. In vivo, HTLV-1 infects T lymphocytes that participate in adaptive immunity but also monocytes and dendritic cells that are major players in innate immunity. Herein, we will review the interplay between HTLV-1 and innate immunity. Particular emphasis is put on HTLV-1-induced alteration of type-I interferon (IFN-I) function. In vitro, the viral Tax protein plays a significant role in the alteration of IFN synthesis and signaling. Despite this, IFN-I/AZT treatment of Adult T-cell Leukemia/Lymphoma (ATLL) patients leads to complete remission. We will discuss a model in which exogenous IFN-I could act both on the microenvironment of the T-cells to protect them from infection, and also on infected cells when combined with other drugs that lead to Tax down-regulation/degradation.     

Genetic Markers of the Host in Persons Living with HTLV-1, HIV and HCV Infections

Human T-cell leukemia virus type 1 (HTLV-1), hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) are prevalent worldwide, and share similar means of transmission. These infections may influence each other in evolution and outcome, including cancer or immunodeficiency. Many studies have reported the influence of genetic markers on the host immune response against different persistent viral infections, such as HTLV-1 infection, pointing to the importance of the individual genetic background on their outcomes. However, despite recent advances on the knowledge of the pathogenesis of HTLV-1 infection, gaps in the understanding of the role of the individual genetic background on the progress to disease clinically manifested still remain. In this scenario, much less is known regarding the influence of genetic factors in the context of dual or triple infections or their influence on the underlying mechanisms that lead to outcomes that differ from those observed in monoinfection. This review describes the main factors involved in the virus–host balance, especially for some particular human leukocyte antigen (HLA) haplotypes, and other important genetic markers in the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other persistent viruses, such as HIV and HCV.     

Research and discovery of the first human cancer virus, HTLV-1

Human T-cell lymphoma virus (HTLV)-1 was the first human retrovirus to be discovered. It has been recognized as the cause of adult T-cell leukemia (ATL). In addition to giving a historical perspective on HTLV-1 and other retrovirus research, this paper discusses the origin of HTLV-1; the modes of transmission and global epidemiology of HTLV-1 infection; the genome of HTLV-1 and the mechanism of HTLV-1-induced leukemogenesis; the role of HTLV-1 in other diseases, and recent breakthroughs in ATL therapy.