We studied the clinical features and laboratory findings in 213 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis as diagnosed in Kagoshima University Hospital. Some aspects of clinical features in HTLV-I-associated myelopathy/tropical spastic paraparesis were characterized by mode of HTLV-I transmission and age of onset. The patients with onset after 15 years old and no history of blood transfusion before the onset of the disease (151 patients, group I) showed a shorter interval between the time of disease onset and that of inability to walk. The patients with onset before 15 years old and without history of blood transfusion (21 patients, group II) had short stature and slow progression of the disease. The interval time and the progression of the disease in patients with history of blood transfusion before onset of disease (41 patients, group III) were in between those of the above two groups. Patients whose ages of onset were older than 61 years old showed a faster progression than those with younger onset regardless of the mode of HTLV-I transmission. HTLV-I-associated myelopathy/tropical spastic paraparesis patients often also showed other organ disorders such as leukoencephalopathy (69%), abnormal findings on chest X-ray (50%), Sjogren syndrome (25%) and arthropathy (17%). The patients with low anti-HTLV-I antibody titers in the cerebrospinal fluid (2X-8X by PA method) had an older age of onset on average, milder clinical symptoms and lesser increase of neopterin in the cerebrospinal fluid than those in the high titer subgroup whose titers were higher than 1024X in cerebrospinal fluid regardless of the mode of HTLV-I transmission. We speculate that the clinical course of HTLV-I-associated myelopathy/tropical spastic paraparesis mainly shows a slow progression which consists of an initial progressive phase (probably an inflammatory phase) and a latter chronic phase, although some patients showed acute/subacute onset and rapid progression.

HTLV-I-associated myelopathy: analysis of 213 patients based on clinical features and laboratory findings

In this study, we examined the methylation status of the CDKN2A gene in patients with different forms of adult T-cell leukemia (ATL) using Southern blot analysis, methylation-specific PCR (MSPCR), and nucleotide sequencing We found that the CDKN2A gene was more frequently methylated in fresh tumor cells isolated from patients with acute ATL (47%) or lymphoma-type ATL (73%) than in those with less malignant chronic (17%) and smoldering (17%) ATL In addition, deletions of the CDKN2A gene were found in 24% of acute ATL patients; thus, abnormalities of the CDKN2A gene totaled 71% in acute ATL patients In contrast, no CDKN2A gene methylation was found in asymptomatic carriers or uninfected individuals Methylation of the p15 gene was not found in any samples from 36 ATL patients Direct sequencing of the CDKN2A gene after sodium bisulfite treatment of genomic DNA revealed that the methylation of CpG sites had occurred in 24 of 32 ATL cases (75%) including chronic and smoldering ATL, even when MSPCR and the Southern blot had failed to detect CDKN2A gene methylation Among fresh ATL samples with methylation, methylation was detected in the promoter region and exon in 17 of 24 cases, and methylation in the exon without promoter region was detected in 7 of 24 cases In one case, the pattern of methylation proved to be different between peripheral blood cells and lymph node cells, suggesting the presence of multiple subclones with regard to methylation patterns, despite the same HTLV-I integration site Quantitative PCR showed a marked decrease in CDKN2A mRNA expression in the cells with a methylated CDKN2A gene, especially if the promoter region was methylated These findings suggest that CpG methylation decreases CDKN2A expression and represents a critical factor in the disease progression of ATL

https://cancerres.aacrjournals.org/content/canres/60/4/1043.full.pdf

Increasing Methylation of the CDKN2A Gene Is Associated with the Progression of Adult T-Cell Leukemia

Mutation of CD95 (Fas/Apo-1) Gene in Adult T-Cell Leukemia Cells

The identification of CD4 as the primary receptor for HIV followed shortly after the discovery of the virus, but the HTLV receptor remained long elusive, until its recent identification as the GLUT1 glucose transporter. In the present review, we describe the status of the literature that surrounded this discovery as well as the in vitro and in vivo observations that led to the identification of GLUT1. Also, we will explore a few tracks to conciliate the in vitro and in vivo data on HTLV-1 tropism within the context of the HTLV literature that has accumulated over the past 25 years. A close examination of these data leads us to conclude that the preferential detection of HTLV-1 in CD4+ T lymphocyte subsets in vivo, even in the absence of leukemia, is not likely to be directly related to envelope receptor interactions, but rather to an array of postentry selection bottlenecks in vivo. Furthermore, we propose that infection of other hematopoietic and nonhematopoietic cells is likely to take place during the lifetime of an individual, with a burst early during the infection.

HTLV-1 tropism and envelope receptor

A human T-lymphotropic virus type I/II (HTLV-I/II) vaccine is necessary in view of two etiologically related, life-threatening diseases, namely, adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-I-associated myelopathy. When the risk of developing autoimmune diseases such as uveitis, polymyositis, and arthritis is included, one can estimate the life-long risk of infected individuals to develop an HTLV associated pathology as approximately 10%. The populations at risk are, in a large majority, from developing countries but the epidemic of HTLV-II infection in intravenous drug users (IVDU) represents a possible reservoir for dissemination in the general population. The number of HTLV-I-infected individuals (15 to 25 million), together with the severity of associated disease, justifies the development of a vaccine. Different vaccine preparations have been developed, using mostly recombinant pox and adenoviruses, but DNA plasmid technology will soon become a feasible approach. Various animal models exist for experimental viral infections, involving rats, rabbits, or monkeys, but up to now, neither hematological nor neurological disorders have been induced by HTLV infection in such animal models. For long-term protection from HTLV-I-associated diseases, vaccination should induce both neutralizing antibodies and specific cell-mediated immunity. This will require the incorporation of both env and gag coding sequences in the vaccine preparations. Preventive clinical trials may involve different cohorts of seronegative young girls from endemic areas prior to sexual activity and IVDU in the industrialized world. In parallel, one should consider therapeutic vaccine trials in HTLV-I-positive mothers and IVDU to protect them against disease development. The observed rate of seroconversion in these different cohorts makes such trials feasible.

An Htlv-i/ii Vaccine: From Animal Models to Clinical Trials?

Human T lymphocyte virus type I (HTLV-I) can be transmitted into several inbred strains of newborn and adult rats by inoculating newly established HTLV-I-immortalized rat T cell lines or the human T cell line MT-2. The transmission efficiency exceeds 80%, regardless of strain differences or the age at transmission. The production of anti-HTLV-I antibodies significantly differs among the strains and depends on the age at the time of transmission. Rats neonatally inoculated with HTLV-I-positive rat or human cells generally become seronegative HTLV-I carriers throughout their lives, whereas adult rats inoculated with HTLV-I-positive cells at 16 wk of age become seropositive HTLV-I carriers. The HTLV-I provirus genome is present in almost all organs, regardless of whether the carriers are seronegative or seropositive. According to antibody titers to HTLV-I, there are three groups of inbred rat strains: ACI, F344, and SDJ (high responders); WKA, BUF, and LEJ (intermediate responders); and LEW (low responder). Three of three 16-mo-old seronegative HTLV-I carrier rats of the WKA strain developed spastic paraparesis of the hind legs. Neuropathological examinations revealed that the lesions were confined primarily to the lateral and anterior funiculi of the spinal cord. Both myelin and axons were extensively damaged in a symmetrical fashion, and infiltration with massive foamy macrophages was evident. The most severe lesions were at levels of the thoracic cord and continued from the cervical to the lumbar area. These histopathological features as well as clinical symptoms largely parallel findings in humans with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). These HTLV-I carrier rats, in particular the WKA rats described above, can serve as a useful animal model for investigating virus-host interactions in the etiopathogenesis of HTLV-I-related immunological diseases, particularly HAM/TSP.

https://rupress.org/jem/article-pdf/176/4/981/1103084/981.pdf

A rat model of human T lymphocyte virus type I (HTLV-I) infection. 1. Humoral antibody response, provirus integration, and HTLV-I-associated myelopathy/tropical spastic paraparesis-like myelopathy in seronegative HTLV-I carrier rats.

Molecular analysis of a HTLV-I pX defective human adult T-cell leukemia

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A rat model of human T lymphocyte virus type I (HTLV-I) infection. 1. Humoral antibody response, provirus integration, and HTLV-I-associated myelopathy/tropical spastic paraparesis-like myelopathy in seronegative HTLV-I carrier rats.

Molecular analysis of a HTLV-I pX defective human adult T-cell leukemia