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Bronchoalveolar lymphocytosis correlates with human T lymphotropic virus type I (HTLV-I) proviral DNA load in HTLV-I carriers.

ABSTRACT: BACKGROUND: A study was undertaken to investigate the pathogenesis of pulmonary involvement in human T lymphotropic virus type I (HTLV-I) carriers. METHODS: The bronchoalveolar lavage (BAL) cell profile of 30 HTLV-I carriers (15 asymptomatic HTLV-I carriers (AHCs) and 15 symptomatic HTLV-I carriers (SHCs)) with chronic inflammatory diseases of respiratory tract and eight patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) was investigated. The HTLV-I proviral deoxyribonucleic acid (DNA) load in peripheral blood mononuclear cells (PBMCs) and BAL fluid from HTLV-I carriers was estimated using the quantitative polymerase chain reaction method and the correlation between the lymphocyte number in BAL fluid and the HTLV-I proviral DNA load in PBMCs and BAL fluid was examined. RESULTS: The percentage of lymphocytes in BAL fluid was increased (>18%) in 11 of 30 HTLV-I carriers although there was no significant difference compared with control subjects. In HTLV-I carriers the lymphocyte number in BAL fluid correlated well with the copy number of HTLV-I proviral DNA in PBMCs. In addition, the copy number of HTLV-I proviral DNA in BAL fluid correlated well with the number of lymphocytes (both CD4+ and CD8+ cells) in BAL fluid. CONCLUSIONS: These findings suggest that pulmonary lymphocytosis can occur in a subset of HTLV-I carriers without HAM/TSP and that the increased HTLV-I proviral DNA load may be implicated in the pathogenesis of pulmonary involvement in HTLV-I carriers.

SUBMITTER: Mori S

PROVIDER: S-EPMC1747290 | biostudies-other | 2005 Feb

REPOSITORIES: biostudies-other

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Bronchoalveolar lymphocytosis correlates with human T lymphotropic virus type I (HTLV-I) proviral DNA load in HTLV-I carriers.

Mori S S Mizoguchi A A Kawabata M M Fukunaga H H Usuku K K Maruyama I I Osame M M

Thorax 20050201 2

<h4>Background</h4>A study was undertaken to investigate the pathogenesis of pulmonary involvement in human T lymphotropic virus type I (HTLV-I) carriers.<h4>Methods</h4>The bronchoalveolar lavage (BAL) cell profile of 30 HTLV-I carriers (15 asymptomatic HTLV-I carriers (AHCs) and 15 symptomatic HTLV-I carriers (SHCs)) with chronic inflammatory diseases of respiratory tract and eight patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) was investigated. The HTLV-I pr ...[more]

PMID: 15681503

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Project description:BACKGROUND: In vitro studies have demonstrated that deletions and point mutations introduced into each 21 bp imperfect repeat of Tax-responsive element (TRE) of the genuine human T-cell leukemia virus type I (HTLV-1) viral promoter abolishes Tax induction. Given these data, we hypothesized that similar mutations may affect the proliferation of HTLV-1-infected cells and alter the proviral load (PvL). To test this hypothesis, we conducted a cross-sectional genetic analysis to compare the near-complete LTR nucleotide sequences that cover the TRE1 region in a sample of HTLV-1 asymptomatic carriers with different PvL burden. METHODS: A total of 94 asymptomatic HTLV-1 carriers with both sequence from the 5' long terminal repeat (LTR) and a PvL for Tax DNA measured using a sensitive SYBR Green real-time PCR were studied. The 94 subjects were divided into three groups based on PvL measurement: 31 low, 29 intermediate, and 34 high. In addition, each group was compared based on sex, age, and viral genotypes. In another analysis, the median PvLs between individuals infected with mutant and wild-type viruses were compared. RESULTS: Using a categorical analysis, a G232A substitution, located in domain A of the TRE-1 motif, was detected in 38.7% (12/31), 27.5% (8/29), and 61.8% (21/34) of subjects with low, intermediate, or high PvLs, respectively. A significant difference in the detection of this mutation was found between subjects with a high or low PvL and between those with a high or intermediate PvL (both p < 0.05), but not between subjects with a low or intermediate PvL (p > 0.05). This result was confirmed by a non-parametric analysis that showed strong evidence for higher PvLs among HTLV-1 positive individuals with the G232A mutation than those without this mutation (p < 0.03). No significant difference was found between the groups in relation to age, sex or viral subtypes (p > 0. 05). CONCLUSIONS: The data described here show that changes in domain A of the HTLV-1 TRE-1 motif resulting in the G232A mutation may increase HTLV-1 replication in a majority of infected subjects.

Project description:BACKGROUND: To address the clinical and virological significance of a high HTLV-1 proviral load (VL) in practical blood samples from asymptomatic and symptomatic carriers, we simultaneously examined VL and clonal expansion status using polymerase chain reaction (PCR) quantification (infected cell % of peripheral mononuclear cells) and Southern blotting hybridization (SBH) methods. RESULTS: The present study disclosed extremely high VL with highly dense smears with or without oligoclonal bands in SBH. A high VL of 10% or more was observed in 16 (43.2%) of a total of 33 samples (one of 13 asymptomatic carriers, 8 of 12 symptomatic carriers, and 7 of 8 patients with lymphoma-type ATL without circulating ATL cells). In particular, an extremely high VL of 50% or more was limited to symptomatic carriers whose band findings always contained at least dense smears derived from polyclonally expanded cells infected with HTLV-1. Sequential samples revealed that the VL value was synchronized with the presence or absence of dense smears, and declined at the same time as disappearing dense smears. Dense smears transiently emerged at the active stage of the underlying disease. After disappearance of the smears, several clonal bands became visible and were persistently retained, explaining the process by which the clonality of HTLV-1-infected cells is established. The cases with only oligoclonal bands tended to maintain a stable VL of around 20% for a long time. Two of such cases developed ATL 4 and 3.5 years later, suggesting that a high VL with oligoclonal bands may be a predisposing risk to ATL. CONCLUSION: The main contributor to extremely high VL seems to be transient emergence of dense smears detected by the sensitivity level of SBH, corresponding to polyclonal expansion of HTLV-1-infected cells including abundant small clones. Major clones retained after disappearance of dense smears stably persist and acquire various malignant characteristics step by step.

Project description:BackgroundHTLV-1 causes proliferation of clonal populations of infected T cells in vivo, each clone defined by a unique proviral integration site in the host genome. The proviral load is strongly correlated with odds of the inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is evidence that asymptomatic HTLV-1 carriers (ACs) have a more effective CD8 + T cell response, including a higher frequency of HLA class I alleles able to present peptides from a regulatory protein of HTLV-1, HBZ. We have previously shown that specific features of the host genome flanking the proviral integration site favour clone survival and spontaneous expression of the viral transactivator protein Tax in naturally infected PBMCs ex vivo. However, the previous studies were not designed or powered to detect differences in integration site characteristics between ACs and HAM/TSP patients. Here, we tested the hypothesis that the genomic environment of the provirus differs systematically between ACs and HAM/TSP patients, and between individuals with strong or weak HBZ presentation.MethodsWe used our recently described high-throughput protocol to map and quantify integration sites in 95 HAM/TSP patients and 68 ACs from Kagoshima, Japan, and 75 ACs from Kumamoto, Japan. Individuals with 2 or more HLA class I alleles predicted to bind HBZ peptides were classified 'strong' HBZ binders; the remainder were classified 'weak binders'.ResultsThe abundance of HTLV-1-infected T cell clones in vivo was correlated with proviral integration in genes and in areas with epigenetic marks associated with active regulatory elements. In clones of equivalent abundance, integration sites in genes and active regions were significantly more frequent in ACs than patients with HAM/TSP, irrespective of HBZ binding and proviral load. Integration sites in genes were also more frequent in strong HBZ binders than weak HBZ binders.ConclusionClonal abundance is correlated with integration in a transcriptionally active genomic region, and these regions may promote cell proliferation. A clone that reaches a given abundance in vivo is more likely to be integrated in a transcriptionally active region in individuals with a more effective anti-HTLV-1 immune response, such those who can present HBZ peptides or those who remain asymptomatic.

Dataset Information

Bronchoalveolar lymphocytosis correlates with human T lymphotropic virus type I (HTLV-I) proviral DNA load in HTLV-I carriers.

Publications

Bronchoalveolar lymphocytosis correlates with human T lymphotropic virus type I (HTLV-I) proviral DNA load in HTLV-I carriers.

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