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Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One.

ABSTRACT: Human T-lymphotropic virus 1 (HTLV-1) was the first recognized human retrovirus. Infection can lead to two main symptomatologies: adult T-cell lymphoma/leukemia (ATLL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Each manifestation is associated with distinct characteristics, as ATLL presents as a leukemia-like disease, while HAM/TSP presents as severe inflammation in the central nervous system, leading to paraparesis. Previous studies have identified molecules associated with disease development, e.g., the downregulation of Foxp3 in Treg cells was associated with increased risk of HAM/TSP. In addition, elevated levels of CXCL10, CXCL9, and Neopterin in cerebrospinal fluid also present increased risk. However, these molecules were only associated with specific patient groups or viral strains. Furthermore, the majority of studies did not jointly compare all clinical manifestations, and robust analysis entails the inclusion of both ATLL and HAM/TSP. The low numbers of samples also pose difficulties in conducting gene expression analysis to identify specific molecular relationships. To address these limitations and increase the power of manifestation-specific gene associations, meta-analysis was performed using publicly available gene expression data. The application of supervised learning techniques identified alterations in two genes observed to act in tandem as potential biomarkers: GBP2 was associated with HAM/TSP, and CD40LG with ATLL. Together, both molecules demonstrated high sample-classification accuracy (AUC values: 0.88 and 1.0, respectively). Next, other genes with expression correlated to these genes were identified, and we attempted to relate the enriched pathways identified with the characteristic of each clinical manifestation. The present findings contribute to knowledge surrounding viral progression and suggest a potentially powerful new tool for the molecular classification of HTLV-associated diseases.

SUBMITTER: Fukutani ER

PROVIDER: S-EPMC6857459 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One.

Fukutani Eduardo Rocha ER Ramos Pablo Ivan Pereira PIP Kasprzykowski José Irahe JI Azevedo Lucas Gentil LG Rodrigues Moreno Magalhães de Souza MMS Lima João Victor de Oliveira Pimenta JVOP de Araújo Junior Helton Fábio Santos HFS Fukutani Kiyoshi Ferreira KF de Queiroz Artur Trancoso Lopo ATL

Frontiers in genetics 20191108

Human T-lymphotropic virus 1 (HTLV-1) was the first recognized human retrovirus. Infection can lead to two main symptomatologies: adult T-cell lymphoma/leukemia (ATLL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Each manifestation is associated with distinct characteristics, as ATLL presents as a leukemia-like disease, while HAM/TSP presents as severe inflammation in the central nervous system, leading to paraparesis. Previous studies have identified molecules associ ...[more]

PMID: 31781157

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Project description:BACKGROUND: Human T-cell Leukemia Virus type 1 (HTLV-1) is the etiological agent of tropical spastic paraparesis/HTLV-associated myelopathy (HAM/TSP) that can be identified in around 0.25%-3.8% of the infected population. Disease progression can be monitored by the proviral load and may depend on genetic factors, however, it is not well understood why some HTLV-1 infected people develop the disease while others do not. The present study attempts to assess the molecular diversity of gp46 glycoprotein in HAM/TSP patients and Health Carrier (HC) individuals. METHODS: Blood samples were collected from 10 individuals, and DNA was extracted from PBMCs to measure the HTLV-1 proviral load. The gp46 coding sequences were amplified PCR, cloned and sequenced. The molecular characterization was performed using bioinformatics tools. RESULTS: The median HTLV-1 proviral load of HC (n?=?5) and HAM/TSP (n?=?5) patients was similar (average 316,227 copies/106 PBMCs). The gp46 molecular characterization of 146 clones (70 HC and 76 HAM/TSP) revealed an overall diversity, within HC and HAM/TSP clones, of 0.4% and 0.6%, respectively. Five frequent mutations were detected among groups (HAM/TSP and HC clone sequences). A single amino acid (aa) substitution (S35L) was exclusive for the HC group, and three gp46 substitutions (F14S, N42H, G72S) were exclusive for the HAM/TSP group. The remaining frequent mutation (V247I) was present in both groups (p?=?0.0014). The in silico protein analysis revealed that the mutated alleles F14S and N42H represent more hydrophilic and flexible protein domains that are likely to be less antigenic. The Receptor Binding Domain is quite variable in the HAM/TSP group. Two other domains (aa 53-75 and 175-209) that contain multiple linear T-cell epitopes showed genetic diversity in both HAM/TSP and HC groups. Further analysis revealed 27 and 13 T-cell epitopes for class I HLA alleles and class II HLA alleles, when analyzing the entire gp46. CONCLUSIONS: The most common gp46 mutations were not associated clinical status because they were found in only one individual, except for the V247I mutation, that was found at viral clones from HAM/TSP ad HC individuals. Because of this, we cannot associate any of the gp46 found mutations with the clinical profile.

Project description:BackgroundHuman T-cell Leukemia Virus type-1 (HTLV-1) is a retrovirus that causes two diseases including Adult T-cell Leukemia/Lymphoma (ATLL cancer) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP, a neurodegenerative disease) after a long latency period as an asymptomatic carrier (AC). There are no obvious explanations about how each of the mentioned diseases develops in the AC carriers. Finding the discriminative molecular factors and pathways may clarify the destiny of the infection.MethodsTo shed light on the involved molecular players and activated pathways in each state, differentially co-expressed modules (DiffCoEx) algorithm was employed to identify the highly correlated genes which were co-expressed differently between normal and ACs, ACs and ATLL, as well as ACs and HAM/TSP samples. Through differential pathway analysis, the dysregulated pathways and the specific disease-genes-pathways were figured out. Moreover, the common genes between the member of DiffCoEx and differentially expressed genes were found and the specific genes in ATLL and HAM/TSP were introduced as possible biomarkers.ResultsThe dysregulated genes in the ATLL were mostly enriched in immune and cancer-related pathways while the ones in the HAM/TSP were enriched in immune, inflammation, and neurological pathways. The differential pathway analysis clarified the differences between the gene players in the common activated pathways. Eventually, the final analysis revealed the involvement of specific dysregulated genes including KIRREL2, RAB36, and KANK1 in HAM/TSP as well as LTB4R2, HCN4, FZD9, GRIK5, CREB3L4, TACR2, FRMD1, LHB, FGF3, TEAD3, GRIN2D, GNRH2, PRLH, GPR156, and CRHR2 in ATLL.ConclusionThe identified potential prognostic biomarkers and therapeutic targets are proposed as the most important platers in developing ATLL or HAM/TSP. Moreover, the proposed signaling network clarifies the differences between the functional players in the activated pathways in ACs, ATLL, and HAM/TSP.

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

Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One.

Publications

Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One.

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