Abstract
Human T-cell Leukemia Virus type-1 (HTLV-1) is an oncovirus that may cause two main life-threatening diseases including a cancer type named Adult T-cell Leukemia/Lymphoma (ATLL) and a neurological and immune disturbance known as HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). However, a large number of the infected subjects remain as asymptomatic carriers (ACs). There is no comprehensive study that determines which dysregulated genes differentiate the pathogenesis routes toward ATLL or HAM/TSP. Therefore, two main algorithms including weighted gene co-expression analysis (WGCNA) and multi-class support vector machines (SVM) were utilized to find major gene players in each condition. WGCNA was used to find the highly co-regulated genes and multi-class SVM was employed to identify the most important classifier genes. The identified modules from WGCNA were validated in the external datasets. Furthermore, to find specific modules for ATLL and HAM/TSP, the non-preserved modules in another condition were found. In the next step, a model was constructed by multi-class SVM. The results revealed 467, 3249, and 716 classifiers for ACs, ATLL, and HAM/TSP, respectively. Eventually, the common genes between the WGCNA results and classifier genes resulted from multi-class SVM that also determined as differentially expressed genes, were identified. Through these step-wise analyses, PAIP1, BCAS2, COPS2, CTNNB1, FASLG, GTPBP1, HNRNPA1, RBBP6, TOP1, SLC9A1, JMY, PABPC3, and PBX1 were found as the possible critical genes involved in the progression of ATLL. Moreover, FBXO9, ZNF526, ERCC8, WDR5, and XRCC3 were identified as the conceivable major involved genes in the development of HAM/TSP. These genes can be proposed as specific biomarker candidates and therapeutic targets for each disease.
Highlights
Human T-cell Leukemia Virus type-1 (HTLV-1) is a human deltaretrovirus, which develops a lifelong infection [1]
The HTLV-1 infection leads to developing two main diseases including Adult T-cell Leukemia/Lymphoma (ATLL) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) in about 5% of the infected subjects, the majority of the infected individuals remain in an asymptomatic carrier (AC) state [2, 3]
The most important genes that classified the disease, were determined by exploring common genes between unique genes in each module and classifier genes identified by support vector machines (SVM)
Summary
Human T-cell Leukemia Virus type-1 (HTLV-1) is a human deltaretrovirus, which develops a lifelong infection [1]. The HTLV-1 infection leads to developing two main diseases including Adult T-cell Leukemia/Lymphoma (ATLL) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) in about 5% of the infected subjects, the majority of the infected individuals remain in an asymptomatic carrier (AC) state [2, 3]. HAM/TSP is another disease caused by HTLV-1 which is specified by perivascular inflammatory infiltrates in the spinal cord and brain. The infiltrating CD8+ and CD4+ lymphocytes are existing in the inflammatory lesions of the spinal cord [6]. The main challenge regarding this virus is which functional players cause the separation of pathogenesis routes to each of the mentioned diseases
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