Investigating the circadian rhythm signaling pathway in HTLV-1 pathogenesis using Boolean analysis

The Human T-cell lymphotropic virus type 1 (HTLV-1), an oncogenic virus belonging to the Deltaretrovirus genus, expresses various proteins, including Tax and HBZ, which can affect many cellular pathways. In this study, we have investigated the role of the circadian rhythm signaling pathway, a key regulator of human health, in the pathogenesis of HTLV-1 using Boolean Network analysis and laboratory methods. After an extensive search of the circadian rhythm pathway, we analyzed the relationships between the genes of this pathway using the R programming language and the BoolNet package. Subsequently, we examined the impact of viral proteins on the cellular clock rhythm genes. Finally, we identified three genes, PER2, CRY1, and DEC1, as the main checkpoints from the attractors obtained. These three genes and two viral genes, Tax and HBZ, were quantitatively assessed on two groups of individuals, including ten asymptomatic carriers infected with HTLV-1 and ten healthy individuals using the qRT-PCR method. Our results showed that the expression level of PER2 and DEC1 genes was significantly higher in the asymptomatic carriers compared to the healthy control group. Also, we recorded positive correlations between PER2 and DEC1, CRY1 and DEC1, and negative correlations between HBZ and CRY1 and DEC1. In this study, we suggested that in asymptomatic carriers, the virus might try to induce a chronic infection by escaping from the immune system due to an alteration in circadian rhythm pathways. We also detected three promising genes in this pathway that could have therapeutic or diagnostic value in these individuals. However, this possibility requires further research in different periods, different groups (e.g., ATLL and HAM/TSP), and examining a more significant number of circadian rhythm genes.