CD4 + T cells play a critical role in HTLV-1 infection and HTLV-1 preferentially infects these cells (13). Despite four decades of researches on HTLV-1, many ambiguity remain about the pathogenicity mechanism and key proteins involved in diverse pathological pathways. In this study, we investigated the gene expression profile of CD4 + T cells in healthy donors, asymptomatic HTLV-1 carriers (ACs), and ATLL based on GPL9686 platform. Among 65 immune genes studied (Box1), we identified immune genes which are more affected than other genes following HTLV-1 infection including: IL-10, IL-6, JAK, IL-15, SOCS1, TNFR6, FOXP3, PD-1, FADD, Ras, BCL2, Rb, RICTOR, RAC1, MAP2K4, BCL2A1, MAP1B, CXCR4, BRCA1, MSH2, ATM, and RIG1. These genes affect on difference processes of immune system such as inflammation, apoptosis, DNA damage, cell proliferation, T cell activation, invasion, angiogenesis, cell survival, and cell migration. Based on various studies, several changes in the cytokine/cytokine receptor signaling cascades are altered in HTLV-I-infected cells (14). It has been shown that the proliferation of HTLV-1 CD4 + T cells is due to JAK/STAT signaling pathway in response to some interleukins, specifically IL-2, IL-6, and IL-15 (15–17). The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating of immune system, especially cytokine receptors (18). The activation of this pathway leads to lymphocyte proliferation. Interleukin-6 (IL-6) is a multifunctional cytokine with a pleiotropic effect on inflammation, immune response, and hematopoiesis (19). The result of our study show that the upregulated of IL-6 gene expression in ATL patients compared to other groups, ACs and healthy donors. It has been reported that the Tax protein involved in the constitutive expression of IL-6 in cells infected with HTLV‐I (20). Moreover, previous studies demonstrated that in ATL patients, serum level of IL6 are significantly higher than in the AC’s and healthy control and survival decrease with increasing in IL6 (21). Several studies showed that the expression of both IL-15 and IL-15 receptor increased in HTLV-I-transformed cells lines (22, 23). Azimi et al. (24, 25) demonstrated that the IL-15 promoter is transactivated by Tax and the level of IL-15 mRNA is increased 3–4-fold in HTLV-I-transformed cells lines. In consistent with observations of Mariner et al. (26), Pise-Masison et al. (27) showed that the level of IL-15R elevated 5–10-fold in the HTLV-I-infected cell samples. Also, in the present study, it was concluded that the expression level of IL-10, TGF-β, and FOXP3 in ATLL cases had increased compared to other groups, ACs and healthy donors. It seems that, increase in expression of IL-10, TGF-β, FOXP3 and PD-1 caused to induction of production of T regulatory cells, immune-suppression and CTLs exhaustion. ATLL is associated with high levels of IL-10 and TGF-β. These immunosuppressive cytokines could promote a protumoral micro-environment. In one study demonstrated that the levels of IL-10 increased in sera from ATL patients compared with sera from healthy subject. Moreover, IL-10 is constitutively produced by ATL cells and HTLV-I-infected cell lines (28). In recent study it has been shown that the anti-inflammatory cytokine IL-10 and its downstream signals through the STAT3 and IRF4 pathways, potentially act as a switch for proliferation in HTLV-1-infected cells (29). It is suggested that an importance function of IL-10 in ATL may be inhibitory activities on macrophages and Th1and also as a means of escaping host defenses. It has been implicated that the negative regulatory programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway has an important role in the induction of CTL exhaustion during chronic viral infection and tumor (30–32). According to previous studies, suppression of immune responses and CTLs exhaustion lead to progression of disease to ATLL (33). In one study, Kozako et al. demonstrated that the PD-1 expression was significantly up-regulated on lymphocytes in ACs and ATLL patients compared to non-HTLV-1-infected individuals (33). In the present study, our result showed an increase in the LogFC of PD-1 in normal people Vs ATLL patient. Then the activity of PD-1/PD-L1 pathway during persistent viral infection may induce the exhausted of CTLs in HTLV-1 infected individuals, which may lead to immune evasion in ACs and ATLL patients. DNA damage also is one of the most important predisposing factors for tumor (34). In our research, expression level of BRCA1 and ATM genes had increased in ATLL patients. these genes are accounted as one of most important biomarkers which upregulated during the DNA damage in this group and defect in BRCA1 and ATM leads to DNA replication errors and cancer growth (35, 36). Breast cancer type 1 susceptibility protein (BRCA1) is a tumor suppressor gene that encodes a nuclear phosphoprotein, which is involved in repair damaged DNA and maintain genome stability. It has been shown that the expression of BRCA1 gene in ATLL patients is significantly reduced compared to normal individuals due to the effects of TAX protein and it is rationally in favor of increasing the tumor state (37). ATM (ataxia telangiectasia) gene like BRCA1 recognizes DNA damage or broken DNA strands. During DNA damages several phosphoproteins of the DDR pathway (H2AX, ATM, CHK1-2, P53, BRCA1) activated that lead to arrest the cell cycle transiently or lead to apoptosis and senescence but it has been demonstrated that the Tax inhibits the DDR machinery by sequestrating key signaling pathway components (38). So, in infected people, the expression level of the ATM gene is higher than normal individuals, which is as follows: ATLL > asymptomatic carriers > normal peoples (39). DNA mismatch repair protein Msh2 also known MSH2 is a tumor suppressor gene which involved in many different forms of DNA repair (40). In line with other studies (41), in the present study, it appears that the expression of this gene is decreased in AC and ATLL. Apoptosis play an critical role in destroying malignant cells (42). It has been demonstrated that in HTLV-1 infection, the virus through Tax, enhances expression of family inhibitor of apoptotic BCL2 and Bcl-xL (43, 44) and suppress expression Bax gene which have role in inducing apoptosis (45). In this regard, our result showed that the expression level of these genes and anti-apoptosis markers (i.e. BCL2, CytC, and BCL-XL) had been upregulated in ATLL. Moreover, in normal individuals compared to asymptomatic carriers with a LogFC = 0.66, indicating an increase in BCL activity in normal individuals and consequently suppression of apoptosis. Various studies showed that BCL2A1 overexpressed in hematological malignancies and solid tumors and may contribute to tumor progression (46). In addition, BCL2A1 by decrease in apoptosis and MDM2 by containment of TP53 caused stimulation of CDKs and protection of cell survival. Regarding of assessments in present study, it was cleared that the expression of BCL2A1 were upregulated in ATLL individuals compared with healthy ones. FADD (Fas associated via death domain) is a cytoplasmic protein that has an important role in apoptosis (47). It has been demonstrated that HTLV-1 transactivator protein Tax inhibits Fas-mediated apoptosis by induction of c-FLIP through activation of NF-κB, as a negative regulator of apoptosis by binding to the DED of FADD (48). Our result indicated that the expression of the FADD is higher in normal people than ATL patient (log FC: 1.99) and therefore the level of apoptosis in ATL patient is decreased. Another protein that affected by Tax is Ras. Ras family proteins have a key role in control intracellular signaling networks. Moreover Ras regulated different processes such as actin cytoskeletal integrity, cell differentiation, cell proliferation, apoptosis, and cell migration (49). It has been reported that Ras family proteins are often deregulated in cancers, leading to increased invasion and metastasis, and decreased apoptosis (50). HTLV-1 infected cells increased RAS expression follow TAX expression, which increase sensitivity to apoptosis by using the antagonist Farnesyl thiosalicylic acid (51). In our study the expression of the RAS gene have been shown an increase in asymptomatic carrier as compared to normal individual and in normal individuals it was less expressed in lymphoma patients. Accordingly, during HTLV-1 infection the expression of TAX as follow as Ras were increased, leading to the proliferation and transformation of cells into malignancies and resistance to apoptosis (52). One of the hallmarks features of tumors is tissue invasion and chemokines and their receptors play a key role (53). Moreover, It is well known that chemokines and their receptors have a role in pathogenesis of HTLV-1 such as: inflammation in the central nervous system (CNS) in cases of HAM/TSP, T cell immortalization and tissue infiltration (54). Several chemokine receptors has been identified in ATLL including: CCR4 (55), CCR7 (56), CCR8 (54), and CXCR4 (57). One of chemokine receptor which is overexpressed in HTLV-1 infection is CXCR4 which interaction with stromal cell-derived factor 1 (SDF1)/CXCL12 play a paramount role in the migration of ATL cells (56). In this study our result indicated that the expression of CXCR4, FGF, EGF, RAC1, and MAPKs were increased in ATLL group and confirmed this hypothesis. Moreover, interestingly, it has been demonstrated that the absence of Rapamycin-insensitive companion of mTOR (RICTOR) increased the expression of CCR2, CCR4 and CXCR4, which associated with the homing and migration of T-cells (58). RICTOR is a key component of the PI3K/AKT/mTOR signal transduction pathway an essential component of the mTORC2 of mTOR complex (59). It is indicated that the RICTOR down-regulation suppresses cell proliferation and tumor formation (60, 61). Log Fc in RICTOR gene in this study shown 1.61 fold change in normal individual compare to ATLL patient that mean dysfunction in RICTOR in ATLL, leading to an error in T cell proliferation and by affecting the expression of chemokine receptor genes in cells and it may affect the homing and migration of virus-infected cells (58, 62). P53 and Rb are the main tumor suppressors, which lead to inhibition of proliferation (63, 64). HTLV-1 oncogenes can induce malignancy through their effects on gene expression of cell cycle checkpoints such as P53 and Rb in the host cell (65). It has been demonstrated that HTLV-1 Tax protein hinders the function of p53 and Rb protein in host cells and lead to deregulate cellular division (66, 67). In line with other studies, in this study, we found decrease in expression of these genes in ATLL group. So, HTLV-1 oncogenes by their effects on function and expression of p53 and Rb induce oncogenesis in host cells.