Cytokine Networks Dysregulation during HTLV-1 Infection and Associated Diseases

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of a neural chronic inflammation, called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and of a malignant lymphoproliferation, called the adult T-cell leukemia/lymphoma (ATLL). The mechanisms through which the HTLV-1 induces these diseases are still unclear, but they might rely on immune alterations. HAM/TSP is associated with an impaired production of pro-inflammatory cytokines and chemokines, such as IFN-γ, TNF-α, CXCL9, or CXCL10. ATLL is associated with high levels of IL-10 and TGF-β. These immunosuppressive cytokines could promote a protumoral micro-environment. Moreover, HTLV-1 infection impairs the IFN-I production and signaling, and favors the IL-2, IL-4, and IL-6 expression. This contributes both to immune escape and to infected cells proliferation. Here, we review the landscape of cytokine dysregulations induced by HTLV-1 infection and the role of these cytokines in the HTLV-1-associated diseases progression.

Keywords: ATLL; HAM/TSP; HTLV-1; cytokines; immune system.

Figure 1

Global cytokine networks dysregulation during an HTLV-1 infection and HTLV-1-associated diseases. Three classes of cytokines can be involved in HTLV-1 persistence and diseases. (A) During the asymptomatic period that follows primo infection (top), IFN-α, IL-2, and IL-13 ensure, respectively, the antiviral control and proliferation of infected cells, both effects allowing viral persistence. (B) During the HAM/TSP disease (left), proinflammatory cytokines (IFN-γ, IL-1, TNF-α, and CXCL10) allow infiltration of the HTLV-1-infected T-cells in neural tissues that, in addition with IL-6, contribute to the chronic inflammatory state and neural damages. (C) During ATLL (right), immunosuppressive cytokines (TGF-β and IL-10) contribute to Cytotoxic T Lymphocytes (CTL) exhaustion, allowing an immunosuppressive state favorable to the malignant proliferation of HTLV-1-transformed cells. Green arrows indicate an increased function, red lines indicate a decreased function, and the curved arrow indicate autocrine proliferation. See text for details.