How does human T-lymphotropic virus type 1 cause central nervous system disease? the importance of cross-talk between infected T cells and astrocytes

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) can cause HTLV-1-associated myelopathy/tropical spastic paraparesis and adult T cell leukemia/lymphoma. The main feature of HTLV-1-associated myelopathy/tropical spastic paraparesis pathogenesis is a virus-induced hyperactive immune response that causes chronic inflammation in the central nervous system (CNS), but the question remains: what is the mechanism by which HTLV-1 deregulates the immune response and induce chronic inflammation? While T cell infiltrates in the CNS include HTLV-1-infected cells, HTLV-1 does not appear to infect the neuronal cells themselves. It has been established that HTLV-1 is a unique virus that mainly infects CD4+ helper T cells. We recently showed that HTLV-1 heavily infects CCR4+ cells, which are known to include regulatory T cells. We showed that HTLV-1 induces a Th1-like state in these CCR4+ cells through T-bet expression. We have also found that CXCL10 plays an important role in a positive feedback loop that maintains inflammation in the CNS. Astrocytes, which were shown to be the main producers of CXCL10 in the CNS, are another key player in the loop. To complete the picture, we showed that the infected CCR4+ Th1-like T cells produce interferon-γ, which is what stimulates astrocytes to produce CXCL10. Now we have a much better understanding of the molecular mechanisms at play in HTLV-1-associated myelopathy/tropical spastic paraparesis pathogenesis, and clearly CCR4+ cells are a significant contributor to the inflammatory pathways. Thus, we are currently carrying out a phase I/IIa clinical trial to test the effects and safety of a therapy that uses antibody-dependent cell-mediated cytotoxicity to target CCR4+ cells.