A-106 Strategy and pathogenesis of human T-cell leukemia virus type 1
Authors: Matsuoka Masao 
Published: April 2019

Human T-cell leukemia virus type 1 (HTLV-1) causes not only adult T-cell leukemia-lymphoma (ATL) but also inflammatory diseases. The most important characteristic of HTLV-1 is that this virus can transmit only through cell-to-cell contact. Therefore, HTLV-1 increases the number of infected cells to facilitate its transmission through breast feeding and sexual intercourse. HTLV-1 promotes proliferation of infected cells, inhibits their apoptosis and facilitates escape from the host immune surveillance. The pathogenesis of these diseases is based on these characteristics of this virus. Infected cells evade the host immune responses to survive in vivo.
Early studies of HTLV-1 focused on Tax that is the trans-activator of viral gene transcription. Tax can immortalize T cellsin vitroand in vivo. Tax activates NFkB pathway, and functionally inhibits p53 function. It is assumed that Tax is the viral oncogene that causes ATL. However, analyses of HTLV-1 proviruses in clinical samples revealed that Tax expression is frequently inactivated in ATL cells by 3 mechanisms: genetic changes of the taxgene (mainly non-sense mutation), deletion of 5′ long terminal repeat (LTR), the promoter/enhancer of the taxgene, and DNA methylation of 5′LTR. On the other hand, 3′ provirus is maintained in all ATL cases and HTLV-1 carriers. This region contains HTLV-1 bZIP factor (HBZ) coding region. HBZ gene is encoded in the minus strand of the provirus. These finding suggest that HBZ is critical for ATL cells and HTLV-1 infected cells. To study the function of HBZZ, we generated HBZ-transgenic mice that express HBZ in CD4+ T cells. HBZ-Tg mice developed T-cell lymphoma and inflammatory diseases, suggesting that HBZ is critical for HTLV-1 associated diseases. Thereafter, we focus on function of HBZ in biology and pathology of HTLV-1.
This strategy is supported by several attributes of this virus. First, HTLV-1 infected T cells possess the specific immunophenotype; CD4, CD45RO, CCR4, CADM1, TIGIT, Foxp3 (approximately 50%) positive T cells. Effector/memory (CD45RO) T cells express higher level of LFA-1, which likely migrate into breast milk and semen. Furthermore, TIGIT suppresses the host immune responses, which facilitates infected cells to escape from immune surveillance. HBZ also induces expression of Foxp3. Foxp3 induces expression of regulatory T (Treg) cell associated molecules. On the other hand, labile Foxp3 expression is associated with inflammation by increased interferon-gproduction. Thus, HTLV-1 bZIP factor (HBZ) is mainly implicated in immunnophenotype of HTLV-1 infected cells and ATL cells. Second, HTLV-1 infected cells need persistent proliferation and survival in vivo. Both HBZ and tax are implicated in proliferation and survival. Third, HTLV-1 infected cells and ATL cells need to minimize expression of immunogenic viral proteins. Tax is a highly immunogenic protein, and a major target of cytotoxic T-lymphocytes (CTLs) in vivo. On the other hand, immunogenicity of HBZ is quite low. Therefore, HTLV-1 infected cells and ATL cells continuously express HBZ. In contrast, Tax is transiently expressed (Mahgoub et al, PNAS 2018). The intermittent expression of Tax plays an important role to maintain ATL cells, and possibly HTLV-1 infected cells.
Pathogenesis of HTLV-1 is based on these characteristics of this virus; infiltration, inflammation, persistent proliferation, and anti-apoptosis. Thus, pro-inflammatory infected cells cause inflammatory diseases, and lead to development of leukemia. In this meeting, I am going to show the roles of HBZ and Tax in the pathogenesis, discuss about complex relation between virus and diseases.