In vivo dynamics and adaptation of HTLV-1-infected clones under different clinical conditions.

Mikiko Izaki,Asami Yamada,Kisato Nosaka,Anat Melamed,Masao Matsuoka,Yasuhiko Sugawara,Yukihiro Inomata,Hirofumi Akari,Hayato Utsunomiya,Kenji Sugata,Charles Bangham,Youko Suehiro,Jun-Ichirou Yasunaga,Takafumi Shichijo,Taizo Hibi,Daniel C Douek

doi:10.1371/journal.ppat.1009271

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) spreads through cell contact. Therefore, this virus persists and propagates within the host by two routes: clonal proliferation of infected cells and de novo infection. The proliferation is influenced by the host immune responses and expression of viral genes. However, the detailed mechanisms that control clonal expansion of infected cells remain to be elucidated. In this study, we show that newly infected clones were strongly suppressed, and then stable clones were selected, in a patient who was infected by live liver transplantation from a seropositive donor. Conversely, most HTLV-1+ clones persisted in patients who received hematopoietic stem cell transplantation from seropositive donors. To clarify the role of cell-mediated immunity in this clonal selection, we suppressed CD8+ or CD16+ cells in simian T-cell leukemia virus type 1 (STLV-1)-infected Japanese macaques. Decreasing CD8+ T cells had marginal effects on proviral load (PVL). However, the clonality of infected cells changed after depletion of CD8+ T cells. Consistent with this, PVL at 24 hours in vitro culture increased, suggesting that infected cells with higher proliferative ability increased. Analyses of provirus in a patient who received Tax-peptide pulsed dendritic cells indicate that enhanced anti-Tax immunity did not result in a decreased PVL although it inhibited recurrence of ATL. We postulate that in vivo selection, due to the immune response, cytopathic effects of HTLV-1 and intrinsic attributes of infected cells, results in the emergence of clones of HTLV-1-infected T cells that proliferate with minimized HTLV-1 antigen expression.

Highlights

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemialymphoma (ATL) and inflammatory diseases such as HTLV-1 associated myelopathy (HAM)/ tropical spastic paraparesis (TSP) [1,2,3]
HTLV-1 spreads in vivo through two routes: de novo infection and clonal proliferation of infected cells
We found that HTLV-1infected clones dramatically changed during de novo infection whereas the clones in the chronic phase survived long-term after transplantation, indicating that HTLV-1-infected clones are selected for survival in vivo

Summary

Introduction

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemialymphoma (ATL) and inflammatory diseases such as HTLV-1 associated myelopathy (HAM)/ tropical spastic paraparesis (TSP) [1,2,3]. Viral genes are responsible for clonal proliferation, survival of HTLV-1-infected cells in vivo and de novo infection. The HTLV-1 transcriptional transactivator protein Tax is essential for de novo infection and anti-apoptosis of expressing cells [6,7]. Tax protein is highly immunogenic and well recognized by cytotoxic T lymphocytes (CTLs) [8,9]. HTLV-1-infected cells and ATL cells can express HBZ in vivo, which enables the expressing cell to proliferate [13]. The special advantage conferred on the virus by the actions of HBZ RNA in both non-malignant HTLV-1-infected cells and ATL cells is that CTLs cannot recognize viral RNA

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