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

Author:

Izaki MikikoORCID,Yasunaga Jun-ichirouORCID,Nosaka KisatoORCID,Sugata Kenji,Utsunomiya Hayato,Suehiro Youko,Shichijo TakafumiORCID,Yamada Asami,Sugawara Yasuhiko,Hibi Taizo,Inomata Yukihiro,Akari HirofumiORCID,Melamed AnatORCID,Bangham CharlesORCID,Matsuoka MasaoORCID

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.

Funder

Project for Cancer Research And Therapeutic Evolution

Research Program on Emerging and Re-emerging Infectious Diseases

Japan Agency for Medical Research and Development /JSPS

JSPS Core-to-Core Program A, Advanced Research Networks

Publisher

Public Library of Science (PLoS)

Subject

Virology,Genetics,Molecular Biology,Immunology,Microbiology,Parasitology

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