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

PLoS Pathog. 2021 Feb 1;17(2):e1009271. doi: 10.1371/journal.ppat.1009271. eCollection 2021 Feb.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Clone Cells / immunology
  • Clone Cells / virology*
  • Dendritic Cells / immunology
  • Female
  • Gene Products, tax / immunology
  • HTLV-I Infections / immunology*
  • HTLV-I Infections / transmission
  • HTLV-I Infections / virology
  • Hematopoietic Stem Cell Transplantation
  • Human T-lymphotropic virus 1 / immunology
  • Human T-lymphotropic virus 1 / physiology*
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / immunology*
  • Leukemia-Lymphoma, Adult T-Cell / virology
  • Liver Transplantation / adverse effects
  • Macaca fuscata
  • Male
  • Middle Aged
  • Natural Killer T-Cells / immunology
  • Proviruses
  • T-Lymphocytes / cytology
  • T-Lymphocytes / virology*
  • Viral Load
  • Virus Replication


  • Gene Products, tax
  • tax protein, Human T-lymphotrophic virus 1

Grant support

This research is supported by a grant from the Project for Cancer Research And Therapeutic Evolution (P-CREATE) (20cm0106306h0005 to M. M.), the Research Program on Emerging and Re-emerging Infectious Diseases (20fk0108088h0002 to M. M.) from the Japan Agency for Medical Research and Development (AMED), JSPS KAKENHI (19H03689 to M.M. and 20H03514 to J-I. Y.). This study was also supported in part by the JSPS Core-to-Core Program A, Advanced Research Networks. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.