Combination antiretroviral therapy and MCL-1 inhibition mitigate HTLV-1 infection in vivo

  • Cell. 2025 Sep 4;188(18):4896-4912.e19. doi: 10.1016/j.cell.2025.06.023.
James P Cooney  1 ,  Ashley Hirons  2 ,  Natasha Jansz  3 ,  Cody C Allison  1 ,  Peter Hickey  4 ,  Charis E Teh  1 ,  Tania Tan  1 ,  Laura F Dagley  5 ,  Jumana Yousef  5 ,  David Yurick  6 ,  Georges Khoury  2 ,  Simon P Preston  1 ,  Philip Arandjelovic  1 ,  Kathryn C Davidson  1 ,  Lewis J Williams  1 ,  Stefanie M Bader  1 ,  Le Wang  7 ,  Reet Bhandari  1 ,  Liana Mackiewicz  7 ,  Merle Dayton  7 ,  William Clow  7 ,  Geoffrey J Faulkner  8 ,  Daniel H Gray  1 ,  Lloyd Einsiedel  9 ,  Damian F J Purcell  2 ,  Marcel Doerflinger  1 ,  Marc Pellegrini  10
Affiliations
  • 1. Division of Infectious Diseases and Immune Defence, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
  • 2. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, VIC, Australia.
  • 3. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, VIC, Australia; Mater Research Institute-University of Queensland, TRI Building, Woolloongabba, QLD 4102, Australia.
  • 4. Division of Infectious Diseases and Immune Defence, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia; Advanced Technology & Biology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • 5. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia; Advanced Technology & Biology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • 6. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, VIC, Australia; UCB Pharma, Smyrna, GA, USA.
  • 7. Division of Infectious Diseases and Immune Defence, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • 8. Mater Research Institute-University of Queensland, TRI Building, Woolloongabba, QLD 4102, Australia; Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia.
  • 9. Department of Medicine, Alice Springs Hospital, Alice Springs, NT, Australia.
  • 10. Division of Infectious Diseases and Immune Defence, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia; Centenary Institute Medical Research Foundation, Camperdown, Sydney, NSW 2050, Australia. Electronic address: [email protected].
PMID: 40645177 DOI: 10.1016/j.cell.2025.06.023
Abstract

This study investigated preventative and therapeutic agents against human T cell lymphotropic virus type-1 subtype-C (HTLV-1c) Infection. We established and characterized a humanized mouse model of HTLV-1c Infection and identified that HTLV-1c disease appears slightly more aggressive than the prevalent HTLV-1 subtype-A (HTLV-1a), which may underpin increased risk for infection-associated pulmonary complications in HTLV-1c. Combination antiretroviral therapy with tenofovir and dolutegravir at clinically relevant doses significantly reduced HTLV-1c transmission and disease progression in vivo. Single-cell RNA Sequencing (scRNA-seq) and intracellular flow cytometry identified that HTLV-1c Infection leads to dysregulated intrinsic Apoptosis in infected cells in vivo. Pharmacological inhibition using BH3 mimetic compounds against Mcl-1, but not Bcl-2, Bcl-xL, or Bcl-W, killed HTLV-1c-infected cells in vitro and in vivo and significantly delayed disease progression when combined with tenofovir and dolutegravir in mice. Our data suggest that combination antiretroviral therapy with Mcl-1 antagonism may represent an effective, clinically relevant, and potentially curative strategy against HTLV-1c.

Keywords
BH3 mimetics; HTLV-1 ATLL; HTLV-1a; HTLV-1c; antiretrovirals; combination therapy; humanized mice; scRNA-seq.
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