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

Cooney, JP; Hirons, A; Jansz, N; Allison, CC; Hickey, P; Teh, CE; Tan, T; Dagley, LF; Yousef, J; Yurick, D; Khoury, G; Preston, SP; Arandjelovic, P; Davidson, KC; Williams, LJ; Bader, SM; Wang, L; Bhandari, R; Mackiewicz, L; Dayton, M; Clow, W; Faulkner, GJ; Gray, DH; Einsiedel, L; Purcell, DFJ; Doerflinger, M; Pellegrini, M

Author(s): Cooney, JP; Hirons, A; Jansz, N; Allison, CC; Hickey, P; Teh, CE; Tan, T; Dagley, LF; Yousef, J; Yurick, D; Khoury, G; Preston, SP; Arandjelovic, P; Davidson, KC; Williams, LJ; Bader, SM; Wang, L; Bhandari, R; Mackiewicz, L; Dayton, M; Clow, W; Faulkner, GJ; Gray, DH; Einsiedel, L; Purcell, DFJ; Doerflinger, M; Pellegrini, M;
Details: Publication Year 2025-09-04,Volume 188,Issue #18,Page 4896-4912 e19
Journal Title: Cell
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.
Publisher: Cell Press
Keywords: Animals; Pyridones; *Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors/metabolism; Piperazines; Humans; Mice; Oxazines; Heterocyclic Compounds, 3-Ring/therapeutic use/pharmacology; *HTLV-I Infections/drug therapy/virology/transmission; *Human T-lymphotropic virus 1/drug effects; Tenofovir/therapeutic use/pharmacology; Disease Models, Animal; *Anti-Retroviral Agents/therapeutic use/pharmacology; Drug Therapy, Combination; Apoptosis/drug effects; BH3 mimetics; Htlv-1 atll; HTLV-1a; HTLV-1c; antiretrovirals; combination therapy; humanized mice; scRNA-seq
Research Division(s): Infection and Global Health; Advanced Technology and Biology; Immunology; Cancer Biology and Stem Cells; Blood Cells and Blood Cancer
PubMed ID: 40645177
Publisher's Version: https://doi.org/10.1016/j.cell.2025.06.023
Open Access at Publisher's Site: https://doi.org/10.1016/j.cell.2025.06.023
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-07-28 03:09:54

Last Modified: 2025-09-23 11:10:33