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

2025-07-01

Cooney, James P

Hirons, Ashley

Jansz, Natasha

Allison, Cody C

Hickey, Peter

Teh, Charis E

Tan, Tania

Dagley, Laura F

Yousef, Jumana

Yurick, David

Khoury, Georges

Preston, Simon P

Arandjelovic, Philip

Davidson, Kathryn C

Williams, Lewis J

Bader, Stefanie M

Wang, Le

Bhandari, Reet

Mackiewicz, Liana

Dayton, Merle

Clow, William

Faulkner, Geoffrey J

Gray, Daniel H

Einsiedel, Lloyd

Purcell, Damian F J

Doerflinger, Marcel

Pellegrini, Marc

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Division of Infectious Diseases and Immune Defence, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

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.

Division of Infectious Diseases and Immune Defence, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

Division of Infectious Diseases and Immune Defence, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

Division of Infectious Diseases and Immune Defence, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

Mater Research Institute-University of Queensland, TRI Building, Woolloongabba, QLD 4102, Australia; Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia.

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.

Department of Medicine, Alice Springs Hospital, Alice Springs, NT, Australia.

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.

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.

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: m.pellegrini@centenary.org.au.

BH3 mimetics

HTLV-1 ATLL

HTLV-1a

HTLV-1c

antiretrovirals

combination therapy

humanized mice

scRNA-seq

Journal Article

Publication

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.

link

Cell . 2025 Jul 1:S0092-8674(25)00689-0. doi: 10.1016/j.cell.2025.06.023. Online ahead of print.

1097-4172

https://pubmed.ncbi.nlm.nih.gov/40645177/?otool=iaurydwlib