Combination antiretroviral therapy and MCL-1 inhibition mitigate HTLV-1 infection in vivo
James P. Cooney, Ashley Hirons, Natasha Jansz, Cody C. Allison, Peter F. Hickey, Charis E. Teh, Tania Tan, Laura F. Dagley, Jumana M. Yousef, David Yurick, Georges Khoury, Simon Preston, Philip Arandjelovic, Kathryn C. Davidson, L.J. Williams, Stefanie M. Bader, Le Wang, Reet Bhandari, Liana Mackiewicz, Merle Dayton, William Clow, Geoffrey J. Faulkner, Daniel H.D. Gray, Lloyd Einsiedel, Damian F. J. Purcell, Marcel Doerflinger, Marc Pellegrini
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.