Satisfactory preventative or therapeutic drugs are lacking for HTLV-1, a retrovirus closely related to HIV. As a result infected individuals frequently present with serious complications including rapidly progressive Adult T Cell Leukaemia (ATL), inflammation of the spinal cord (HTLV-1-assocaited myelitis, HAM) and chronic bronchiectasis. HTLV-1 subtype c (HTLV-1c) is highly prevalent in indigenous communities in Central Australia, with infection rates unparalleled globally. Novel approaches that both inhibit viral replication and reduce the number of HTLV-1 infected cells are urgently required.
We investigated the efficacy of antiretroviral and pro-apoptotic BH3 mimetic compounds as preventative and therapeutic agents in a humanised mouse model of HTLV-1 subtype c (HTLV-1c) infection, the first of its kind. We characterised infection in this model and compared disease to the globally prevalent HTLV-1 subtype a (HTLV-1a). Tenofovir, a reverse transcriptase inhibitor, significantly reduced HTLV-1 transmission in vivo at clinically relevant doses and attenuated de novo viral spread and disease progression during early infection in combination with dolutegravir, an integrase inhibitor. HTLV-1 infection was associated with dysregulation of the intrinsic apoptotic pathway at the transcriptional level, and we found that pharmacological inhibition of MCL-1, but not BCL-2, BCL-xL or BCL-w, killed HTLV-1-infected cells in vitro and in vivo, significantly delaying disease progression in combination with tenofovir and dolutegravir. Our data demonstrate that combination antiretroviral and MCL-1 antagonism may represent an effective, clinically relevant, curative strategy against HTLV-1. We are now expanding our efforts towards next-generation therapeutics with decreased treatment off-target effects and increased cell specificity by utilizing precsion targeting of T cells by LNP-based delivery of RNA therapeutics against MCL-1.