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ItemDeveloping Preventative and Therapeutic Strategies Against HTLV-1 Using a Novel Humanised Mouse Model( 2022)Satisfactory preventative or therapeutic drugs are lacking for human T cell leukaemia virus 1 (HTLV-1), a disease which lags several decades behind its distantly related cousin HIV in this regard. Consequentially, 5-10 percent of the approximately 10 million people infected with HTLV-1 will progress to serious complications. These include fatalities resulting from a rapidly progressive blood cancer, adult T cell leukaemia/lymphoma, and inflammation of the spinal cord, HTLV-1-assocaited myelitis. Other clinically recognised disease associations include inflammatory diseases involving the eyes, lungs, and skin. In Central Australia, a region in which the adult prevalence of HTLV-1c approaches 40% in some remote Aboriginal communities, HTLV-1 subtype c (HTLV-1c) infection is strongly associated with chronic pulmonary disease and death due to bronchiectasis and is a significant health burden in these communities. Although HTLV-1 subtype a (HTLV-1a) is also associated with pulmonary disease, the extraordinarily high burden of pulmonary disease in Central Australia suggests that there may differences between HTLV-1a and HTLV-1c, which are the two most divergent subtypes. Novel preventative and therapeutic interventions are required to tackle HTLV-1. I investigated the efficacy of antiretroviral and pro-apoptotic BH3 mimetic compounds as preventative and therapeutic agents in a novel humanised mouse model of HTLV-1c infection, the first of its kind. I characterised infection in this model and compared disease to the globally prevalent HTLV-1a. Disease was indistinguishable in mice suggesting that HTLV-1 subtype does not drive distinct disease associations, including HTLV-1 associated pulmonary disease. Tenofovir, a reverse iv 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 pharmacological inhibition of MCL-1, but not BCL-2, BCL-xL or BCL-w, killed HTLV-1-infected cells ex vivo and mitigated disease progression in vivo in combination with tenofovir and dolutegravir. Collectively, these data provide evidence that combination antiretroviral and MCL1 antagonism may represent an effective, clinically relevant, curative strategy against HTLV-1. Routine clinical use of these compounds will facilitate their rapid translation to HTLV-1 treatment.