Introduction
Human T-leukemia virus 1 (HTLV-1) is an oncogenic retrovirus that infects approximately 10-20 million people worldwide and is the causative agent of adult T-cell leukemia and HTLV-1-associated myelitis. HTLV-1 subgroup c (HTLV-1c) is endemic to communities in rural Central Australia and increases the incidence of pulmonary disease and bacterial bloodstream infections in these communities to levels not matched anywhere else globally. Current therapeutic interventions are ineffective at controlling HTLV-1 infection and new therapeutics are urgently required. The HTLV-1 reverse transcriptase may be susceptible to some approved anti-retrovirals developed for HIV, but only at high intracellular concentrations. Clinically achievable doses of approved reverse transcriptase inhibitors, such as tenofovir disoproxil fumarate, are ineffective at inhibiting the HTLV-1 replication cycle due to insufficient intracellular concentration.
Methods and results
We have developed and characterised a novel humanised mouse model of HTLV-1c infection that recapitulates many aspects of human disease and is an ideal tool to investigate the efficacy of therapeutic interventions. We show abrogation of HTLV-1c proviral load in early infection by up to 90% compared to untreated mice by prophylactic administration of the recently FDA approved nucleotide reverse transcriptase inhibitor, tenofovir alafenamide, initially developed to inhibit HIV infection. Tenofovir alafenamide is designed to deliver higher concentrations of intracellular tenofovir to target cells than its preceding formulation, tenofovir disoproxil fumarate. This study demonstrates for the first time, in-vivo efficacy of tenofovir as a prophylactic measure in HTLV-1 infection.
Impact
This work is generating pre-clinical data that aims to provide grounds to a conduct a clinical trial investigating the efficacy of tenofovir alafenamide in preventing transmission of HTLV-1. Moreover, recent FDA approval of tenofovir alafenamide for use in HIV significantly reduces the barriers to its implementation in the context of HTLV-1 disease.