Abstract
Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg2+ ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection.
Highlights
Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1)
Human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus and one of the most oncogenic human viruses[1]. It is the causative agent of a severe form of blood cancer called adult T-cell leukaemia/lymphoma (ATLL)[2] and a range of debilitating neuromuscular disorders—HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP)[3], which often lead to paralysis
Only 5–10% of the estimated 10–20 million people[4] infected with HTLV-1 worldwide will develop ATLL2, a recent report showed that the vast majority of otherwise asymptomatic patients suffer from issues that severely impact their quality of life, including pain, discomfort and depression5. 12.7% of HAM/TSP patients reported their quality of life was worse than death[5], based on the Euroqol five dimension questionnaire (EQ-5D)
Summary
Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). We recently reported that the first- and second-generation HIV INSTIs are effective at inhibiting HTLV-1 strand transfer in vitro and integration in tissue culture[9]. Technical advances in cryogenic electron microscopy (cryo-EM), recently allowed the structural characterisation of HIV-114 and a closely related red-capped mangabey simian immunodeficiency virus (SIVrcm)[15] intasomes in complexes with clinical and experimental INSTIs at near-atomic resolution. We recently determined the cryo-EM structure of the deltaretroviral simian T-cell lymphotropic virus type 1 (STLV-1) intasome bound to its host factor B56γ16. In addition to characterising three compounds that block HTLV-1 transmission two- to fivefold more potently than raltegravir (RAL), we report three high-resolution cryo-EM structures of a deltaretroviral intasome bound to three different INSTIs. The 3D reconstructions allow for direct comparison between the binding modes of these inhibitors in lentiviral and deltaretroviral intasomes. Our findings have important implications for establishing therapies targeted at HTLV-1 and provides a framework for understanding the mechanism of INSTI action on the HTLV-1 intasome at the atomic scale
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call