Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures

Nat Commun. 2021 Aug 17;12(1):4996. doi: 10.1038/s41467-021-25284-1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology*
  • Catalytic Domain
  • Cryoelectron Microscopy*
  • Deltaretrovirus
  • Drug Resistance, Viral / drug effects
  • HIV Integrase / drug effects
  • HIV-1
  • HTLV-I Infections / drug therapy*
  • Heterocyclic Compounds, 3-Ring
  • Human T-lymphotropic virus 1 / drug effects*
  • Human T-lymphotropic virus 1 / genetics
  • Humans
  • Naphthyridines / pharmacology
  • Piperazines
  • Pyridones
  • Recombinant Proteins


  • Amides
  • Antiviral Agents
  • Heterocyclic Compounds, 3-Ring
  • Naphthyridines
  • Piperazines
  • Pyridones
  • Recombinant Proteins
  • bictegravir
  • HIV Integrase