When HIV infects a host cell, the pathogen converts its RNA code to DNA and then docks the genetic material in a host’s genome. The first glimpse of the HIV machinery that performs this insertion comes courtesy of a team of researchers led by Dmitry Lyumkis at the Salk Institute for Biological Studies (Science 2017, DOI: 10.1126/science.aah5163). Called the intasome, HIV’s insertion machinery is targeted and blocked by drugs such as raltegravir and elvitegravir. To develop these drugs and to study HIV’s intasome, scientists had relied on biochemical techniques, computer modeling, prior X-ray crystallography work describing individual domains within the insertion machinery and the structures of intasomes from related viruses, such as PFV, the prototype foamy virus. Lyumkis’s team used cryo-electron microscopy to image HIV’s intasome with a resolution of 3.5 to 4.5Å. The group found that several amino acid residues in and near the machinery’s active site are positioned differently in HIV compared with PFV. The new work “provides important guidance for rationally improving clinically relevant inhibitors,” notes the team. In another study published in Science, researchers led by Peter Cherepanov at London’s Francis Crick Institute report the cryo-electron structure of an intasome from a maedi-visna lentivirus, which could provide a platform for screening HIV intasome inhibitors (DOI: 10.1126/science.aah7002).