A supramolecular assembly mediates lentiviral DNA integration

Retroviral integrase (IN) functions within the intasome nucleoprotein complex to catalyze the insertion of viral DNA into cellular chromatin. The lack of lentiviral intasome structural information has hampered the development of anti-HIV drugs and the understanding of viral resistance. Using cryo-electron microscopy, we now visualize the functional maedi-visna lentivirus intasome at 4.9 Å resolution. The intasome, which comprises a homo-hexadecamer of IN with a tetramer-of-tetramers architecture, harbors eight structurally distinct types of IN protomers including two catalytically competent subunits. The conserved intasomal core, previously observed in simpler retroviral systems, is formed between two IN tetramers, with a pair of Cterminal domains from flanking tetramers completing the synaptic interface. Our results explain how HIV-1 IN, which self-associates into higher order multimers, can form a functional intasome, reconcile the bulk of early HIV-1 IN biochemical and structural data, and provide a lentiviral platform for structure-guided design of HIV-1 IN inhibitors