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In PNAS, Jurado et al. (1) describe an unexpected mechanism of action of a new class of HIV type 1 (HIV-1) integrase (IN) inhibitors. Several years ago it was discovered that the HIV-1 IN was targeted to sites in chromatin by the host protein lens epithelium-derived growth factor (LEDGF)/p75 (2). The site of interaction between IN and LEDGF/p75 was defined, and inhibitors to block that interaction were sought and identified. In PNAS, Jurado et al. (1) show that although these inhibitors (termed Allosteric IN inhibitors, or ALLINIs) have some potency to block steps involved in integration, their most dramatic effect is to cause the virus particle to assemble into a noninfectious structure. The IN protein contains three structural domains: the N-terminal domain (NTD; a series of α-helices and a zinc-binding motif), the central catalytic core domain (CCD), and the C-terminal domain (structurally similar to a SH3 β-barrel fold) (3). The CCD has a structure that makes it a member of an ancient family of polynucleotide transferases (also seen in the RNase H domain at the C terminus of HIV-1 reverse transcriptase), with a D,DX35E catalytic triad comprising the active site by coordinating two essential Mg2+ ions. IN must complete two enzymatic steps to insert viral DNA into the host cell genome. In the first reaction, IN cleaves the two terminal nucleotides at the 3′ ends of the newly synthesized linear viral DNA to create the 3′-OH nucleophiles that will be used in the second reaction. In the second reaction, the strand transfer, IN uses the new 3′ ends of viral DNA to break phosphodiester bonds in the host DNA, and simultaneously insert viral DNA. The prototype foamy virus intasome …

Integrating the HIV-1 assembly/maturation pathway