Inositol phosphates are assembly co-factors for HIV-1

A short, 14-amino-acid segment called SP1, located in the Gag structural protein¹, has a critical role during the formation of the HIV-1 virus particle. During virus assembly, the SP1 peptide and seven preceding residues fold into a six-helix bundle, which holds together the Gag hexamer and facilitates the formation of a curved immature hexagonal lattice underneath the viral membrane^2,3. Upon completion of assembly and budding, proteolytic cleavage of Gag leads to virus maturation, in which the immature lattice is broken down; the liberated CA domain of Gag then re-assembles into the mature conical capsid that encloses the viral genome and associated enzymes. Folding and proteolysis of the six-helix bundle are crucial rate-limiting steps of both Gag assembly and disassembly, and the six-helix bundle is an established target of HIV-1 inhibitors^4,5. Here, using a combination of structural and functional analyses, we show that inositol hexakisphosphate (InsP6, also known as IP₆) facilitates the formation of the six-helix bundle and assembly of the immature HIV-1 Gag lattice. IP₆ makes ionic contacts with two rings of lysine residues at the centre of the Gag hexamer. Proteolytic cleavage then unmasks an alternative binding site, where IP₆ interaction promotes the assembly of the mature capsid lattice. These studies identify IP₆ as a naturally occurring small molecule that promotes both assembly and maturation of HIV-1.