HIV-1 Gag: Flipped out for PI(4,5)P₂

The plasma membrane of virus-infected cells constitutes a barrier to the egress of newly assembled virus particles but also can serve as a platform that viruses use to facilitate their assembly. In the case of HIV-1, virus assembly is driven by the Gag precursor protein, Pr55^Gag (1–3), and it has been established for many years that the association of Pr55^Gag with the plasma membrane is an essential step in the virus assembly pathway. Less clear are the precise mechanism by which Pr55^Gag binds membrane and the identity of host cell components that dictate the specificity of the membrane-binding process. In most cell types, HIV-1 assembly appears to take place primarily at the plasma membrane, although in some cells, including the physiologically relevant macrophage, assembly may occur in intracellular compartments known as multivesicular bodies (MVBs) (4–7). Recent findings indicate that a particular member of the phosphoinositide family of lipids, phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P₂], serves an important function in directing Pr55^Gag to the plasma membrane (8). In this issue of PNAS, Saad et al. (9) present evidence for a direct interaction between Gag and PI(4,5)P₂ and provide a compelling structural model to help explain the role that PI(4,5)P₂ plays in promoting the association of Pr55^Gag with the plasma membrane. In a broader context, the proposed model suggests a novel mechanism by which phosphoinositides can help stabilize the association of proteins with cellular membranes.

Pr55^Gag is composed of several major domains that are cleaved from the Gag precursor by the viral protease during particle release from the cell. These domains are as follows (from N to C terminus): matrix (MA), capsid (CA), nucleocapsid (NC), and p6 (Fig. 1 A). Each of these domains serves critical functions in virus assembly and …

*E-mail: efreed{at}nih.gov