Crafty rafting

Lentiviruses, including HIV-1, assemble at the host-cell plasma membrane. Although this multistage process is known to be mediated by viral Gag proteins, the exact nature of the membrane-assembly programme is poorly understood. Reporting in Proceedings of the National Academy of Sciences Ono and Freed show that HIV-1 Gag associates with cholesterol-enriched microdomains (rafts) at the plasma membrane, and that this process is crucial for HIV-1 particle formation and release.

The idea that viruses might bud from distinct microdomains in the plasma membrane is based on the finding that the lipid composition of envelope membranes from numerous viruses differs from the host plasma membrane from which they are derived. The HIV-1 lipid bilayer is enriched in sphingolipids and cholesterol. To investigate whether HIV-1 Gag associates with rafts at the plasma membrane, the authors homogenized cells expressing Pr55^Gag (the Gag-precursor protein) and isolated rafts as detergent-resistant membranes (DRMs). They found that 50% of membrane-bound Pr55^Gag specifically associated with rafts.

To identify the domains of Pr55^Gag that are required for DRM association, Ono and Freed characterized the DRM-association of Gag mutants. These experiments showed that the N-terminal matrix domain of Gag is required for raft binding, and that sequences downstream of this domain which promote Gag–Gag interactions stabilize raft association.

But is this Gag–raft association physiologically relevant in HIV-1 particle assembly and release? The authors disrupted rafts in HIV-1-infected cells with cholesterol-depleting drugs and showed that this caused impaired HIV-1 release and infectivity. Therefore, the association of Gag with rafts is crucial for efficient HIV-1 assembly and release, and the authors conclude that these findings might permit the development of new strategies to suppress HIV-1 replication in vivo.