Intracellular trafficking of HIV-1 Gag: how Gag interacts with cell membranes and makes viral particles.

The Gag polyprotein of retroviruses and lentiviruses is the master orchestrator of viral particle formation. HIV-1 Gag is synthesized on cytosolic polysomes where it is co-translationally modified with the 14-carbon fatty acid myristate. New findings shed light on how myristoylated HIV-1 Gag traffics through the cell, binds to specific membranes, and assembles into virions. The affinity of Gag for membrane bilayers is regulated by a myristoyl switch; Gag multimerization induces the fatty acid to flip away from the protein, thereby promoting membrane binding during assembly. Several recent studies have shown that newly synthesized Gag traffics first to multivesicular bodies (MVB), endosomal compartments that contain protein complexes necessary for particle budding. Signals within Gag, as well as specific host-cell lipids and proteins, promote MVB localization. In macrophages, Gag is retained in MVBs; viral particles are formed within the MVB lumen and released from the cell via exocytosis. In other cell types, Gag and/or MVBs rapidly transit to the plasma membrane where particle release occurs. Given that MVB exocytosis is an essential host-cell pathway, effective antiviral agents will need to specifically target interaction of Gag with the endocytic pathway without perturbing the normal host-cell trafficking network.