The endosomal trafficking protein Rab27a supports HIV-1 replication by promoting PI(4,5)P2 production at the plasma membrane (PM), Pereyra Gerber et al. reveal.
New HIV-1 particles assemble at specialized PM domains that are enriched in the phospholipid PI(4,5)P2 and recruit the viral polyprotein Pr55Gag. Because endosomal trafficking has been implicated in viral assembly and release, Pereyra Gerber et al. investigated whether HIV-1 replication was controlled by Rab27a, a small GTPase that promotes the delivery of late endosomes and multivesicular bodies to the PM.
Viral replication was impaired in T cells lacking Rab27a, the researchers found. These cells showed reduced levels of PI(4,5)P2 at the PM and thus failed to recruit Pr55Gag to form viral assembly sites. Knocking down Rab27a also suppressed PI(4,5)P2 production and viral replication in macrophages, which normally recruit Pr55Gag to PM invaginations called virus-containing compartments.
Rab27a boosted PI(4,5)P2 production at the PM by delivering the late endosome-associated lipid kinase PI4KIIα, which generates the PI(4,5)P2 precursor PI(4)P. Several Rab27a effectors were also required for HIV-1 replication. T cells lacking the endosomal docking protein Slp2a, for example, also failed to deliver PI4KIIα to the PM to promote PI(4,5)P2 production and Pr55Gag recruitment.
Senior author Matías Ostrowski says that these results open a path to investigate whether manipulating endosomal traffic could be a new target for anti–HIV-1 therapies. He now wants to investigate how endosomes carrying PI4KIIα fuse with the PM once they have been docked there by Rab27a and its effectors.
Text by Ben Short