Release of HIV-1 particles from macrophages is promoted by an anchored cytoskeleton and driven by mechanical constraints.

A feature of HIV-1 replication in macrophages is that viral assembly occurs at the limiting membrane of a compartment often named the virus-containing compartment (VCC). Assembled virions accumulate in the lumen of the VCC, from where they can be released into the extracellular medium via mechanisms that remain poorly described. Here, we show that the actin cytoskeleton contributes to this process by performing experiments combining pharmacological and mechanical perturbations with imaging and biochemical analysis. We found that jasplakinolide inhibited HIV-1 release from macrophages and led to scattering of the compartment. Concomitantly, both the integrin CD18 (ß2-integrin) and the phosphorylated form of PYK2 (also known as PTK2B) were displaced away from the VCC. Inhibition of PYK2 activity promoted retention of viral particles in VCCs that lost their connections to the surface. Finally, in infected macrophages undergoing frustrated phagocytosis, VCCs rapidly trafficked to the basal membrane and released their viral content, in a manner dependent on their association with the actin cytoskeleton. These results highlight that the trafficking of VCCs and virus release are intimately linked to a reorganization of the macrophage actin cytoskeleton that can be modulated by external physical cues.

Conservation of antiviral systems across domains of life reveals immune genes in humans.

Deciphering the immune organization of eukaryotes is important for human health and for understanding ecosystems. The recent discovery of antiphage systems revealed that various eukaryotic immune proteins originate from prokaryotic antiphage systems. However, whether bacterial antiphage proteins can illuminate immune organization in eukaryotes remains unexplored. Here, we use a phylogeny-driven approach to uncover eukaryotic immune proteins by searching for homologs of bacterial antiphage systems. We demonstrate that proteins displaying sequence similarity with recently discovered antiphage systems are widespread in eukaryotes and maintain a role in human immunity. Two eukaryotic proteins of the anti-transposon piRNA pathway are evolutionarily linked to the antiphage system Mokosh. Additionally, human GTPases of immunity-associated proteins (GIMAPs) as well as two genes encoded in microsynteny, FHAD1 and CTRC, are respectively related to the Eleos and Lamassu prokaryotic systems and exhibit antiviral activity. Our work illustrates how comparative genomics of immune mechanisms can uncover defense genes in eukaryotes.