Plasma Membrane Is the Site of Productive HIV-1 Particle Assembly

TLDR

HIV‑1 morphogenesis has been widely modeled as starting with Gag targeting to late endosomal membranes, which then deliver Gag or assembled virions to the plasma membrane and extracellular space. The study aims to challenge this prevailing model by presenting findings inconsistent with endosomal initiation of HIV‑1 assembly. The authors show that newly synthesized Gag assembles at the plasma membrane, with a fraction later internalized by endocytosis or phagocytosis, explaining endosomal localization. They demonstrate that HIV‑1 Gag is delivered to the plasma membrane and virions are efficiently released into the extracellular medium even when late endosome motility is abolished; virions are released when assembly is targeted to the plasma membrane but not to late endosomes, concluding that HIV‑1 assembly is initiated and completed at the plasma membrane, not at endosomal membranes.

Abstract

Recently proposed models that have gained wide acceptance posit that HIV-1 virion morphogenesis is initiated by targeting the major structural protein (Gag) to late endosomal membranes. Thereafter, late endosome-based secretory pathways are thought to deliver Gag or assembled virions to the plasma membrane (PM) and extracellular milieu. We present several findings that are inconsistent with this model. Specifically, we demonstrate that HIV-1 Gag is delivered to the PM, and virions are efficiently released into the extracellular medium, when late endosome motility is abolished. Furthermore, we show that HIV-1 virions are efficiently released when assembly is rationally targeted to the PM, but not when targeted to late endosomes. Recently synthesized Gag first accumulates and assembles at the PM, but a proportion is subsequently internalized via endocytosis or phagocytosis, thus accounting for observations of endosomal localization. We conclude that HIV-1 assembly is initiated and completed at the PM, and not at endosomal membranes.