ADAM17 is a broad HIV-1 restriction factor targeted by Nef to restore Env maturation

HIV-1 uses the accessory protein Nef to enhance the infectivity of newly produced virus particles, but the host defenses counteracted by Nef remain incompletely defined. The membrane protein SERINC5 contributes to this defense but primarily restricts laboratory-adapted HIV-1 strains, suggesting that other cellular factors influence the requirement for Nef. Here we show that ADAM17, a cell-surface protein best known for cleaving inflammatory mediators, restricts both laboratory-adapted and primary HIV-1 isolates. ADAM17 acts independently of its enzymatic activity: its signal peptide, which normally directs proteins into the cellular secretory pathway, binds the HIV-1 envelope precursor gp160 and retains it in the endoplasmic reticulum. This prevents envelope maturation, transport to the cell surface and incorporation into virus particles, thereby reducing viral infectivity. Nef counteracts this restriction through a PxxP protein-interaction motif that promotes the release of ADAM17 in extracellular vesicles, reducing its abundance within cells and restoring envelope maturation. Disruption of ADAM17 in CD4-positive T-cell lines and primary human lymphocytes reduced the requirement for Nef during viral replication. These findings establish ADAM17 as a regulator of HIV-1 envelope production and show how Nef redirects host-cell trafficking to promote the formation of infectious virus particles. Here, the authors show that the cell-surface protein ADAM17 blocks HIV-1 by preventing maturation of the viral envelope protein, while the viral protein Nef counteracts this effect by redirecting ADAM17 out of infected cells.