ADAM17 is an HIV-1 Restriction Factor Antagonized by Nef

Nef is an HIV-1 accessory protein critical to viral pathogenesis. While its role in immune evasion is well established, the mechanism by which Nef enhances virion infectivity remains incompletely understood. Here, we identify ADAM17 (TACE) as a host restriction factor through affinity purification–mass spectrometry. ADAM17 associates with HIV-1 Env in the endoplasmic reticulum (ER), reducing Env expression and incorporation into virions, leading to an approximately 100-fold reduction in infectivity. This restriction is independent of ADAM17’s metalloprotease activity and instead depends on its prodomain, which alters Env intracellular trafficking and broadly inhibits both laboratory-adapted and circulating HIV-1 strains. Nef counteracts this restriction by decreasing cellular ADAM17 levels through Rab11^⁺ endosome– and CD63^⁺ exosome–mediated extracellular export. Given ADAM17’s known role in TNF signaling, these findings reveal a previously unrecognized link between Nef-induced pro-inflammatory responses and evasion of host restriction during HIV-1 pathogenesis.