# ADAM17 is an HIV-1 Restriction Factor Antagonized by Nef

## TL;DR

This study shows that ADAM17 restricts HIV-1 infectivity, and Nef helps the virus evade this restriction by reducing ADAM17 levels.

## Contribution

Identifies ADAM17 as a novel HIV-1 restriction factor and reveals how Nef antagonizes it.

## Key findings

- ADAM17 reduces HIV-1 Env expression and virion infectivity by about 100-fold.
- Nef counteracts ADAM17 by exporting it via Rab11+ endosomes and CD63+ exosomes.
- ADAM17's restriction is independent of its metalloprotease activity and depends on its prodomain.

## Abstract

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.