ADAM17 is an HIV-1 Restriction Factor Antagonized by Nef

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• Nef is a critical HIV-1 accessory protein involved in viral pathogenesis and immune evasion.
• The precise mechanisms by which Nef enhances virion infectivity are not fully understood.
• Host factors can restrict HIV-1 replication and infectivity.

Purpose of the Study:

• To identify host factors that restrict HIV-1 infectivity.
• To elucidate the mechanism by which Nef enhances HIV-1 virion infectivity.
• To understand the interplay between Nef, host restriction factors, and viral pathogenesis.

Main Methods:

• Affinity purification coupled with mass spectrometry to identify host-viral protein interactions.
• Analysis of HIV-1 Env expression and incorporation into virions.
• Investigation of intracellular trafficking pathways involving endosomes and exosomes.
• Assessment of viral infectivity using laboratory-adapted and circulating HIV-1 strains.

Main Results:

• ADAM17 (A Disintegrin and Metalloproteinase domain-containing protein 17) was identified as a host restriction factor that associates with HIV-1 Env in the ER.
• ADAM17 binding to Env reduces Env expression and incorporation into virions, decreasing infectivity by approximately 100-fold.
• This restriction is mediated by the ADAM17 prodomain, affecting Env trafficking independently of its metalloprotease activity.
• Nef counteracts ADAM17 restriction by reducing cellular ADAM17 levels via Rab11-positive endosome and CD63-positive exosome-mediated export.
• Nef's action links pro-inflammatory responses (via ADAM17/TNF signaling) to HIV-1 evasion of host restriction.

Conclusions:

• ADAM17 acts as a host restriction factor inhibiting HIV-1 infectivity by interfering with Env processing and incorporation.
• Nef antagonizes ADAM17-mediated restriction through a novel exosomal pathway, enhancing viral infectivity.
• This study reveals a new mechanism of HIV-1 immune evasion and pathogenesis, connecting viral proteins to host inflammatory pathways.