The ISG15-Protease USP18 Is a Pleiotropic Enhancer of HIV-1 Replication

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Interferon (IFN)-induced restriction factors, including ISG15, p21, and SAMHD1, are crucial for the innate immune response against viruses.
• The ISG15-specific protease USP18 can inhibit IFN production, and HIV-1 may exploit this to evade immune surveillance.

Purpose of the Study:

• To investigate the role of USP18 in HIV-1 replication and its interaction with host antiviral factors.
• To elucidate the mechanisms by which USP18 enhances viral replication and interferes with immune sensing pathways.

Main Methods:

• Analysis of USP18 expression during HIV-1 infection.
• Assessment of p21 antiviral function and p53 activity.
• Investigation of de novo dNTP biosynthesis pathways and SAMHD1 activity.
• Evaluation of cGAS-STING pathway activation and STING ISGylation.

Main Results:

• HIV-1 infection induces USP18, which enhances viral replication by abrogating p21's antiviral function.
• USP18 leads to the accumulation of misfolded p53, inactivating wild-type p53 and upregulating dNTP biosynthesis, thus inactivating SAMHD1.
• Despite increased viral DNA, USP18 abrogates cGAS-STING-mediated viral DNA sensing, and ISG15 is essential for this sensing.
• STING ISGylation at specific residues (K224, K236, K289, K347, K338, K370) is critical for its oligomerization and IFN induction, with inhibition of K289 ISGylation suppressing these processes.

Conclusions:

• Human USP18 is a novel factor that significantly contributes to HIV-1 replication through multiple mechanisms.
• USP18 disrupts key antiviral pathways, including p21 function and STING-mediated immune sensing, presenting a potential therapeutic target.