The emerging roles of ubiquitin-like modifications in regulating HIV replication and host defense.

As a post-translational modification (PTM) mechanism analogous to ubiquitination, ubiquitin-like (UBL) modification plays a crucial regulatory role in virus-host interactions. With the increasing discovery of UBL modification types, their roles in diverse biological process, including HIV infection, have gained growing attention. Rather than merely serving as anti-HIV defenses or being exploited by the virus, UBLs often exert dual roles by modulating both host restriction factors and viral proteins, thereby impacting key steps of HIV life cycle, immune evasion, and intracellular signaling. This article summarizes recent advances on the contribution of UBLs in regulating HIV replication and host defense, highlighting their indispensable roles in arms races between HIV and host, aiming to provide a theoretical framework for developing novel therapeutic strategies against HIV-1 targeting virus-host interactions.