TARDBP as a Gatekeeper of HIV-1 Assembly and Infection: Targeting the Viral Capsid Precursor Pr55Gag and Limiting Viral Core Entry

TARDBP (TDP-43), a multifunctional RNA-binding protein, has emerged as a critical host factor controlling HIV-1 replication by destabilizing the viral capsid protein (CA) 55 kDa Gag precursor (Pr55Gag). TARDBP promotes HDAC6-mediated autophagic degradation of HIV-1 Pr55Gag and Vif, impairing nascent virion assembly and infectivity. Simultaneously, TARDBP disrupts viral entry by modulating HDAC6-dependent microtubule (MT) deacetylation, blocking the viral core at the pore fusion step in target cells. These dual mechanisms position TARDBP as a central antiviral defender, paralleling the CA (viral core)-targeting activity of TRIM5α and novel therapeutic inhibitors such as lenacapavir. This review synthesizes evidence for TARDBP’s roles in HIV-1 restriction, highlighting its potential to destabilize the CA-formed viral core during both viral assembly and entry. We propose that enhancing TARDBP activity, combined with destabilizing CA-binding drugs, could offer a synergistic strategy to combat drug-resistant HIV-1 strains and target viral reservoirs, providing hope for functional cure approaches.