TARDBP as a regulator of HIV-1 assembly and infection: a review of 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 Pr55Gag polyprotein, precursor to capsid (CA), matrix, and nucleocapsid. 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- and viral core-targeting activity of nonhuman 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. TARDBP (TDP-43) is a protein that normally helps cells manage RNA, but recent studies have shown that TARDBP also plays a surprisingly powerful role in fighting HIV-1. This protein weakens the virus in two main ways. First, TARDBP regulates and works with another protein called HDAC6 to break down important viral components (particularly HIV-1 Pr55Gag and Vif) through the cell’s natural recycling system, known as autophagy. Since Pr55Gag is needed to construct the viral core that contains and protects the viral genome, as well as the matrix and nucleocapsid, destroying it prevents new virus particles from forming correctly or becoming infectious. Second, TARDBP hinders HIV-1´s ability to enter cells. It does this by affecting the microtubules inside the cells, which are similar to tiny tracks that the virus uses to reach the nucleus. By modulating the effect of HDAC6 on microtubules, TARDBP prevents HIV-1 from completing the fusion step needed to release its viral core (capsid) and genome into the host cell. Together, these two actions make TARDBP a strong natural defender against HIV-1 by avoiding CA (viral core) formation and/or viral core entry into the cells. Its behaviour is complementary and in phase to that of other antiviral factors, such as nonhuman TRIM5α, as well as to that of new drugs that target the CA (viral core), such as lenacapavir. Researchers propose that boosting TARDBP activity, especially alongside capsid-targeting drugs, could offer a dual strategy: combating drug-resistant HIV-1 and helping to reduce the viral reservoir.