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<p>TARDBP (TDP-43), a multifunctional RNA-binding protein, has emerged as a critical host factor controlling HIV-1 replication by destabilizing the viral Pr55<sup>Gag</sup> polyprotein, precursor to capsid (CA), matrix, and nucleocapsid. TARDBP promotes HDAC6-mediated autophagic degradation of HIV-1 Pr55<sup>Gag</sup> 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.</p>

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TARDBP as a regulator of HIV-1 assembly and infection: a review of targeting the viral capsid precursor Pr55Gag and limiting viral core entry

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月3日

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  • Romina Cabrera-Rodríguez,
  • Anna Pons-Grifols,
  • María Pernas,
  • Concepción Casado,
  • Rodrigo Trujillo-González,
  • Iria Lorenzo-Sánchez,
  • Iriome Reyes-Castañeda,
  • Benjamin Trinité,
  • Julià Blanco,
  • Agustin Valenzuela-Fernández

摘要

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.