Transactive Response DNA-Binding Protein (TARDBP/TDP-43) Regulates Cell Permissivity to HIV-1 Infection by Acting on HDAC6

  1. Cabrera-Rodríguez, Romina 1
  2. Pérez-Yanes, Silvia 1
  3. Montelongo, Rafaela
  4. Lorenzo-Salazar, José M.
  5. Estévez-Herrera, Judith 1
  6. García-Luis, Jonay 1
  7. Íñigo-Campos, Antonio
  8. Rubio-Rodríguez, Luis A.
  9. Muñoz-Barrera, Adrián
  10. Trujillo-González, Rodrigo 1
  11. Dorta-Guerra, Roberto 1
  12. Casado, Concha
  13. Pernas, María
  14. Blanco, Julià
  15. Flores, Carlos 1
  16. Valenzuela-Fernández, Agustín 1
  1. 1 Universidad de La Laguna

    Universidad de La Laguna

    San Cristobal de La Laguna, España


International Journal of Molecular Sciences

ISSN: 1422-0067

Year of publication: 2022

Volume: 23

Issue: 11

Pages: 6180

Type: Article

DOI: 10.3390/IJMS23116180 GOOGLE SCHOLAR lock_openOpen access editor


The transactive response DNA-binding protein (TARDBP/TDP-43) influences the processing of diverse transcripts, including that of histone deacetylase 6 (HDAC6). Here, we assessed TDP-43 activity in terms of regulating CD4+ T-cell permissivity to HIV-1 infection. We observed that overexpression of wt-TDP-43 increased both mRNA and protein levels of HDAC6, resulting in impaired HIV-1 infection independently of the viral envelope glycoprotein complex (Env) tropism. Consistently, using an HIV-1 Env-mediated cell-to-cell fusion model, the overexpression of TDP-43 levels negatively affected viral Env fusion capacity. Silencing of endogenous TDP-43 significantly decreased HDAC6 levels and increased the fusogenic and infection activities of the HIV-1 Env. Using pseudovirus bearing primary viral Envs from HIV-1 individuals, overexpression of wt-TDP-43 strongly reduced the infection activity of Envs from viremic non-progressors (VNP) and rapid progressors (RP) patients down to the levels of the inefficient HIV-1 Envs observed in long-term non-progressor elite controllers (LTNP-EC). On the contrary, silencing endogenous TDP-43 significantly favored the infectivity of primary Envs from VNP and RP individuals, and notably increased the infection of those from LTNP-EC. Taken together, our results indicate that TDP-43 shapes cell permissivity to HIV-1 infection, affecting viral Env fusion and infection capacities by altering the HDAC6 levels and associated tubulin-deacetylase anti-HIV-1 activity.

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