Cabrera-Rodríguez, RominaPérez-Yanes, SilviaMontelongo, RafaelaLorenzo-Salazar, José MEstévez-Herrera, JudithGarcía-Luis, JonayÍñigo-Campos, AntonioRubio-Rodríguez, Luis AMuñoz-Barrera, AdriánTrujillo-González, RodrigoDorta-Guerra, RobertoCasado, ConcepcionPernas, MariaBlanco, JuliàFlores, CarlosValenzuela-Fernández, Agustín2022-11-172022-11-172022-05-31Int J Mol Sci. 2022 May 31;23(11):6180.http://hdl.handle.net/20.500.12105/15178The 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.engVoRhttps://creativecommons.org/licenses/by/4.0/TARDBP/TDP-43HDAC6Pore fusion formationCell-permissivityHIV-1 infectionHIV InfectionsHIV-1DNA-Binding ProteinsHistone Deacetylase 6HumansT-LymphocytesAttribution 4.0 Internacional356828622311618010.3390/ijms231161801422-0067International journal of molecular sciencesopen access