RT info:eu-repo/semantics/article
T1 Transactive response DNA-binding Protein (TDP-43) regulates early HIV-1 entry and infection.
A1 Valenzuela Fernández, Agustín
A1 Cabrera Rodríguez, Romina
A1 Pérez Yanes, Silvia
A1 González Montelongo, Rafaela
A1 Lorenzo Salazar, José M.
A1 Estévez Herrera, Judith
A1 García Luis, Jonay
A1 Íñigo Campos, Antonio
A1 Rubio Rodríguez, Luis A.
A1 Muñoz Barrera, Adrián
A1 Trujillo González, Rodrigo Francisco
A1 Dorta Guerra, Roberto
A1 Casado, Concha
A1 Pernas, María
A1 Blanco, Julià
A1 Flores, Carlos
A2 Medicina Física y Farmacología
A2 Grupo "inmunología Celular y Viral".
K1 TDP-43
K1 HDAC6
K1 pore fusion formation
K1 cell-permissibility
K1 HIV infection
AB The transactive response DNA-binding protein (TDP-43) is an important regulator ofmRNA, being reported to stabilize the anti-HIV factor, histone deacetylase 6 (HDAC6).However, little is known about the role of TDP-43 in HIV infection. In this work, weseek for the TDP-43 function on regulating CD4+ T cell permissibility to HIV infection.We observed that over-expression of wt-TDP-43 in CD4+ T cells stabilized HDAC6,increasing mRNA and the protein levels of this antiviral enzyme. Under thisexperimental condition, HIV-1 infection was impaired, independently of the viralenvelope glycoprotein (Env) complex tropism. The results obtained by using an HIV-1Env-mediated cell-to-cell fusion model, under the same experimental conditions,suggest that the increase in TDP-43 levels negatively affects the viral Env fusioncapacity. Moreover, the specific siRNA silencing of endogenous TDP-43 in target cellslead to a significant decrease in the levels of HDAC6 which consistently induces anincrease in the fusogenic and infection activities of the HIV-1 Env. These observationswere confirmed by using primary viral Envs from HIV+ individuals with differentclinical phenotypes. An increase in the level of expression of wt-TDP-43 stronglyreduced the Envs infection activity of viremic non-progressors (VNP) and rapidprogressors (RP) HIV+ individuals down to the levels of the inefficient HIV-1 Envsfrom long-term non-progressor elite controllers (LTNP-EC) individuals. On thecontrary, low levels of endogenous TDP-43, obtained after specific siRNA-TDP-43knocking-down, significantly favors the infection activity of primary HIV-1 Envs ofVNP and RP individuals, leading to an increase in the infection ability of the primaryHIV-1/LTNP-EC Envs. Based on this evidence, we interpret that TDP-43 conditionscell permissibility to HIV infection by affecting viral Env fusion and infectioncapacities, at least by altering the cellular levels of the antiviral enzyme HDAC6.
YR 2021
FD 2021
LK http://riull.ull.es/xmlui/handle/915/35335
UL http://riull.ull.es/xmlui/handle/915/35335
LA en
NO bioRxiv preprint doi: https://doi.org/10.1101/2021.12.06.471424; this version posted December 7, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
DS Repositorio institucional de la Universidad de La Laguna
RD 12-sep-2024