Transactive response DNA-binding Protein (TDP-43) regulates early HIV-1 entry and infection.
Autor
Valenzuela Fernández, Agustín; Cabrera Rodríguez, Romina; Pérez Yanes, Silvia; González Montelongo, Rafaela; Lorenzo Salazar, José M.; Estévez Herrera, Judith; García Luis, Jonay; Íñigo Campos, Antonio; Rubio Rodríguez, Luis A.; Muñoz Barrera, Adrián; Trujillo González, Rodrigo Francisco; Dorta Guerra, Roberto; Casado, Concha; Pernas, María; Blanco, Julià; Flores, CarlosFecha
2021Resumen
The transactive response DNA-binding protein (TDP-43) is an important regulator of
mRNA, 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, we
seek 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 this
experimental condition, HIV-1 infection was impaired, independently of the viral
envelope glycoprotein (Env) complex tropism. The results obtained by using an HIV-1
Env-mediated cell-to-cell fusion model, under the same experimental conditions,
suggest that the increase in TDP-43 levels negatively affects the viral Env fusion
capacity. Moreover, the specific siRNA silencing of endogenous TDP-43 in target cells
lead to a significant decrease in the levels of HDAC6 which consistently induces an
increase in the fusogenic and infection activities of the HIV-1 Env. These observations
were confirmed by using primary viral Envs from HIV+ individuals with different
clinical phenotypes. An increase in the level of expression of wt-TDP-43 strongly
reduced the Envs infection activity of viremic non-progressors (VNP) and rapid
progressors (RP) HIV+ individuals down to the levels of the inefficient HIV-1 Envs
from long-term non-progressor elite controllers (LTNP-EC) individuals. On the
contrary, low levels of endogenous TDP-43, obtained after specific siRNA-TDP-43
knocking-down, significantly favors the infection activity of primary HIV-1 Envs of
VNP and RP individuals, leading to an increase in the infection ability of the primary
HIV-1/LTNP-EC Envs. Based on this evidence, we interpret that TDP-43 conditions
cell permissibility to HIV infection by affecting viral Env fusion and infection
capacities, at least by altering the cellular levels of the antiviral enzyme HDAC6.