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HIV-1 Tat Protein Modulates the Generation of Cytotoxic T Cell Epitopes by Modifying Proteasome Composition and Enzymatic Activity¹

Riccardo Gavioli^2,*, Eleonora Gallerani^*, Cinzia Fortini^*, Marina Fabris, Arianna Bottoni^*, Alessandro Canella^*, Angela Bonaccorsi, Mauro Marastoni, Fabiola Micheletti, Aurelio Cafaro, Paola Rimessi, Antonella Caputo and Barbara Ensoli

Departments of ^* Biochemistry and Molecular Biology, Experimental and Diagnostic Medicine, and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy; and Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy

Tat, the trans activation protein of HIV, is produced early upon infection to promote and expand HIV replication and transmission. However, Tat appears to also have effects on target cells, which may affect Ag recognition both during infection and after vaccination. In particular, Tat targets dendritic cells and induces their maturation and Ag-presenting functions, increasing Th1 T cell responses. We show in this work that Tat modifies the catalytic subunit composition of immunoproteasomes in B and T cells either expressing Tat or treated with exogenous biological active Tat protein. In particular, Tat up-regulates latent membrane protein 7 and multicatalytic endopeptidase complex like-1 subunits and down-modulates the latent membrane protein 2 subunit. These changes correlate with the increase of all three major proteolytic activities of the proteasome and result in a more efficient generation and presentation of subdominant MHC-I-binding CTL epitopes of heterologous Ags. Thus, Tat modifies the Ag processing and modulates the generation of CTL epitopes. This may have an impact on both the control of virally infected cells during HIV-1 infection and the use of Tat for vaccination strategies.

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