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*
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy;
Department of Experimental Medicine, Tor Vergata University, Rome, Italy; and
Department of Biochemistry and Molecular Biology, Ferrara University, Ferrara, Italy
Vaccination of cynomolgus monkeys with the biologically active
HIV-1 Tat protein induces specific Th1 responses, including CTLs.
Similar responses are also induced by vaccination with
tat DNA, but not by vaccination with inactivated Tat or
Tat peptides. This suggested that the native Tat protein may act
differently on APC as compared with inactivated Tat or peptide Ag. In
this study, we show that biologically active Tat is very efficiently
taken up by monocyte-derived dendritic cells (MDDC) in a time (within
minutes)- and dose-dependent (starting from 0.1 ng/ml) fashion, whereas
uptake is very poor or absent with other APC, including T cell blasts
and B lymphoblastoid cell lines. Although maturation of MDDC reduces
their pino/phagocytic activity, mature MDDC take up Tat much more
efficiently than immature cells. In addition, Tat uptake is abolished
or greatly hampered by oxidation/inactivation of the protein or by
performing the experiments at 4°C, suggesting that MDDC take up
native Tat by a receptor-mediated endocytosis. After uptake, active Tat
protein induces up-regulation of MHC and costimulatory molecules and
production of IL-12, TNF-
, and 
chemokines, which drive Th1-type
immune response. In contrast, these effects are lost by oxidation and
inactivation of the protein. Finally, native Tat enhances Ag
presentation by MDDC, increasing Ag-specific T cell responses. These
data indicate that native Tat selectively targets MDDC, is taken up by
these cells via specialized pathways, and promotes their maturation and
Ag-presenting functions, driving Th1-type immune responses. Thus, Tat
can act as both Ag and adjuvant, capable of driving T cell-mediated
immune responses.
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