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HIV-1 Tat Addresses Dendritic Cells to Induce a Predominant Th1-Type Adaptive Immune Response That Appears Prevalent in the Asymptomatic Stage of Infection¹

Emanuele Fanales-Belasio^*, Sonia Moretti^*, Valeria Fiorelli^*, Antonella Tripiciano, Maria R. Pavone Cossut^*, Arianna Scoglio, Barbara Collacchi^*, Filomena Nappi^*, Iole Macchia^*, Stefania Bellino^*, Vittorio Francavilla, Antonella Caputo, Giovanni Barillari^*, Mauro Magnani, Maria Elena Laguardia, Aurelio Cafaro^*, Fausto Titti^*, Paolo Monini^*, Fabrizio Ensoli and Barbara Ensoli^2,*

^* National AIDS Center, Istituto Superiore di Sanità, Rome, Italy; Department of Pathology and Microbiology, Istituti Fisioterapici Ospitalieri—S. Gallicano Hospital, IRCCS, Rome, Italy; Department of Histology, Microbiology and Medical Biotechnology, University of Padua, Padua, Italy; and Institute for Biological Chemistry "G. Fornaini", University of Urbino, Urbino, Italy

Tat is an early regulatory protein that plays a major role in human HIV-1 replication and AIDS pathogenesis, and therefore, it represents a key target for the host immune response. In natural infection, however, Abs against Tat are produced only by a small fraction (20%) of asymptomatic individuals and are rarely seen in progressors, suggesting that Tat may possess properties diverting the adaptive immunity from generating humoral responses. Here we show that a Th1-type T cell response against Tat is predominant over a Th2-type B cell response in natural HIV-1 infection. This is likely due to the capability of Tat to selectively target and very efficiently enter CD1a-expressing monocyte-derived dendritic cells (MDDC), which represent a primary target for the recognition and response to virus Ag. Upon cellular uptake, Tat induces MDDC maturation and Th1-associated cytokines and β-chemokines production and polarizes the immune response in vitro to the Th1 pattern through the transcriptional activation of TNF- gene expression. This requires the full conservation of Tat transactivation activity since neither MDDC maturation nor TNF- production are found with either an oxidized Tat, which does not enter MDDC, or with a Tat protein mutated in the cysteine-rich region (cys22 Tat), which enters MDDC as the wild-type Tat but is transactivation silent. Consistently with these data, inoculation of monkeys with the native wild-type Tat induced a predominant Th1 response, whereas cys22 Tat generated mostly Th2 responses, therefore providing evidence that Tat induces a predominant Th1 polarized adaptive immune response in the host.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National AIDS Program, and from the Italian Concerted Action on HIV/AIDS Vaccine Development, Istituto Superiore di Sanità, Rome, Italy and by the EC Commission under the VI Framework Programme of Research and Technological Development (2002–2006), Project no. LSHP-CT-2004-503487, AIDS Vaccine Integrated Project.

² Address correspondence and reprint requests to Dr. Barbara Ensoli, National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail address: barbara.ensoli{at}iss.it

³ Abbreviations used in this paper: SHIV, simian HIV; MDDC, monocyte derived dendritic cells; wt, wild type; ICS, intracellular cytokine staining; CBA, cytometric bead assay; SFC, spot forming cells.