HIV-1 tat addresses dendritic cells to induce a predominant th1-type adaptive immune response that appears prevalent in the asymptomatic stage of infection

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, Barbara Ensoli

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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-αgene expression. This requires the full conservation of Tat transactivation activity since neither MDDC maturation nor TNF-α 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.

Original languageEnglish
Pages (from-to)2888-2897
Number of pages10
JournalJournal of Immunology
Volume182
Issue number5
DOIs
Publication statusPublished - Mar 1 2009

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Asymptomatic Infections
Adaptive Immunity
Dendritic Cells
HIV-1
Monocytes
Transcriptional Activation
tat Gene Products
Th2 Cells
Th1 Cells
Chemokines
HIV Infections
Haplorhini
Cysteine
Acquired Immunodeficiency Syndrome
B-Lymphocytes
Cytokines
Viruses
T-Lymphocytes
Gene Expression
Infection

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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

In: Journal of Immunology, Vol. 182, No. 5, 01.03.2009, p. 2888-2897.

Research output: Contribution to journalArticle

Fanales-Belasio, E, Moretti, S, Fiorelli, V, Tripiciano, A, Cossut, MRP, Scoglio, A, Collacchi, B, Nappi, F, Macchia, I, Bellino, S, Francavilla, V, Caputo, A, Barillari, G, Magnani, M, Laguardia, ME, Cafaro, A, Titti, F, Monini, P, Ensoli, F & Ensoli, B 2009, 'HIV-1 tat addresses dendritic cells to induce a predominant th1-type adaptive immune response that appears prevalent in the asymptomatic stage of infection', Journal of Immunology, vol. 182, no. 5, pp. 2888-2897. https://doi.org/10.4049/jimmunol.0711406
Fanales-Belasio, Emanuele ; Moretti, Sonia ; Fiorelli, Valeria ; Tripiciano, Antonella ; Cossut, Maria R Pavone ; Scoglio, Arianna ; Collacchi, Barbara ; Nappi, Filomena ; Macchia, Iole ; Bellino, Stefania ; Francavilla, Vittorio ; Caputo, Antonella ; Barillari, Giovanni ; Magnani, Mauro ; Laguardia, Maria Elena ; Cafaro, Aurelio ; Titti, Fausto ; Monini, Paolo ; Ensoli, Fabrizio ; Ensoli, Barbara. / HIV-1 tat addresses dendritic cells to induce a predominant th1-type adaptive immune response that appears prevalent in the asymptomatic stage of infection. In: Journal of Immunology. 2009 ; Vol. 182, No. 5. pp. 2888-2897.
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AU - Fanales-Belasio, Emanuele

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AU - Tripiciano, Antonella

AU - Cossut, Maria R Pavone

AU - Scoglio, Arianna

AU - Collacchi, Barbara

AU - Nappi, Filomena

AU - Macchia, Iole

AU - Bellino, Stefania

AU - Francavilla, Vittorio

AU - Caputo, Antonella

AU - Barillari, Giovanni

AU - Magnani, Mauro

AU - Laguardia, Maria Elena

AU - Cafaro, Aurelio

AU - Titti, Fausto

AU - Monini, Paolo

AU - Ensoli, Fabrizio

AU - Ensoli, Barbara

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N2 - 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-αgene expression. This requires the full conservation of Tat transactivation activity since neither MDDC maturation nor TNF-α 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.

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