TY - JOUR
T1 - Surface-bound Tat inhibits antigen-specific CD8+T-cellsactivation in an integrin-dependent manner
AU - Chiozzini, Chiara
AU - Collacchi, Barbara
AU - Nappia, Filomena
AU - Bauer, Tanja
AU - Arenaccioa, Claudia
AU - Tripiciano, Antonella
AU - Longo, Olimpia
AU - Ensoli, Fabrizio
AU - Cafaro, Aurelio
AU - Ensoli, Barbara
AU - Federico, Maurizio
PY - 2014
Y1 - 2014
N2 - Objective: The identification of still unrevealed mechanisms affecting the anti-HIV CD8+T- cellsresponse in HIV-1 infection. Design: Starting from the observation that anti-Tat immunization is associated with improved CD8+T- cellsimmunity, we developed both in-vitro and ex-vivo assays to characterize the effects of extra-cellular Tat on the adaptive CD8+T- cells response. Methods: The effects of Tat on CD8+T- cells activation were assayed using CD8+T- cells clones specific for either cellular (MART-1) or viral (HIV-1 Nef) antigens, and HIV-1 Gag-specific CD8 T cells from HIV-1 patients. Results: The interaction between CD8 T lymphocytes and immobilized Tat, but not its soluble form, inhibits peptide-specific CD8+T lymphocyte activation. The inhibition does not depend on Tat trans-activation activity, but on the interaction of the Tat RGD domain with α5β1 and αvβ3 integrins. Impaired CD8+T activation was also observed in cocultures of CD8+T- cells with HIV-1-infected cells. Anti-Tat Abs abrogate the inhibitory effect, consistently with the evidence that extracellular Tat accumulates on the cell membrane of virus-producing cells. The Tat-induced inhibition of cell activation associates with increased apoptosis of CD8+T- cells. Finally, the inhibition of cell activation also takes place in Gag-specific CD8+T lymphocytes from HIV-1- infected patients. Conclusion: Our results support the idea that CD8+T- cells apoptosis induced by surface-bound extracellular Tat can contribute to the dysregulation of the CD8+T- cells adaptive response against HIV as well as other pathogens present in AIDS patients.
AB - Objective: The identification of still unrevealed mechanisms affecting the anti-HIV CD8+T- cellsresponse in HIV-1 infection. Design: Starting from the observation that anti-Tat immunization is associated with improved CD8+T- cellsimmunity, we developed both in-vitro and ex-vivo assays to characterize the effects of extra-cellular Tat on the adaptive CD8+T- cells response. Methods: The effects of Tat on CD8+T- cells activation were assayed using CD8+T- cells clones specific for either cellular (MART-1) or viral (HIV-1 Nef) antigens, and HIV-1 Gag-specific CD8 T cells from HIV-1 patients. Results: The interaction between CD8 T lymphocytes and immobilized Tat, but not its soluble form, inhibits peptide-specific CD8+T lymphocyte activation. The inhibition does not depend on Tat trans-activation activity, but on the interaction of the Tat RGD domain with α5β1 and αvβ3 integrins. Impaired CD8+T activation was also observed in cocultures of CD8+T- cells with HIV-1-infected cells. Anti-Tat Abs abrogate the inhibitory effect, consistently with the evidence that extracellular Tat accumulates on the cell membrane of virus-producing cells. The Tat-induced inhibition of cell activation associates with increased apoptosis of CD8+T- cells. Finally, the inhibition of cell activation also takes place in Gag-specific CD8+T lymphocytes from HIV-1- infected patients. Conclusion: Our results support the idea that CD8+T- cells apoptosis induced by surface-bound extracellular Tat can contribute to the dysregulation of the CD8+T- cells adaptive response against HIV as well as other pathogens present in AIDS patients.
KW - Apoptosis
KW - CD8<sup>+</sup>T- cells
KW - Integrins
KW - Interferon-gamma
KW - Tat
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UR - http://www.scopus.com/inward/citedby.url?scp=84927734771&partnerID=8YFLogxK
U2 - 10.1097/QAD.0000000000000389
DO - 10.1097/QAD.0000000000000389
M3 - Article
C2 - 25313583
AN - SCOPUS:84927734771
VL - 28
SP - 2189
EP - 2200
JO - AIDS
JF - AIDS
SN - 0269-9370
IS - 15
ER -