Surface-bound Tat inhibits antigen-specific CD8⁺T-cellsactivation in an integrin-dependent manner

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.