HUMAN-IMMUNODEFICIENCY-VIRUS TAT INDUCES FUNCTIONAL UNRESPONSIVENESS IN T-CELLS

Soluble proteins of the human immunodeficiency virus (HIV) might play a significant role in the pathogenesis of HIV infection. The effects o f regulatory proteins of HIV, Tat, Nef, and Vif, on normal If-cell fun ction were investigated. The addition of synthetic Tat peptides, but n ot that of the recombinant Nef or Vif protein, inhibited proliferative responses of CD4(+) tetanus antigen-specific, exogenous interleukin-2 (IL-2)independent T-cell clones in a dose-dependent manner. In additi on, Tat peptides inhibited the anti-CD3 monoclonal antibody-induced pr oliferative responses of both purified CD4(+) and CD8(+) T cells. Tat did not affect proliferative responses induced by phorbol myristate ac etate plus ionomycin. The Tat peptides at the concentrations used (0.1 to 3 mu g/ml) did not affect the viability of the cells as determined by trypan blue exclusion. Treatment of Tat peptides with polyclonal T at antibodies abrogated the inhibitory effect of Tat. Soluble Tat prot eins secreted by HeLa cells transfected with the tat gene also inhibit ed antigen-induced proliferation of the T-cell clones. Tat inhibited t he anti-CD3 monoclonal antibody-induced IL-2 mRNA expression and IL-2 secretion but did not affect IL-2 receptor alpha-chain mRNA or protein expression on peripheral blood T cells. Finally, treatment of T-cell clones with the Tat peptide did not affect the antigen-induced increas e in intracellular calcium, hydrolysis of phosphatidyl inositol to ino sitol trisphosphate, or translocation of protein kinase C from the cyt osol to the membrane. These studies demonstrate that the mechanism of the Tat-mediated inhibition of T-cell functions involves a phospholipa se C gamma(1)-independent pathway.