HIV-1 Tat mutants in the cysteine-rich region down-regulate HLA class II expression in T lymphocytic and macrophage cell lines

Human macrophage and T cell lines were stably transfected with HIV-1 wild-t ype Tat or Tat mutants in the cysteine-rich region displaying trans-dominan t negative effects on HIV-1 life cycle. The expression of HLA class I and c lass II molecules was not affected by wild-type Tat. Tat mutants, instead, profoundly down-regulated in a dose-dependent fashion the expression of cla ss II, but not of class I, in both cell types by acting at the transcriptio nal level. Down-regulation was manifested on constitutive and IFN-gamma-ind uced class II gene expression and did not correlate with reduced transcript ion of the AlR-1 gene product CIITA, the major transcriptional activator of class II genes, indicating that Tat mutants did not act by inhibiting AlR- 1 gene expression. Class II down-modulation had important functional implic ations in macrophages, as both antigen processing and presenting capacity w ere inhibited. These results represent the first evidence that a modified H IV-1 Tat product can act as a potent immunosuppressor by inhibiting the HLA class II expression necessary for triggering both cellular and humoral res ponses against pathogens. The use of these HIV-1 Tat mutants also discloses new opportunities to investigate the molecular mechanisms underlying the c oordinate HLA class II gene transcription.