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-type Tat or Tat
mutants in the cysteine-rich region displaying trans-dominant negative effects on HIV-1 life
cycle. The expression of HLA class I and class II molecules was not affected by wild-type
Tat. Tat mutants, instead, profoundly down-regulated in a dose-dependent fashion the
expression of class II, but not of class I, in both cell types by acting at the transcriptional
level. Down-regulation was manifested on constitutive and IFN- + -induced class II gene
expression and did not correlate with reduced transcription of the AIR-1 gene product CIITA,
the major transcriptional activator of class II genes, indicating that Tat mutants did not act by
inhibiting AIR-1 gene expression. Class II down-modulation had important functional implications
in macrophages, as both antigen processing and presenting capacity were inhibited.
These results represent the first evidence that a modified HIV-1 Tat product can act as a
potent immunosuppressor by inhibiting the HLA class II expression necessary for triggering
both cellular and humoral responses against pathogens. The use of these HIV-1 Tat mutants
also discloses new opportunities to investigate the molecular mechanisms underlying the
coordinate HLA class II gene transcription.