C-maf, NFAT2 and NFkB p65 specifically cooperate to augment HIV-1 transcription in IL-4 producing CD4 T cells (35.28)

Abstract

Abstract HIV-1, the cause of AIDS, preferentially replicates in IL-4 producing cells, and this coincides with a Th2 switch linked with disease progression. Others suggested differential chemokine receptor expression accounts for increased infectivity of Th2 cells. However, we confirm HIV-1 expression is increased in IL-4 producing CD4 T cells but is irrespective of viral tropism (T-tropic, M-tropic) for different chemokine receptors. Instead, we note increased HIV-1 long terminal repeat (LTR) transcription in IL-4 producing primary CD4 T cells. Using in vitro footprinting, we identified a binding site for the Th2 restricted transcription factor, c-maf (required for IL-4), located adjacent and proximal to the dual NFkB/NFAT sites in the proximal LTR. We show c-maf from activated primary CD4 T cells binds the HIV-1 LTR in vitro (EMSA) and in vivo (ChIP of virally infected cells). Interestingly, c-maf binds in conjunction with NFAT2, but not NFAT1, and with NFkB p65, but not p50. Over-expression of c-maf, NFAT2, and NFkB p65 synergistically augment HIV-1 transcription and p24/gag expression. Conversely, c-maf specific siRNA introduced into IL-4 producing primary CD4 T cells inhibits HIV-1 transcription. Thus, we identified a host factor, c-maf, present in IL-4 producing CD4 T cells that contributes to increased HIV-1 transcription in Th2 cells via binding to the LTR in cooperation with specific NFAT and NFkB family members.