FIG 11.

PU.1 inhibits transcription from the HIV-1 LTR but activates the MRC1 promoter. PU.1 is a myeloid-specific transcription factor that regulates expression of multiple genes, including mannose receptor (MRC1). PU.1-mediated upregulation (blue arrow) of MRC1 (a) (see Fig. 4) accounts for the previously observed inhibition of HIV-1 virus release (b) (3). We now report that this effect is counteracted by the HIV-encoded Tat protein that inhibits PU.1 function (c) (see Fig. 5). Inhibition of PU.1 function by Tat reduces MRC1 expression, which contributes to enhanced virus release. While PU.1 upregulates MRC1 expression, it has an inhibitory effect on HIV-1 LTR promoter activity (d) (see Fig. 8 and 9). This leads to reduced Tat protein synthesis (e), which, in turn, increases the inhibition of HIV-1 LTR transcription by PU.1 (d). However, a positive feedback loop ensures continued Tat synthesis via TAR-dependent activation of HIV-1 transcription (f) and thus control of PU.1 expression (see Fig. 1C and E and Fig. 8B). Aside from Tat, HIV-1 Vpr (15) and Nef (14, 15) have been implicated in the regulation of MRC1 (h).