While adaptive immunity has been extensively studied, very little is known about host's innate immunity to HTLV-I infection. HTLV-I infected ATL patients have pronounced immunodeficiency associated with frequent opportunistic infections and in these patients, concurrent infections with bacteria and/or parasites are known to increase risks of progression to ATL. The Toll like receptor-4 (TLR4) activation in response to bacterial infection is essential for dendritic cell maturation and links the innate and adaptive immune responses. Recent reports indicate that TLR4 is targeted by viruses such as RSV, HCV and MMTV. Here we report that HTLV-I has also evolved a protein that interferes with TLR4 signaling; p30 interacts with and inhibits the DNA binding and transcription activity of PU.1 resulting in the down-regulation of the TLR4 expression from the cell surface. Expression of p30 hampers the release of pro-inflammatory cytokines MCP-1, TNF-a and IL-8 and stimulates release of anti-inflammatory IL-10 following stimulation of TLR4 in human macrophage. Finally, we found that p30 increases phosphorylation and inactivation of GSK3 beta a key step for IL-10 production. Our study suggests a novel function of p30 which may instigate immune tolerance by reducing activation of adaptive immunity in ATL patients.