HIV-1 Tat protein binds to TLR4-MD2 and signals to induce TNF-[alpha] and IL-10

Background HIV-1 infection results in hyper-immune activation and immunological disorders as early as the asymptomatic stage. Here, we hypothesized that during early HIV-1 infection, HIV-1 Tat protein acts on monocytes/macrophages to induce anti-inflammatory and proinflammatory cytokines and participates in immune dysregulation. Results In this work we showed that Tat protein: i) by its N-terminal domain induces production of both IL-10 and TNF-[alpha] in a TLR4-MD2 dependent manner, ii) interacts specifically with TLR4-MD2 and MD2 with high affinity but not with CD14, iii) induces in vivo TNF-[alpha] and IL-10 in a TLR4 dependent manner. Conclusions Collectively, our data showed for the first time that, HIV-1 Tat interacts physically with high affinity with TLR4-MD2 to promote proinflammatory cytokines (TNF-[alpha]) and the immunosuppressive cytokine IL-10 both involved in immune dysregulation during early HIV-1 infection and AIDS progression. Keywords: HIV-1, TLR4, Tat, IL-10, TNF-[alpha]