The powerful immunosuppressive properties of IL-10, the strong association between elevated serum concentrations of this immunosuppressive Th2 cytokine with disease progression in HIV-1-infected patients together with the capacity of the retroviral Tat protein to stimulate IL-10 release through TLR4 binding strongly supports that inhibition of Tat/TLR4-MD2 interactions may represent a good candidate to decrypt the mechanisms responsible for IL-10 deregulation in HIV infection. The gene discussed is TAT; the disease is HIV infectious disease.