Prothymosin-α inhibits HIV-1 via Toll-like receptor 4-mediated type I interferon induction

Induction of type I interferons (IFN) is a central feature of innate immune responses to microbial pathogens and is mediated via Toll-like receptor (TLR)-dependent and -independent pathways. Prothymosin-alpha (ProT alpha), a small acidic protein produced and released by CD8(+) T cells, inhibits HIV-1, although the mechanism for its antiviral activity was not known. We demonstrate that exogenous ProT alpha acts as a ligand for TLR4 and stimulates type I IFN production to potently suppress HIV-1 after entry into cells. These activities are induced by native and recombinant ProT alpha, retained by an acidic peptide derived from ProT alpha, and lost in the absence of TLR4. Furthermore, we demonstrate that ProT alpha accounts for some of the soluble postintegration HIV-1 inhibitory activity long ascribed to CD8(+) cells. Thus, a protein produced by CD8(+) T cells of the adaptive immune system can exert potent viral suppressive activity through an innate immune response. Understanding the mechanism of IFN induction by ProT alpha may provide therapeutic leads for IFN-sensitive viruses.