58: IL-27 inhibits HIV-1 infection in human macrophages by down-regulating host factor SPTBN1 during monocyte to macrophage differentiation

Macrophages represent a major target and viral reservoir of HIV-1 infection. The susceptibility of macrophages to HIV-1 infection is modulated during monocyte differentiation. IL-27 is an antiviral cytokine which also plays a role in monocyte activation. Here, we present new evidence that IL-27 promotes monocyte differentiation into macrophages that are non-permissive for HIV-1 infection. While IL-27 treatment does not affect expression of macrophage differentiation markers or macrophage biological functions, it confers HIV resistance by down-regulating SPTBN1, a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 during monocyte differentiation through a TAK-1-mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27 treated macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect macrophages from HIV-1 infection by down-regulating SPTBN1 during monocyte to macrophage differentiation without altering other macrophage biological functions, thus indicating IL-27 as a potential immunotherapeutic reagent to prevent HIV-1 infection.