IFN-λ3 Inhibits HIV Infection of Macrophages through the JAK-STAT Pathway

Background: Interferon lambda 3 (IFN-lambda 3) is a newly identified cytokine with antiviral activity, and its single nucleotide polymorphisms are strongly associated with the treatment effectiveness and development of chronic hepatitis C virus infection. We thus examined the potential of IFN-lambda 3 to inhibit HIV replication and the possible mechanisms of the anti-HIV action by IFN-lambda 3 in human macrophages. Principal Findings: Under different conditions (before, during, and after HIV infection), IFN-lambda 3 significantly inhibited viral replication in macrophages, which was associated with the induction of multiple antiviral cellular factors (ISG56, MxA, OAS1, A3G/F and tetherin) and IFN regulatory factors (IRF-1, 3, 5, 7 and 9). This anti-HIV action of IFN-lambda 3 could be compromised by the JAK-STAT inhibitor. In addition, IFN-lambda 3 treatment of macrophages induced the expression of toll-like receptor 3 (TLR3) and two key adaptors (MyD88 and TRIF) in type I IFN pathway activation. However, HIV infection compromised IFN-lambda 3-mediated induction of the key elements in JAK-STAT signaling pathway. Conclusions: These data indicate that IFN-lambda 3 exerts its anti-HIV function by activating JAK-STAT pathway-mediated innate immunity in macrophages. Future in vivo studies are necessary in order to explore the potential for developing IFN-lambda 3-based therapy for HIV disease.