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

Abstract

BackgroundInterferon lambda 3 (IFN-λ3) 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-λ3 to inhibit HIV replication and the possible mechanisms of the anti-HIV action by IFN-λ3 in human macrophages.Principal FindingsUnder different conditions (before, during, and after HIV infection), IFN-λ3 significantly inhibited viral replication in macrophages, which was associated with the induction of multiple antiviral cellular factors (ISG56, MxA, OAS-1, A3G/F and tetherin) and IFN regulatory factors (IRF-1, 3, 5, 7 and 9). This anti-HIV action of IFN-λ3 could be compromised by the JAK-STAT inhibitor. In addition, IFN-λ3 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-λ3-mediated induction of the key elements in JAK-STAT signaling pathway.ConclusionsThese data indicate that IFN-λ3 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-λ3-based therapy for HIV disease.

Lambda-Interferons Inhibit Herpes Simplex Virus Type 2 Replication in Human Cervical Epithelial Cells by Activating the JAK/STAT Pathway

“…Furthermore, the inhibitory effect of IFN-3 on HSV-2 was more potent than that of IFN-1 and IFN-2 ( Fig. 1A and B), which is consistent with previous publications (33,34).…”

Influence of Common Mucosal Co‐Factors on HIV Infection in the Female Genital Tract

“…Interestingly, when IFN-e was used in an intranasal/intramuscular heterologous HIV prime-boost immunization, increased HIV-specific CD8 T-cell responses were observed in the spleen, genito-rectal draining lymph nodes, and Peyer's patches. 27 Furthermore, the recently described type III IFN-k (IL-28/29), which has similar antiviral properties to Type I IFN, has been shown to block HIV-1 infection in macrophages in vitro 28,29 by inhibiting HIV-1 integration and post-transcriptional events. 30 Interestingly, IFN-k receptors are largely restricted to cells of epithelial origin.…”

Elevated Serum Levels of Interleukin-29 Are Associated with Disease Activity in Rheumatoid Arthritis Patients with Anti-Cyclic Citrullinated Peptide Antibodies

“…We also compared the serum IL-29 levels at baseline between the ACR20 positive group (1,051.8 (387.8-5,337.7) pg/ml) and the ACR20 negative group (777.7 (347.9-1,874.9) pg/ml) with no significant difference (P > 0.05). (Kotenko 2011;Liu et al 2012). Examples of the latter include the connective tissue disorders such as RA and systemic lupus erythematosus (Wu et al 2011).…”

“…As a newly described member of the IFN family, Type III IFNs include IFN-λ1, IFN -λ2, and IFN-λ3, which are also known as interleukin (IL)-29, IL-28A, and IL-28B respectively (Sheppard et al 2003;Uze and Monneron 2007;Dickensheets et al 2013). Through binding to respective receptors, IFN-λs activate the Janus kinase-signal transducer and activator of transcript (JAK-STAT), mitogenactivated protein kinase (MAPK) or Akt signaling pathways to induce antiviral, anti-proliferative, antitumor and immune responses (Donnelly and Kotenko 2010;Zhang et al 2011;Liu et al 2012). IL-29, as the most active cytokine among all type III IFNs (Xu et al 2015a), has been implicated in protecting against viral infection and modulating autoimmune inflammation (He et al 2010(He et al , 2011de Groen et al 2014).…”