Abstract
IL-27, a member of the IL-12 family of cytokines, plays an important and diverse role in the function of the immune system. Whilst generally recognized as an anti-inflammatory cytokine, in addition IL-27 has been found to have broad anti-viral effects. Recently, IL-27 has been shown to be a potent inhibitor of HIV-1 infection in CD4+ T cells and macrophages. The main objective of this study was to see whether IL-27 has a similar inhibitory effect on HIV-1 replication in dendritic cells (DCs). Monocytes were differentiated into immature DCs (iDCs) and mature DCs (mDCs) with standard techniques using a combination of GM-CSF, IL-4 and LPS. Following differentiation, iDCs were infected with HIV-1 and co-cultured in the presence or absence of IL-27. IL-27 treated DCs were shown to be highly potent inhibitors of cis HIV-1, particularly of CCR5 tropic strains. Of note, other IL-12 family members (IL-12, IL-23 and IL-35) had no effect on HIV-1 replication. Microarray studies of IL-27 treated DCs showed no up-regulation of Type I (IFN) gene expression. Neutralization of the Type-I IFN receptor had no impact on the HIV inhibition. Lastly, IL-27 mediated inhibition was shown to act post-viral entry and prior to completion of reverse transcription. These results show for the first time that IL-27 is a potent inhibitor of cis HIV-1 infection in DCs by a Type I IFN independent mechanism. IL-27 has previously been reported to inhibit HIV-1 replication in CD4+ T cells and macrophages, thus taken together, this cytokine is a potent anti-HIV agent against all major cell types targeted by the HIV-1 virus and may have a therapeutic role in the future.
Highlights
IL-27, a member of the IL-12 family of cytokines [1], has been shown to play important roles in both the innate and adaptive immune systems
This was suggestive that immature DCs (iDCs) and mature DCs (mDCs) would be responsive to IL-27 and that LLCs would not respond to IL-27
The lack of detectable IFNa or IFNb in the supernatant of IL-27 treated iDCs and the fact that an IFN neutralizing antibody when added to IL27 treated iDCs did not abrogate the antiviral effect, strongly suggest that IFN is not acting as an intermediary protective factor post IL-27 treatment
Summary
IL-27, a member of the IL-12 family of cytokines [1], has been shown to play important roles in both the innate and adaptive immune systems. The IL-12 family (IL-23, IL-27 and IL-35) is made of various combinations of shared a-chains and b-chains [2] and IL27 is made up of two subunits, namely the IL-27p28 subunit and an Epstein-Barr virus induced gene 3 (EBI3) subunit [3]. The first description of the function of IL-27 demonstrated that it could lead to proliferation of naıve T cells with subsequent differentiation into T helper 1 cells [3,6], and IL-27 was initially thought of as a pro-inflammatory cytokine. Due to itsability to affect the function ofmultiple T cell subsets such as Tr1 cells, T follicular cells (Tfh), Th17 cells and T regulatory cells (Tregs) and ability to modulate the production of antiinflammatory cytokines such as IL-10, IL-27 is thought to be predominantly an anti-inflammatory cytokine [7]
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