Interferon-α Alters Host Glycosylation Machinery During Treated HIV Infection

Background: A comprehensive understanding of host factors modulated by the antiviral cytokine interferon-α (IFNα) is imperative for harnessing its beneficial effects while avoiding its detrimental side-effects during HIV infection. Cytokines modulate host glycosylation which plays a critical role in mediating immunological functions. However, the impact of IFNα on host glycosylation has never been characterized.

Methods: We assessed the impact of pegylated IFNα2a on IgG glycome, as well as CD8 T and NK cell-surface glycomes, of 18 HIV-infected individuals on suppressive antiretroviral therapy. We linked these glycomic signatures to changes in inflammation, CD8 T and NK cell phenotypes, and HIV DNA.

Findings: We identified significant interactions that support a model in which a) IFNα increases the proportion of pro-inflammatory, bisecting GlcNAc glycans (known to enhance FcγR binding) within the IgG glycome, which in turn b) increases inflammation, which c) leads to poor CD8 T cell phenotypes and poor IFNα-mediated reduction of HIV DNA. Examining cell-surface glycomes, IFNα increases levels of the immunosuppressive GalNAc-containing glycans (T/Tn antigens) on CD8 T cells. This induction is associated with lower HIV-gag-specific CD8 T cell functions. Last, IFNα increases levels of fucose on NK cells. This induction is associated with higher NK functions upon K562 stimulation.

Interpretation: IFNα causes host glycomic alterations that are known to modulate immunological responses. These alterations are associated with both detrimental and beneficial consequences of IFNα. Manipulating host glycomic interactions may represent a strategy for enhancing the positive effects of IFNα while avoiding its detrimental side-effects.

Funding: NIH grants R21AI143385, U01AI110434.