Interferon-α alters host glycosylation machinery during treated HIV infection
Leila B. Giron,
Florent Colomb,
Emmanouil Papasavvas,
Livio Azzoni,
Xiangfan Yin,
Matthew Fair,
Alitzel Anzurez,
Mohammad Damra,
Karam Mounzer,
Jay R. Kostman,
Pablo Tebas,
Una O'Doherty,
Hiroaki Tateno,
Qin Liu,
Michael R. Betts,
Luis J. Montaner,
Mohamed Abdel-Mohsen
Affiliations
Leila B. Giron
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
Florent Colomb
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
Emmanouil Papasavvas
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
Livio Azzoni
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
Xiangfan Yin
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
Matthew Fair
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
Alitzel Anzurez
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
Mohammad Damra
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
Karam Mounzer
Philadelphia FIGHT, Philadelphia, PA 19107, USA
Jay R. Kostman
Philadelphia FIGHT, Philadelphia, PA 19107, USA
Pablo Tebas
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Una O'Doherty
Department of Laboratory Medicine and Therapeutic Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Hiroaki Tateno
National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan
Qin Liu
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
Michael R. Betts
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Luis J. Montaner
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA; Corresponding authors.
Mohamed Abdel-Mohsen
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA; Corresponding authors.
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.
