Interferon-α alters host glycosylation machinery during treated HIV infection

Abstract

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.

Host variation in type I interferon signaling genes (MX1),CCR5Δ32, and MHC class I alleles in treated HIV+ non-controllers predict viral reservoir size

“…We performed both “common” variant (polymorphisms observed at minor allele frequency, MAF, ≧5%) and rare-variant, gene-based analyses. Overall, our findings support prior data suggesting an important role for type I interferon signaling [28], the “transcriptionally active” HIV reservoir [29–32], and glycosylation [33–35]) in the maintenance of the HIV reservoir. In addition, our findings link previously reported genetic associations with viral control during untreated HIV disease (e.g., with MHC class I alleles [13, 20] and CCR5 Δ 32 [23, 24, 36]), now with the HIV reservoir during treated disease, and highlight additional novel pathways that warrant further study in downstream functional studies.…”

“…Although no single gene was statistically significantly associated with HIV reservoir measures, gene set enrichment analyses (GSEA) [43, 61] demonstrated statistically significant associations with HIV total DNA, unspliced RNA, and intact DNA (FDR q-value <0.25) ( Figure 6, Table S8 ). Interestingly, two gene sets that are again linked to type I IFN signaling (glycosylation [33] and HIV total DNA; STAT signaling [62] and HIV intact DNA) were statistically significant. HIV total DNA was associated with “N-Glycan Processing” (normalized enrichment score, NES=1.76, q=0.13), consistent with recent emerging data of the critical role of glycosylation in HIV persistence.…”

“…HIV unspliced RNA was associated with variants in PLVAP , which encodes a protein regulating the transmigration of lymphocytes into lymph nodes [56] and lies <30kb of BST2 , which encodes for the host HIV restriction factor, tetherin [57]. We also identified additional genes linking HIV DNA measures to type I IFN responses in the rare variant gene-based analyses: glycosylation (IFN-α has been shown to alter host glycosylation during treated HIV disease, potentially contributing to modulation of the host immune response [33]) and STAT signaling (type I IFNs activate JAK-STAT signaling pathways [62]). HIV usRNA was also associated with gene sets related to retroviral transcription and viral entry into host cells.…”

“…Indeed, glycomic biomarkers were shown to predict time-to-viral rebound during treatment interruption, a clinical measure of the size of the HIV reservoir in previously ART-suppressed HIV-infected individuals, in at least 2 studies [35,63]. A recent study suggests that changes in IFN-α signaling may induce glycomic alterations that then modulate the host immune response (e.g., CD8+ T and NK cell responses) [33]. HIV unspliced RNA was associated with retroviral genome replication ("Single-Stranded Viral RNA Replication via Double-Stranded DNA Intermediate," NES=1.73, q=0.16), which is in agreement with growing evidence of the transcriptionally "active," rather than just "latent," or quiescent reservoir [29][30][31][32].…”

Glycosylation tips the scales: Novel insights into the dual role of type-I interferons in treated HIV infection

“…In an article in EBioMedicine, Giron and colleagues address the dual role of type-I IFNs by investigating the impact of Peg-IFNa2a treatment on host glycosylation during ART-suppressed chronic HIV infection [6]. To this end, the authors profiled IgG glycome as well as cell surface glycomic signatures of CD8 + T cells and NK cells in peripheral blood mononuclear cells (PBMCs) from 18 HIV-infected individuals treated with a combination of ART and Peg-IFNa2a.…”