Interferome profiling in the blood links IFNα5-Mucin-1 axis to HIV-1 pathogenesis
6 affiliations
- 1Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA
- 2RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, Colorado, USA
- 3Center for Innovative Design and Analysis, Department of Biostatistics and Informatics, University of Colorado School of Medicine, Aurora, Colorado, USA
- 4Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
- 5Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- 6Institute for the Research on HIV and AIDS-associated Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Abstract
Type I interferons (IFN-Is) are essential for antiviral immunity, but contribute to immune dysfunction during chronic HIV-1 infection. IFN-Is comprise multiple IFNα subtypes that signal through a common receptor yet exhibit distinct biological activities, but their qualitative roles in HIV-1 pathogenesis remain incompletely defined. We previously identified IFNα5 as the dominant IFN-I in the systemic circulation of untreated people with HIV (PWH). Here, we delineated IFNα subtype-specific interferomes in peripheral blood mononuclear cells (PBMCs) from HIV-uninfected donors by transcriptomic profiling, and integrated these signatures with blood transcriptomes from untreated PWH, and matched controls. Although the IFN-Is tested induced canonical interferon-stimulated genes (ISGs) in vitro, they also induced different transcriptional programs. In vivo, dysregulation of multiple canonical ISGs, including CD38, LAG3, and CMPK2, correlated with plasma HIV-1 RNA levels, CD4 T-cell depletion, and/or systemic inflammatory markers. By contrast, the IFN-downregulated genes CXCL5 and VSIG4 were repressed in PWH and inversely correlated with viral load. Notably, MUC1, a non-canonical ISG that was most strongly induced by IFNα5, was significantly upregulated in PWH and associated with the inhibitory receptor LAG3, and markers of IL-6-driven inflammation. Flow cytometric analysis demonstrated increased Mucin-1 surface density on circulating CD4 T cells of PWH vs controls. Together, these findings demonstrate that IFNα subtypes can drive qualitatively distinct responses in bulk PBMC, identify IFNα5-associated gene programs in blood that may contribute to immune dysregulation among untreated PWH, and refine current models of IFN-I involvement in HIV-1 pathogenesis.
IMPORTANCE: People living with HIV experience persistent immune activation and inflammation that contribute to immune system damage and long-term health complications. Molecules known as type I interferons (IFN-Is) help control viruses early in infection, but prolonged exposure to these signals may also worsen immune dysfunction. Here, we show that IFNα5 is the dominant interferon present in the blood of people with untreated HIV and activates a distinct gene program in circulating immune cells. This program includes genes linked to immune activation, metabolic dysfunction, and immune exhaustion. IFNα5 strongly induces Mucin-1 on CD4 T cells, which is associated with systemic inflammation. These findings identify IFN pathways that may contribute to immune dysfunction during chronic HIV infection and highlight potential targets for restoring immune health.
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BibTeX
@article{guo2026interferome,
title = {{Interferome profiling in the blood links IFNα5-Mucin-1 axis to HIV-1 pathogenesis}},
author = {Kejun Guo and Stephanie M. Dillon and Emily C. Meneses and Bradley S. Barrett and Alexandra Norman and Kaylee L. Mickens and James H. Morrison and Ulf Dittmer and Kathrin Sutter and Eric M. Poeschla and Katerina Kechris and Cara C. Wilson and Mario L. Santiago},
journal = {Journal of Virology},
year = {2026},
month = sep,
doi = {10.1128/jvi.01089-26},
url = {https://doi.org/10.1128/jvi.01089-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Interferome profiling in the blood links IFNα5-Mucin-1 axis to HIV-1 pathogenesis
AU - Kejun Guo
AU - Stephanie M. Dillon
AU - Emily C. Meneses
AU - Bradley S. Barrett
AU - Alexandra Norman
AU - Kaylee L. Mickens
AU - James H. Morrison
AU - Ulf Dittmer
AU - Kathrin Sutter
AU - Eric M. Poeschla
AU - Katerina Kechris
AU - Cara C. Wilson
AU - Mario L. Santiago
PY - 2026
DA - 2026/09/25
JO - Journal of Virology
DO - 10.1128/jvi.01089-26
UR - https://doi.org/10.1128/jvi.01089-26
AB - Type I interferons (IFN-Is) are essential for antiviral immunity, but contribute to immune dysfunction during chronic HIV-1 infection. IFN-Is comprise multiple IFNα subtypes that signal through a common receptor yet exhibit distinct biological activities, but their qualitative roles in HIV-1 pathogenesis remain incompletely defined. We previously identified IFNα5 as the dominant IFN-I in the systemic circulation of untreated people with HIV (PWH). Here, we delineated IFNα subtype-specific interferomes in peripheral blood mononuclear cells (PBMCs) from HIV-uninfected donors by transcriptomic profiling, and integrated these signatures with blood transcriptomes from untreated PWH, and matched controls. Although the IFN-Is tested induced canonical interferon-stimulated genes (ISGs) in vitro, they also induced different transcriptional programs. In vivo, dysregulation of multiple canonical ISGs, including CD38, LAG3, and CMPK2, correlated with plasma HIV-1 RNA levels, CD4 T-cell depletion, and/or systemic inflammatory markers. By contrast, the IFN-downregulated genes CXCL5 and VSIG4 were repressed in PWH and inversely correlated with viral load. Notably, MUC1, a non-canonical ISG that was most strongly induced by IFNα5, was significantly upregulated in PWH and associated with the inhibitory receptor LAG3, and markers of IL-6-driven inflammation. Flow cytometric analysis demonstrated increased Mucin-1 surface density on circulating CD4 T cells of PWH vs controls. Together, these findings demonstrate that IFNα subtypes can drive qualitatively distinct responses in bulk PBMC, identify IFNα5-associated gene programs in blood that may contribute to immune dysregulation among untreated PWH, and refine current models of IFN-I involvement in HIV-1 pathogenesis. IMPORTANCE: People living with HIV experience persistent immune activation and inflammation that contribute to immune system damage and long-term health complications. Molecules known as type I interferons (IFN-Is) help control viruses early in infection, but prolonged exposure to these signals may also worsen immune dysfunction. Here, we show that IFNα5 is the dominant interferon present in the blood of people with untreated HIV and activates a distinct gene program in circulating immune cells. This program includes genes linked to immune activation, metabolic dysfunction, and immune exhaustion. IFNα5 strongly induces Mucin-1 on CD4 T cells, which is associated with systemic inflammation. These findings identify IFN pathways that may contribute to immune dysfunction during chronic HIV infection and highlight potential targets for restoring immune health.
SN - 0022-538X
SN - 1098-5514
ER -