Interferome profiling in the blood links IFNα5-Mucin-1 axis to HIV-1 pathogenesis

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.