{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T19:37:50Z","timestamp":1793129870462,"version":"4.5.0"},"reference-count":75,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI134220"],"award-info":[{"award-number":["AI134220"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["BX006270"],"award-info":[{"award-number":["BX006270"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2026,10,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Type I interferons (IFN-Is) are essential for antiviral immunity, but contribute to immune dysfunction during chronic HIV-1 infection. IFN-Is comprise multiple IFN\u03b1 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 IFN\u03b15 as the dominant IFN-I in the systemic circulation of untreated people with HIV (PWH). Here, we delineated IFN\u03b1 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)\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , they also induced different transcriptional programs.\n                      <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                      , dysregulation of multiple canonical ISGs, including\n                      <jats:italic toggle=\"yes\">CD38<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">LAG3<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">CMPK2<\/jats:italic>\n                      , correlated with plasma HIV-1 RNA levels, CD4 T-cell depletion, and\/or systemic inflammatory markers. By contrast, the IFN-downregulated genes\n                      <jats:italic toggle=\"yes\">CXCL5<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">VSIG4<\/jats:italic>\n                      were repressed in PWH and inversely correlated with viral load. Notably,\n                      <jats:italic toggle=\"yes\">MUC1<\/jats:italic>\n                      , a non-canonical ISG that was most strongly induced by IFN\u03b15, was significantly upregulated in PWH and associated with the inhibitory receptor\n                      <jats:italic toggle=\"yes\">LAG3<\/jats:italic>\n                      , 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 IFN\u03b1 subtypes can drive qualitatively distinct responses in bulk PBMC, identify IFN\u03b15-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.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>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 IFN\u03b15 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. IFN\u03b15 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.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01089-26","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T13:02:08Z","timestamp":1790341328000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Interferome profiling in the blood links IFN\u03b15-Mucin-1 axis to HIV-1 pathogenesis"],"prefix":"10.1128","volume":"100","author":[{"given":"Kejun","family":"Guo","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, University of Colorado School of Medicine","place":["Aurora, USA"]},{"name":"RNA Bioscience Initiative, University of Colorado School of Medicine","place":["Aurora, 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Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6397-6551","authenticated-orcid":true,"given":"Kathrin","family":"Sutter","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04mz5ra38","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Virology, University Hospital Essen, University of Duisburg-Essen","place":["Essen, Germany"]},{"id":[{"id":"https:\/\/ror.org\/04mz5ra38","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for the Research on HIV and AIDS-associated Diseases, University Hospital Essen, University of Duisburg-Essen","place":["Essen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1598-5415","authenticated-orcid":true,"given":"Eric M.","family":"Poeschla","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Colorado School of Medicine","place":["Aurora, 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