{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T23:50:24Z","timestamp":1793058624620,"version":"4.5.0"},"reference-count":44,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"729","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,1,10]]},"abstract":"<jats:p>\n            CD8\n            <jats:sup>+<\/jats:sup>\n            T cells are key antiviral effectors against hepatitis B virus (HBV), yet their number and function can be compromised in chronic infections. Preclinical HBV models displaying CD8\n            <jats:sup>+<\/jats:sup>\n            T cell dysfunction showed that interleukin-2 (IL-2)\u2013based treatment, unlike programmed cell death ligand 1 (PD-L1) checkpoint blockade, could reverse this defect, suggesting its therapeutic potential against HBV. However, IL-2\u2019s effectiveness is hindered by its pleiotropic nature, because its receptor is found on various immune cells, including regulatory T (T\n            <jats:sub>reg<\/jats:sub>\n            ) cells and natural killer (NK) cells, which can counteract antiviral responses or contribute to toxicity, respectively. To address this, we developed a cis-targeted CD8-IL2 fusion protein, aiming to selectively stimulate dysfunctional CD8\n            <jats:sup>+<\/jats:sup>\n            T cells in chronic HBV. In a mouse model, CD8-IL2 boosted the number of HBV-reactive CD8\n            <jats:sup>+<\/jats:sup>\n            T cells in the liver without substantially altering T\n            <jats:sub>reg<\/jats:sub>\n            or NK cell counts. These expanded CD8\n            <jats:sup>+<\/jats:sup>\n            T cells exhibited increased interferon-\u03b3 and granzyme B production, demonstrating enhanced functionality. CD8-IL2 treatment resulted in substantial antiviral effects, evidenced by marked reductions in viremia and antigenemia and HBV core antigen\u2013positive hepatocytes. In contrast, an untargeted CTRL-IL2 led to predominant NK cell expansion, minimal CD8\n            <jats:sup>+<\/jats:sup>\n            T cell expansion, negligible changes in effector molecules, and minimal antiviral activity. Human CD8-IL2 trials in cynomolgus monkeys mirrored these results, achieving a roughly 20-fold increase in peripheral blood CD8\n            <jats:sup>+<\/jats:sup>\n            T cells without affecting NK or T\n            <jats:sub>reg<\/jats:sub>\n            cell numbers. These data support the development of CD8-IL2 as a therapy for chronic HBV infection.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adi1572","type":"journal-article","created":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T18:58:47Z","timestamp":1704913127000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":29,"title":["CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5710-3671","authenticated-orcid":true,"given":"Francesco","family":"Andreata","sequence":"first","affiliation":[{"name":"Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy."},{"name":"Vita-Salute San Raffaele University, 20132 Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6200-7863","authenticated-orcid":true,"given":"Kelly D.","family":"Moynihan","sequence":"additional","affiliation":[{"name":"Asher Biotherapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2583-2498","authenticated-orcid":true,"given":"Valeria","family":"Fumagalli","sequence":"additional","affiliation":[{"name":"Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy."},{"name":"Vita-Salute San Raffaele University, 20132 Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0726-1532","authenticated-orcid":true,"given":"Pietro","family":"Di Lucia","sequence":"additional","affiliation":[{"name":"Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0412-3588","authenticated-orcid":true,"given":"Danielle C.","family":"Pappas","sequence":"additional","affiliation":[{"name":"Asher Biotherapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0985-1111","authenticated-orcid":true,"given":"Keigo","family":"Kawashima","sequence":"additional","affiliation":[{"name":"Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Ni","sequence":"additional","affiliation":[{"name":"Asher Biotherapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul H.","family":"Bessette","sequence":"additional","affiliation":[{"name":"Asher Biotherapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3010-8576","authenticated-orcid":true,"given":"Chiara","family":"Perucchini","sequence":"additional","affiliation":[{"name":"Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5212-3446","authenticated-orcid":true,"given":"Elisa","family":"Bono","sequence":"additional","affiliation":[{"name":"Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3462-7891","authenticated-orcid":true,"given":"Leonardo","family":"Giustini","sequence":"additional","affiliation":[{"name":"Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6142-8807","authenticated-orcid":true,"given":"Henry C.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Asher Biotherapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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