![]() Among the pandemics currently affecting the world, the acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) that began in 1981 ( Barré-Sinoussi et al., 1983) is an ongoing major public issue. The SARS-CoV-2 coronavirus pandemic and the new multi-country monkeypox outbreak in non-endemic regions highlight how essential is for the global public health the development of effective vaccines that protect people from viral infection outbreaks. Our results confirm the importance of ISG15 as an immune adjuvant in the vaccine field and highlights its role as a potential relevant component in HIV-1 immunization protocols. In mice immunized with the heterologous DNA prime/MVA boost regimen, the expression of the mutant ISG15AA from MVA-Δ3-ISG15AA vector in combination with MVA-B induced an increase in the magnitude and quality of HIV-1-specific CD8 T cells as well as in the levels of IFN-I released, providing a better immunostimulatory activity than the wild-type ISG15GG. For this, we generated and characterized two novel MVA recombinants expressing different forms of ISG15, the wild-type ISG15GG (able to perform ISGylation) or the mutated ISG15AA (unable to perform ISGylation). Here we extended these results evaluating the adjuvant effect of ISG15 when expressed by an MVA vector. In previous studies we proved the adjuvant effect of ISG15 when delivered by a DNA-vector in heterologous prime-boost combination with a Modified Vaccinia virus Ankara (MVA)-based recombinant virus expressing HIV-1 antigens Env/Gag-Pol-Nef (MVA-B). However, ISG15 can also interact with intracellular proteins via non-covalent binding or act as a cytokine in the extracellular space after secretion. ISG15 is a modifier protein that covalently binds to its targets via a reversible bond, a process known as ISGylation, which is the best-characterized activity of this protein to date. The Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that is induced by interferons and plays a critical role in the immune response. The human immunodeficiency virus (HIV), responsible of the Acquired Immune Deficiency Syndrome (AIDS), continues to be a major global public health issue with any cure or vaccine available. 4Biocomputing Unit and Computational Genomics, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.3Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.2Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain. ![]() 1Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid, Madrid, Spain.Sorzano 4, Mariano Esteban 2, Carmen Elena Gómez 2,3 and Susana Guerra 1* Michela Falqui 1, Beatriz Perdiguero 2,3, Rocio Coloma 1, Manuel Albert 1, Laura Marcos-Villar 2, Joseph Patrick McGrail 1, Carlos Óscar S.
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