title: Structural variants of IFNα preferentially promote antiviral functions.
abstract: IFNα, a cytokine with multiple functions in innate and adaptive immunity and a potent inhibitor of HIV, exerts antiviral activity, in part, by enhancing apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3 (APOBEC3) family members. Although IFNα therapy is associated with reduced viral burden, this cytokine also mediates immune dysfunction and toxicities. Through detailed mapping of IFNα receptor binding sites, we generated IFNα hybrids and mutants and determined that structural changes in the C-helix alter the ability of IFN to limit retroviral activity. Selective IFNα constructs differentially block HIV replication and their directional magnitude of inhibition correlates with APOBEC3 levels. Importantly, certain mutants exhibited reduced toxicity as reflected by induced indoleamine 2,3-dioxygenase (IDO), suggesting discreet and shared intracellular signaling pathways. Defining IFN structure and function relative to APOBEC and other antiviral genes may enable design of novel IFN-related molecules preserving beneficial antiviral roles while minimizing negative effects.
authors.affiliation: Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. nvazquez@mail.nih.gov
authors.forename: Nancy
authors.initials: N
authors.lastname: Vázquez
authors.forename: Hana
authors.initials: H
authors.lastname: Schmeisser
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dolan
authors.forename: Joseph
authors.initials: J
authors.lastname: Bekisz
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Zoon
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Wahl
mesh_terms: D000071478:APOBEC Deaminases; D002147:Calmodulin / Q000502:physiology; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis* / Q000235:genetics; D016898:Interferon-alpha / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D008958:Models, Molecular; D016328:NF-kappa B / Q000502:physiology; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D053633:Receptor, Interferon alpha-beta / Q000737:chemistry / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000502:physiology*
chemical_list: D002147:Calmodulin; C554158:IFNA2 protein, human; C554326:IFNA21 protein, human; C508033:IFNAR2 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016898:Interferon-alpha; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D053633:Receptor, Interferon alpha-beta; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase