title: IFN-α induces APOBEC3G, F, and A in immature dendritic cells and limits HIV-1 spread to CD4+ T cells.
abstract: Cytokines and IFNs, such as TNF-α and IFN-α, upregulate costimulatory molecules in monocyte-derived dendritic cells (MDDCs), enabling effective Ag presentation to T cells. This activation of MDDCs is often accompanied by upregulation of apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3 (APOBEC3) (A3) family proteins that are able to restrict HIV-1 replication in MDDCs by inducing hypermutations in the viral genome. In this study, we show that TNF-α upregulates costimulatory molecules and are able to restrict HIV-1BaL replication in MDDCs without significant induction of A3G, A3A, or A3F. Conversely, low quantities of IFN-α failed to upregulate costimulatory molecules, did not induce IL-12p40 or migration, but significantly induced A3G, A3A, and A3F mRNA expression and restricted viral replication in MDDCs. We also showed that transmission of HIV-1 from MDDCs to autologous T cells was significantly reduced in the presence of IFN-α. Sequence analyses detected the induction of high frequency of G-to-A hypermutations in the env genes from HIV-1BaL-infected MDDCs treated with low quantities of IFN-α2b. These findings show that low quantities of IFN-α can induce functional A3 family proteins and restrict HIV-1 replication in MDDCs while keeping an immature nonmigratory phenotype, supporting further investigations of modalities that enhance retroviral restriction factors. In addition, the findings highlight the role of IFN-α as a double-edged sword in HIV-1 infection, and we show that IFN-α can be powerful in reducing HIV-1 infection both in MDDCs and T cells.
authors: Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
authors: Venkatramanan
authors: V
authors: Mohanram
authors: Annette E
authors: AE
authors: Sköld
authors: Susanna M
authors: SM
authors: Bächle
authors: Sushil Kumar
authors: SK
authors: Pathak
authors: Anna-Lena
authors: AL
authors: Spetz
mesh_terms: D000071480:APOBEC-3G Deaminase; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000821:virology*; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D009154:Mutation / Q000187:drug effects; D011092:Polyethylene Glycols / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011506:Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D054299:env Gene Products, Human Immunodeficiency Virus; D011092:Polyethylene Glycols; C492906:APOBEC3F protein, human; D043525:Cytosine Deaminase; D000071480:APOBEC-3G Deaminase; C121399:APOBEC3A protein, human; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase; C417083:peginterferon alfa-2b