title: IFN-α treatment inhibits acute Friend retrovirus replication primarily through the antiviral effector molecule Apobec3.
abstract: Therapeutic administration of IFN-α in clinical trials significantly reduced HIV-1 plasma viral load and human T-lymphotropic virus type I proviral load in infected patients. The mechanism may involve the concerted action of multiple antiretroviral effectors collectively known as "restriction factors," which could vary in relative importance according to the magnitude of transcriptional induction. However, direct genetic approaches to identify the relevant IFN-α restriction factors will not be feasible in humans in vivo. Meanwhile, mice encode an analogous set of restriction factor genes and could be used to obtain insights on how IFN-α could inhibit retroviruses in vivo. As expected, IFN-α treatment of mice significantly upregulated the transcription of multiple restriction factors including Tetherin/BST2, SAMHD1, Viperin, ISG15, OAS1, and IFITM3. However, a dominant antiretroviral factor, Apobec3, was only minimally induced. To determine whether Apobec3 was necessary for direct IFN-α antiretroviral action in vivo, wild-type and Apobec3-deficient mice were infected with Friend retrovirus, then treated with IFN-α. Treatment of infected wild-type mice with IFN-α significantly reduced acute plasma viral load 28-fold, splenic proviral load 5-fold, bone marrow proviral load 14-fold, and infected bone marrow cells 7-fold, but no inhibition was observed in Apobec3-deficient mice. These findings reveal that IFN-α inhibits acute Friend retrovirus infection primarily through the antiviral effector Apobec3 in vivo, demonstrate that transcriptional induction levels did not predict the mechanism of IFN-α-mediated control, and highlight the potential of the human APOBEC3 proteins as therapeutic targets against pathogenic retrovirus infections.
authors: Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors: Michael S
authors: MS
authors: Harper
authors: Bradley S
authors: BS
authors: Barrett
authors: Diana S
authors: DS
authors: Smith
authors: Sam X
authors: SX
authors: Li
authors: Kathrin
authors: K
authors: Gibbert
authors: Ulf
authors: U
authors: Dittmer
authors: Kim J
authors: KJ
authors: Hasenkrug
authors: Mario L
authors: ML
authors: Santiago
mesh_terms: D000208:Acute Disease; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005622:Friend murine leukemia virus / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012192:Retroviridae Infections / Q000276:immunology / Q000628:therapy* / Q000821:virology*; D014766:Viremia / Q000276:immunology / Q000628:therapy / Q000821:virology; D014779:Virus Replication / Q000276:immunology*
chemical_list: D000998:Antiviral Agents; C554327:Ifna protein, mouse; D016898:Interferon-alpha; C503504:Apobec3 protein, mouse; D003564:Cytidine Deaminase