title: HIV restriction by APOBEC3 in humanized mice.
abstract: Innate immune restriction factors represent important specialized barriers to zoonotic transmission of viruses. Significant consideration has been given to their possible use for therapeutic benefit. The apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3) family of cytidine deaminases are potent immune defense molecules capable of efficiently restricting endogenous retroelements as well as a broad range of viruses including Human Immunodeficiency virus (HIV), Hepatitis B virus (HBV), Human Papilloma virus (HPV), and Human T Cell Leukemia virus (HTLV). The best characterized members of this family are APOBEC3G (A3G) and APOBEC3F (A3F) and their restriction of HIV. HIV has evolved to counteract these powerful restriction factors by encoding an accessory gene designated viral infectivity factor (vif). Here we demonstrate that APOBEC3 efficiently restricts CCR5-tropic HIV in the absence of Vif. However, our results also show that CXCR4-tropic HIV can escape from APOBEC3 restriction and replicate in vivo independent of Vif. Molecular analysis identified thymocytes as cells with reduced A3G and A3F expression. Direct injection of vif-defective HIV into the thymus resulted in viral replication and dissemination detected by plasma viral load analysis; however, vif-defective viruses remained sensitive to APOBEC3 restriction as extensive G to A mutation was observed in proviral DNA recovered from other organs. Remarkably, HIV replication persisted despite the inability of HIV to develop resistance to APOBEC3 in the absence of Vif. Our results provide novel insight into a highly specific subset of cells that potentially circumvent the action of APOBEC3; however our results also demonstrate the massive inactivation of CCR5-tropic HIV in the absence of Vif.
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America. john_foster@med.unc.edu
authors.forename: John F
authors.initials: JF
authors.lastname: Krisko
authors.forename: Francisco
authors.initials: F
authors.lastname: Martinez-Torres
authors.forename: John L
authors.initials: JL
authors.lastname: Foster
authors.forename: J Victor
authors.initials: JV
authors.lastname: Garcia
mesh_terms: D000071478:APOBEC Deaminases; D000818:Animals; D001483:Base Sequence; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism; D004279:DNA, Viral; D004195:Disease Models, Animal; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D013047:Specific Pathogen-Free Organisms; D060168:Thymocytes / Q000378:metabolism / Q000821:virology; D014779:Virus Replication / Q000235:genetics*; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D004279:DNA, Viral; D054320:vif Gene Products, Human Immunodeficiency Virus; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase
references.citation: J Virol. 2012 May;86(10):5497-507
references.pmid: 22379088
references.citation: PLoS Pathog. 2012;8(7):e1002800
references.pmid: 22807680
references.citation: Nature. 2003 Jul 3;424(6944):94-8
references.pmid: 12808465
references.citation: Retrovirology. 2012 May 28;9:44
references.pmid: 22640559
references.citation: J Virol. 2009 Sep;83(18):9474-85
references.pmid: 19587057
references.citation: J Virol. 2005 May;79(9):5705-12
references.pmid: 15827185
references.citation: J Virol. 2012 May;86(9):5000-13
references.pmid: 22357275
references.citation: PLoS Pathog. 2005 Sep;1(1):e6
references.pmid: 16201018
references.citation: Science. 2008 Apr 11;320(5873):230-3
references.pmid: 18403710
references.citation: J Virol. 2004 Jun;78(11):6073-6
references.pmid: 15141007
references.citation: J Virol. 2010 Nov;84(21):11067-75
references.pmid: 20702622
references.citation: Top Antivir Med. 2011 Nov;19(4):156-64
references.pmid: 22156218
references.citation: J Virol. 2010 Sep;84(18):9546-56
references.pmid: 20610708
references.citation: J Virol. 2011 Aug;85(15):7582-93
references.pmid: 21593172
references.citation: Nat Struct Mol Biol. 2004 May;11(5):435-42
references.pmid: 15098018
references.citation: Nat Rev Immunol. 2012 Nov;12(11):786-98
references.pmid: 23059428
references.citation: AIDS Res Hum Retroviruses. 1999 Jan 20;15(2):143-8
references.pmid: 10029246
references.citation: Trends Microbiol. 2005 Jun;13(6):269-77
references.pmid: 15936659
references.citation: Nature. 2002 Aug 8;418(6898):646-50
references.pmid: 12167863
references.citation: J Biol Chem. 2010 May 28;285(22):16546-52
references.pmid: 20363737
references.citation: Mol Cell. 2003 Sep;12(3):591-601
references.pmid: 14527406
references.citation: Virology. 2008 Jun 20;376(1):101-11
references.pmid: 18436274
references.citation: Nat Biotechnol. 2008 Oct;26(10):1187-92
references.pmid: 18806783
references.citation: J Virol. 2010 Mar;84(6):2740-52
references.pmid: 20042504
references.citation: Nature. 1998 Dec 17;396(6712):690-5
references.pmid: 9872319
references.citation: AIDS Rev. 2011 Jul-Sep;13(3):135-48
references.pmid: 21799532
references.citation: Cell. 2003 Jun 13;113(6):803-9
references.pmid: 12809610
references.citation: PLoS Med. 2008 Jan 15;5(1):e16
references.pmid: 18198941
references.citation: Science. 2004 Mar 19;303(5665):1829
references.pmid: 15031497
references.citation: Nat Rev Immunol. 2012 Oct;12(10):687-95
references.pmid: 22976433
references.citation: J Exp Med. 2007 Apr 16;204(4):705-14
references.pmid: 17389241
references.citation: J Virol. 2005 Jul;79(14):8724-31
references.pmid: 15994766
references.citation: J Virol. 2012 Jan;86(1):630-4
references.pmid: 22013053
references.citation: J Virol. 1996 Mar;70(3):1505-11
references.pmid: 8627668
references.citation: Virology. 1991 Dec;185(2):661-72
references.pmid: 1683726
references.citation: J Virol. 2010 Sep;84(18):9613-7
references.pmid: 20592068
references.citation: Curr HIV Res. 2004 Apr;2(2):177-83
references.pmid: 15078181
references.citation: Clin Exp Immunol. 2002 Feb;127(2):321-30
references.pmid: 11876757
references.citation: J Virol. 2010 Jul;84(14):7396-404
references.pmid: 20463080
references.citation: PLoS One. 2010 Jan 21;5(1):e8829
references.pmid: 20098623
references.citation: J Immunol. 1998 Oct 1;161(7):3702-10
references.pmid: 9759895
references.citation: Curr Biol. 2004 Aug 10;14(15):1392-6
references.pmid: 15296758
references.citation: Virus Res. 2010 May;149(2):211-6
references.pmid: 20138932
references.citation: J Virol. 2006 Sep;80(18):9259-69
references.pmid: 16940537
references.citation: J Infect Dis. 2000 Apr;181(4):1479-82
references.pmid: 10762580
references.citation: Curr Opin Virol. 2011 Dec;1(6):526-32
references.pmid: 22278313
references.citation: Curr Biol. 2004 Aug 10;14(15):1385-91
references.pmid: 15296757
references.citation: J Virol. 1996 Jan;70(1):494-507
references.pmid: 8523563
references.citation: Nat Med. 2006 Nov;12(11):1316-22
references.pmid: 17057712
references.citation: Nucleic Acids Res. 2005 Apr 04;33(6):1913-23
references.pmid: 15809227
references.citation: Science. 2003 May 16;300(5622):1112
references.pmid: 12750511
references.citation: Nature. 1996 Jun 20;381(6584):661-6
references.pmid: 8649511
references.citation: Retrovirology. 2005 May 19;2:32
references.pmid: 15943885
references.citation: Curr Biol. 2008 Jun 3;18(11):819-24
references.pmid: 18501607
references.citation: Nucleic Acids Res. 1990 Jun 25;18(12):3587-96
references.pmid: 2194165
references.citation: J Virol. 2001 Sep;75(17):7973-86
references.pmid: 11483742
references.citation: PLoS Pathog. 2009 Feb;5(2):e1000292
references.pmid: 19197360
references.citation: Nature. 2003 Jul 3;424(6944):99-103
references.pmid: 12808466
references.citation: J Virol. 2009 Jun;83(11):5956-60
references.pmid: 19297501
references.citation: J Neurosci. 2011 Mar 2;31(9):3148-57
references.pmid: 21368026
references.citation: Science. 1987 May 15;236(4803):819-22
references.pmid: 3646751
references.citation: Nucleic Acids Res. 2010 Jul;38(13):4274-84
references.pmid: 20308164
references.citation: Nature. 2005 Jan 27;433(7024):430-3
references.pmid: 15674295