APOBEC3G contributes to HIV-1 variation through sublethal mutagenesis.
The mammalian APOBEC3 proteins are an important component of the cellular innate immune response to retroviral infection. APOBEC3G can extinguish HIV-1 infectivity by its incorporation into virus particles and subsequent cytosine deaminase activity that attacks the nascent viral cDNA during reverse transcription, causing lethal mutagenesis. It has been suggested, but not formally shown, that APOBEC3G can also induce sublethal mutagenesis, which would maintain virus infectivity and contribute to HIV-1 variation. To test this, we developed a novel model system utilizing an HIV-1 vector and a panel of APOBEC3G-expressing cells. We observed proviruses with single APOBEC3G-mediated mutations (in the presence or absence of Vif), occurring at distinct hot spots and which could be rescued and shown to have infectivity. These data indicate that APOBEC3G-dependent restriction of HIV-1 can result in viable viral progeny that harbor sublethal levels of G-to-A mutations. Such mutations have the potential to contribute significantly to HIV-1 evolution, pathogenesis, immune escape, and drug resistance.
Sadler
Holly A
HA
Institute for Molecular Virology, 18-242 Moos Tower, 515 Delaware St. SE, University of Minnesota, Minneapolis, MN 55455, USA.
Stenglein
Mark D
MD
Harris
Reuben S
RS
Mansky
Louis M
LM
D000071480:APOBEC-3G Deaminase; D001483:Base Sequence; D002460:Cell Line; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D016341:Genes, vif; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011533:Proviruses / Q000235:genetics / Q000378:metabolism; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase
J Virol. 1995 Nov;69(11):6705-11
7474080
Biochem J. 2004 Nov 1;383(Pt. 3):475-82
15315477
Hum Mol Genet. 2004 Aug 15;13(16):1785-91
15198990
Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4653-8
9114046
Nucleic Acids Res. 2009 Jun;37(11):3660-9
19369217
Annu Rev Immunol. 2008;26:317-53
18304004
J Virol. 2001 Sep;75(17):7973-86
11483742
Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3092-6
7512722
J Virol. 2007 Jul;81(13):7238-48
17428847
J Virol. 2007 Oct;81(20):11322-31
17670826
J Virol. 1992 Nov;66(11):6547-54
1404602
J Biol Chem. 2004 Aug 6;279(32):33177-84
15159405
J Biol Chem. 2007 Nov 2;282(44):32065-74
17855362
Nature. 2002 Aug 8;418(6898):646-50
12167863
Virology. 2008 Mar 1;372(1):147-56
18037155
Virology. 1995 Oct 20;213(1):70-9
7483281
Cell Host Microbe. 2008 Jun 12;3(6):388-98
18541215
Cell. 2003 Jun 13;113(6):803-9
12809610
J Virol. 1995 Aug;69(8):5087-94
7541846
AIDS Rev. 2006 Jul-Sep;8(3):148-57
17078485
Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5501-6
18391217
J Virol. 2008 Aug;82(16):8172-82
18550667
Nat Med. 2003 Nov;9(11):1404-7
14528300
J Biol Chem. 1989 Oct 5;264(28):16948-56
2476448
Methods. 1997 Aug;12(4):288-93
9245608
J Virol. 2006 Apr;80(7):3634-43
16537631
J Virol. 2006 Dec;80(23):11710-22
16971427
J Virol. 2007 Jul;81(13):7099-110
17428871
J Virol. 1998 Oct;72(10):7941-9
9733832
J Biol Chem. 2002 Oct 11;277(41):38053-61
12151398
Virology. 1995 Feb 1;206(2):935-44
7531918
Nature. 2003 Jul 3;424(6944):94-8
12808465
J Virol. 2008 Mar;82(6):2652-60
18184715
Retrovirology. 2008 Jun 24;5:51
18577210
Virology. 2009 May 10;387(2):313-21
19304304
J Virol. 2007 Dec;81(24):13346-53
17928335
J Biol Chem. 1992 Feb 25;267(6):3589-96
1371272
Retrovirology. 2009 Feb 13;6:16
19216784
PLoS Pathog. 2009 Apr;5(4):e1000367
19343218
J Biol Chem. 2007 Jan 26;282(4):2587-95
17121840
Virology. 2007 Apr 10;360(2):247-56
17126871
PLoS Pathog. 2008 Dec;4(12):e1000231
19057663
Curr Biol. 2008 Jun 3;18(11):819-24
18501607
Nature. 2003 Jul 3;424(6944):99-103
12808466
J Virol. 2003 Nov;77(21):11398-407
14557625