title: The antiviral efficacy of HIV-specific CD8⁺ T-cells to a conserved epitope is heavily dependent on the infecting HIV-1 isolate.
abstract: A major challenge to developing a successful HIV vaccine is the vast diversity of viral sequences, yet it is generally assumed that an epitope conserved between different strains will be recognised by responding T-cells. We examined whether an invariant HLA-B8 restricted Nef₉₀₋₉₇ epitope FL8 shared between five high titre viruses and eight recombinant vaccinia viruses expressing Nef from different viral isolates (clades A-H) could activate antiviral activity in FL8-specific cytotoxic T-lymphocytes (CTL). Surprisingly, despite epitope conservation, we found that CTL antiviral efficacy is dependent on the infecting viral isolate. Only 23% of Nef proteins, expressed by HIV-1 isolates or as recombinant vaccinia-Nef, were optimally recognised by CTL. Recognition of the HIV-1 isolates by CTL was independent of clade-grouping but correlated with virus-specific polymorphisms in the epitope flanking region, which altered immunoproteasomal cleavage resulting in enhanced or impaired epitope generation. The finding that the majority of virus isolates failed to present this conserved epitope highlights the importance of viral variance in CTL epitope flanking regions on the efficiency of antigen processing, which has been considerably underestimated previously. This has important implications for future vaccine design strategies since efficient presentation of conserved viral epitopes is necessary to promote enhanced anti-viral immune responses.
authors: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. srinika.ranasinghe@bnc.oxon-org
authors: Srinika R F
authors: SR
authors: Ranasinghe
authors: Holger B
authors: HB
authors: Kramer
authors: Cynthia
authors: C
authors: Wright
authors: Benedikt M
authors: BM
authors: Kessler
authors: Katalin
authors: K
authors: di Gleria
authors: Yonghong
authors: Y
authors: Zhang
authors: Geraldine M
authors: GM
authors: Gillespie
authors: Marie-Eve
authors: ME
authors: Blais
authors: Abigail
authors: A
authors: Culshaw
authors: Tica
authors: T
authors: Pichulik
authors: Alison
authors: A
authors: Simmons
authors: Sarah L
authors: SL
authors: Rowland-Jones
authors: Andrew J
authors: AJ
authors: McMichael
authors: Tao
authors: T
authors: Dong
references: J Virol. 2009 May;83(9):4605-15
references: 19244334
references: Immunity. 2003 Jan;18(1):97-108
references: 12530979
references: Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1890-5
references: 9050875
references: Nature. 1998 Jan 22;391(6665):397-401
references: 9450757
references: Nat Immunol. 2004 Jul;5(7):661-9
references: 15224091
references: Nat Rev Immunol. 2003 Dec;3(12):952-61
references: 14647477
references: J Virol Methods. 2009 Nov;161(2):297-304
references: 19643141
references: AIDS. 2008 Feb 19;22(4):447-56
references: 18301057
references: Nat Immunol. 2001 Jun;2(6):473-5
references: 11376327
references: PLoS Med. 2006 Oct;3(10):e403
references: 17076553
references: Nature. 1996 May 9;381(6578):166-8
references: 8610016
references: J Clin Invest. 2004 Jul;114(2):250-9
references: 15254592
references: J Biol Chem. 2006 Mar 10;281(10):6358-65
references: 16407287
references: Nature. 2009 Apr 2;458(7238):641-5
references: 19242411
references: J Biol Chem. 1999 Feb 5;274(6):3363-71
references: 9920878
references: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7755-60
references: 12810958
references: J Clin Invest. 2007 Nov;117(11):3563-75
references: 17975674
references: Science. 2002 Jun 28;296(5577):2354-60
references: 12089434
references: J Exp Med. 2004 Apr 5;199(7):905-15
references: 15067030
references: Mol Cell Proteomics. 2008 Nov;7(11):2215-28
references: 18596065
references: J Immunol. 2001 May 15;166(10):6164-9
references: 11342637
references: J Immunol. 2000 Apr 15;164(8):4003-10
references: 10754291
references: Lancet. 2008 Nov 29;372(9653):1894-1905
references: 19012957
references: Trends Immunol. 2006 Nov;27(11):504-10
references: 16997629
references: J Virol. 2004 Feb;78(3):1324-32
references: 14722287
references: Trends Immunol. 2005 Mar;26(3):166-71
references: 15745859
references: Vaccine. 2002 May 6;20(15):1918-21
references: 11983245
references: J Exp Med. 2004 Dec 6;200(11):1455-66
references: 15583017
references: Mol Immunol. 2002 Oct;39(3-4):171-9
references: 12200049
references: Nat Med. 2007 Jan;13(1):46-53
references: 17173051
references: Nat Immunol. 2003 Apr;4(4):375-9
references: 12598896
references: J Virol. 1997 Apr;71(4):3120-8
references: 9060675
references: EMBO J. 2001 May 15;20(10):2357-66
references: 11350924
references: PLoS One. 2007 Oct 03;2(10):e984
references: 17912361
references: Curr Opin Immunol. 2004 Feb;16(1):76-81
references: 14734113
references: J Exp Med. 2009 Jun 8;206(6):1253-72
references: 19487423
references: J Exp Med. 2008 May 12;205(5):1003-7
references: 18458116
references: J Infect Dis. 2008 Feb 1;197(3):337-9
references: 18184092
references: Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9213-7
references: 7937744
references: J Exp Med. 2004 Dec 20;200(12):1547-57
references: 15596521
references: AIDS Res Hum Retroviruses. 2007 Oct;23(10):1283-92
references: 17961117
references: Nature. 2001 Apr 19;410(6831):980-7
references: 11309628
references: Annu Rev Immunol. 2006;24:227-55
references: 16551249
references: Nat Rev Mol Cell Biol. 2001 Mar;2(3):179-87
references: 11265247
references: Nature. 2002 Nov 28;420(6914):434-9
references: 12459786
references: J Exp Med. 2003 May 19;197(10):1365-75
references: 12743169
references: Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9089-90
references: 15967978
references: Nat Protoc. 2009;4(4):461-9
references: 19282851
references: PLoS One. 2009;4(1):e4256
references: 19165342
references: J Virol. 2009 Aug;83(15):7641-8
references: 19458000
references: Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10489-94
references: 18650391
references: J Virol. 2007 Mar;81(6):2624-34
references: 17192314
references: J Immunol. 2005 Oct 1;175(7):4618-26
references: 16177107
references: J Virol. 2007 Feb;81(4):2031-8
references: 17108020
references: J Virol. 2003 Jul;77(13):7330-40
references: 12805431
references: Nat Immunol. 2009 Jun;10(6):636-46
references: 19412183
references: J Virol. 2005 Apr;79(8):4870-6
references: 15795272
references: J Virol. 2004 Jul;78(13):7069-78
references: 15194783
references: J Immunol. 2008 Mar 15;180(6):4075-81
references: 18322217
references: J Infect Dis. 2008 Feb 1;197(3):390-7
references: 18184090
references: J Exp Med. 2008 May 12;205(5):1009-17
references: 18426987
references: Science. 2002 May 24;296(5572):1439-43
references: 12029127