title: Nef-specific CD8+ T cell responses contribute to HIV-1 immune control.
abstract: Recent studies in the SIV-macaque model of HIV infection suggest that Nef-specific CD8+ T-cell responses may mediate highly effective immune control of viraemia. In HIV infection Nef recognition dominates in acute infection, but in large cohort studies of chronically infected subjects, breadth of T cell responses to Nef has not been correlated with significant viraemic control. Improved disease outcomes have instead been associated with targeting Gag and, in some cases, Pol. However analyses of the breadth of Nef-specific T cell responses have been confounded by the extreme immunogenicity and multiple epitope overlap within the central regions of Nef, making discrimination of distinct responses impossible via IFN-gamma ELISPOT assays. Thus an alternative approach to assess Nef as an immune target is needed. Here, we show in a cohort of >700 individuals with chronic C-clade infection that >50% of HLA-B-selected polymorphisms within Nef are associated with a predicted fitness cost to the virus, and that HLA-B alleles that successfully drive selection within Nef are those linked with lower viral loads. Furthermore, the specific CD8+ T cell epitopes that are restricted by protective HLA Class I alleles correspond substantially to effective SIV-specific epitopes in Nef. Distinguishing such individual HIV-specific responses within Nef requires specific peptide-MHC I tetramers. Overall, these data suggest that CD8+ T cell targeting of certain specific Nef epitopes contributes to HIV suppression. These data suggest that a re-evaluation of the potential use of Nef in HIV T-cell vaccine candidates would be justified.
authors.affiliation: Department of Paediatrics, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Adland
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Paolo
authors.initials: P
authors.lastname: Paioni
authors.forename: Henrik
authors.initials: H
authors.lastname: Kløverpris
authors.forename: Roger
authors.initials: R
authors.lastname: Shapiro
authors.forename: Anthony
authors.initials: A
authors.lastname: Ogwu
authors.forename: Lynn
authors.initials: L
authors.lastname: Riddell
authors.forename: Graz
authors.initials: G
authors.lastname: Luzzi
authors.forename: Fabian
authors.initials: F
authors.lastname: Chen
authors.forename: Thambiah
authors.initials: T
authors.lastname: Balachandran
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Anette
authors.initials: A
authors.lastname: Stryhn
authors.forename: Anne
authors.initials: A
authors.lastname: Edwards
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Søren
authors.initials: S
authors.lastname: Buus
authors.forename: Philip
authors.initials: P
authors.lastname: Goulder
authors.forename: Philippa C
authors.initials: PC
authors.lastname: Matthews
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017124:Conserved Sequence; D019143:Evolution, Molecular; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D015235:HLA-B Antigens / Q000378:metabolism; D006801:Humans; D007114:Immunization; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D019562:Viral Load / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D015235:HLA-B Antigens; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1
references.citation: J Immunol. 2011 May 15;186(10):5675-86
references.pmid: 21498667
references.citation: J Virol. 2006 Feb;80(3):1311-20
references.pmid: 16415008
references.citation: J Virol. 2012 Dec;86(23):12643-54
references.pmid: 22973023
references.citation: Nat Med. 1997 Feb;3(2):212-7
references.pmid: 9018241
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
references.pmid: 12883005
references.citation: J Infect Dis. 2011 Sep 1;204(5):768-76
references.pmid: 21844303
references.citation: AIDS Res Hum Retroviruses. 2001 Nov 1;17(16):1527-31
references.pmid: 11709097
references.citation: AIDS. 2004 Apr 9;18(6):871-6
references.pmid: 15060434
references.citation: PLoS One. 2012;7(10):e47799
references.pmid: 23094091
references.citation: Nature. 2009 Apr 2;458(7238):641-5
references.pmid: 19242411
references.citation: J Virol. 2008 Feb;82(4):1723-38
references.pmid: 18057253
references.citation: J Virol. 2008 Sep;82(17):8548-59
references.pmid: 18596105
references.citation: AIDS Res Hum Retroviruses. 1996 Dec 10;12(18):1691-8
references.pmid: 8959245
references.citation: Retrovirology. 2010 Apr 09;7:34
references.pmid: 20380698
references.citation: Nat Med. 1999 Nov;5(11):1270-6
references.pmid: 10545993
references.citation: AIDS. 2004 Jul 2;18(10):1383-92
references.pmid: 15199314
references.citation: J Virol. 2008 Sep;82(18):9216-27
references.pmid: 18614631
references.citation: AIDS Res Hum Retroviruses. 2007 Mar;23(3):477-81
references.pmid: 17411382
references.citation: J Immunol. 2012 Apr 1;188(7):3364-70
references.pmid: 22387557
references.citation: J Virol. 2009 May;83(9):4605-15
references.pmid: 19244334
references.citation: J Virol. 2012 Nov;86(21):11493-500
references.pmid: 22896606
references.citation: J Virol. 2008 Sep;82(17):8422-30
references.pmid: 18562530
references.citation: Nature. 2004 Dec 9;432(7018):769-75
references.pmid: 15592417
references.citation: J Exp Med. 2005 Mar 21;201(6):891-902
references.pmid: 15781581
references.citation: J Virol. 2007 Nov;81(22):12608-18
references.pmid: 17728232
references.citation: J Virol. 2009 Feb;83(4):1845-55
references.pmid: 19036810
references.citation: Retrovirology. 2008 Sep 22;5:84
references.pmid: 18808677
references.citation: AIDS. 2013 Mar 27;27(6):899-905
references.pmid: 23276808
references.citation: AIDS. 1997 Mar 15;11(4):536-8
references.pmid: 9084804
references.citation: Retrovirology. 2013 Jan 07;10:1
references.pmid: 23289738
references.citation: Nat Med. 2007 Jan;13(1):46-53
references.pmid: 17173051
references.citation: J Immunol. 2002 Jul 1;169(1):210-9
references.pmid: 12077247
references.citation: J Virol. 2012 Jul;86(14):7596-604
references.pmid: 22573864
references.citation: J Virol. 2012 Dec;86(24):13202-16
references.pmid: 23055555
references.citation: Science. 2007 Mar 16;315(5818):1583-6
references.pmid: 17363674
references.citation: PLoS One. 2007 Nov 14;2(11):e1152
references.pmid: 18000532
references.citation: Nat Med. 2004 Mar;10(3):282-9
references.pmid: 14770175
references.citation: AIDS Res Hum Retroviruses. 2001 Nov 20;17(17):1681-7
references.pmid: 11779357
references.citation: Tissue Antigens. 1994 Nov;44(5):311-7
references.pmid: 7878657
references.citation: J Virol. 2013 Apr;87(7):3952-65
references.pmid: 23365420
references.citation: J Virol. 2003 Aug;77(16):9029-40
references.pmid: 12885919
references.citation: J Virol. 2010 Oct;84(20):10543-57
references.pmid: 20686036
references.citation: J Virol. 2013 May;87(10):5461-7
references.pmid: 23468488
references.citation: PLoS One. 2008 Feb 27;3(2):e1678
references.pmid: 18301755
references.citation: AIDS Res Hum Retroviruses. 2007 Feb;23(2):204-15
references.pmid: 17331028
references.citation: J Virol. 2010 Nov;84(22):12018-29
references.pmid: 20826686
references.citation: PLoS Comput Biol. 2008 Nov;4(11):e1000225
references.pmid: 19023406
references.citation: J Virol. 1993 Aug;67(8):4639-50
references.pmid: 8043040
references.citation: J Virol. 2009 Jan;83(1):470-8
references.pmid: 18945774
references.citation: PLoS One. 2011 Mar 28;6(3):e17969
references.pmid: 21464919
references.citation: J Virol. 2010 Oct;84(19):9879-88
references.pmid: 20660184
references.citation: Nat Struct Mol Biol. 2004 Jul;11(7):672-5
references.pmid: 15208690
references.citation: J Infect Dis. 2008 Mar 15;197(6):871-9
references.pmid: 18279072
references.citation: J Transl Med. 2011 Dec 07;9:208
references.pmid: 22152067
references.citation: Nat Rev Immunol. 2008 Aug;8(8):619-30
references.pmid: 18617886
references.citation: J Immunol. 2009 Jun 15;182(12):7763-75
references.pmid: 19494300
references.citation: J Immunol. 2007 Mar 1;178(5):2746-54
references.pmid: 17312117
references.citation: Curr HIV Res. 2011 Oct;9(7):496-504
references.pmid: 22103833
references.citation: J Immunol. 2011 Sep 1;187(5):2502-13
references.pmid: 21821798
references.citation: J Virol. 2009 Jan;83(1):88-97
references.pmid: 18945771
references.citation: Sex Health. 2006 Dec;3(4):281-6
references.pmid: 17112441
references.citation: J Virol. 1999 Jul;73(7):5497-508
references.pmid: 10364298
references.citation: Biochemistry. 1995 Aug 15;34(32):10130-8
references.pmid: 7543776
references.citation: Virology. 2008 May 25;375(1):307-14
references.pmid: 18328525
references.citation: AIDS. 2003 Dec 5;17(18):2581-91
references.pmid: 14685052
references.citation: PLoS One. 2013;8(1):e54300
references.pmid: 23342126