title: Functional avidity and IL-2/perforin production is linked to the emergence of mutations within HLA-B*5701-restricted epitopes and HIV-1 disease progression.
abstract: Viral escape from HIV-1-specific CD8(+) T cells has been demonstrated in numerous studies previously. However, the qualitative features driving the emergence of mutations within epitopes are still unclear. In this study, we aimed to distinguish whether specific functional characteristics of HLA-B*5701-restricted CD8(+) T cells influence the emergence of mutations in high-risk progressors (HRPs) versus low-risk progressors (LRPs). Single-genome sequencing was performed to detect viral mutations (variants) within seven HLA-B*5701-restricted epitopes in Gag (n = 4) and Nef (n = 3) in six untreated HLA-B*5701 subjects followed from early infection up to 7 y. Several well-characterized effector markers (IFN-γ, IL-2, MIP-1β, TNF, CD107a, and perforin) were identified by flow cytometry following autologous (initial and emerging variant/s) epitope stimulations. This study demonstrates that specific functional attributes may facilitate the outgrowth of mutations within HLA-B*5701-restricted epitopes. A significantly lower fraction of IL-2-producing cells and a decrease in functional avidity and polyfunctional sensitivity were evident in emerging epitope variants compared with the initial autologous epitopes. Interestingly, the HRPs mainly drove these differences, whereas the LRPs maintained a directed and maintained functional response against emerging epitope variants. In addition, LRPs induced improved cell-cycle progression and perforin upregulation after autologous and emerging epitope variant stimulations in contrast to HRPs. The maintained quantitative and qualitative features of the CD8(+) T cell responses in LRPs toward emerging epitope variants provide insights into why HLA-B*5701 subjects have different risks of HIV-1 disease progression.
authors.affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm S-141 86, Sweden;
authors.forename: Marcus
authors.initials: M
authors.lastname: Buggert
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Norström
authors.forename: Marco
authors.initials: M
authors.lastname: Salemi
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
authors.forename: Annika C
authors.initials: AC
authors.lastname: Karlsson
mesh_terms: D001483:Base Sequence; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018450:Disease Progression; D000939:Epitopes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D054353:Perforin / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D000939:Epitopes; D015683:Gene Products, gag; D015235:HLA-B Antigens; C484830:HLA-B*57:01 antigen; C508594:IL2 protein, human; D007376:Interleukin-2; D054353:Perforin
references.citation: Nat Med. 2007 Jan;13(1):46-53
references.pmid: 17173051
references.citation: Nat Immunol. 2012 Jun 10;13(7):691-700
references.pmid: 22683743
references.citation: PLoS Pathog. 2010 Jan 29;6(1):e1000747
references.pmid: 20126441
references.citation: Nat Med. 1997 Feb;3(2):212-7
references.pmid: 9018241
references.citation: J Immunol. 2010 May 1;184(9):5383-91
references.pmid: 20363973
references.citation: J Virol. 2004 Jul;78(13):7069-78
references.pmid: 15194783
references.citation: Immunity. 2008 Dec 19;29(6):1009-21
references.pmid: 19062316
references.citation: Cytometry A. 2011 Feb;79(2):167-74
references.pmid: 21265010
references.citation: J Exp Med. 2004 Apr 5;199(7):905-15
references.pmid: 15067030
references.citation: J Virol. 2003 Jun;77(12):6743-52
references.pmid: 12767994
references.citation: J Immunol. 2005 Jun 15;174(12):7524-30
references.pmid: 15944251
references.citation: PLoS Pathog. 2011 Feb 10;7(2):e1001273
references.pmid: 21347345
references.citation: J Virol. 2009 Mar;83(6):2743-55
references.pmid: 19116253
references.citation: Nature. 2011 May 26;473(7348):523-7
references.pmid: 21562493
references.citation: Ann Intern Med. 1997 Jun 15;126(12):946-54
references.pmid: 9182471
references.citation: Science. 1995 Dec 15;270(5243):1811-5
references.pmid: 8525373
references.citation: J Virol. 2004 Feb;78(3):1324-32
references.pmid: 14722287
references.citation: PLoS Pathog. 2010 Jan 29;6(1):e1000748
references.pmid: 20126442
references.citation: Nat Med. 2004 Aug;10(8):806-10
references.pmid: 15286782
references.citation: Nature. 2004 Dec 9;432(7018):769-75
references.pmid: 15592417
references.citation: Annu Rev Med. 2003;54:535-51
references.pmid: 12525683
references.citation: PLoS One. 2007 Feb 21;2(2):e225
references.pmid: 17311088
references.citation: J Virol. 2010 Apr;84(8):3868-78
references.pmid: 20130059
references.citation: J Immunol. 2010 Nov 1;185(9):5093-101
references.pmid: 20881189
references.citation: J Virol. 2006 Oct;80(19):9519-29
references.pmid: 16973556
references.citation: AIDS. 2010 Jun 19;24(10):1425-35
references.pmid: 20539088
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2709-14
references.pmid: 10694578
references.citation: PLoS One. 2012;7(7):e39874
references.pmid: 22792193
references.citation: Retrovirology. 2013 Dec 12;10:152
references.pmid: 24330837
references.citation: J Clin Invest. 2013 Jan;123(1):380-93
references.pmid: 23221345
references.citation: PLoS Med. 2008 May 6;5(5):e100
references.pmid: 18462013
references.citation: Nat Med. 2004 Mar;10(3):282-9
references.pmid: 14770175
references.citation: Science. 2010 Dec 10;330(6010):1551-7
references.pmid: 21051598
references.citation: AIDS. 2002 May 24;16(8):1119-29
references.pmid: 12004270
references.citation: Blood. 2011 Aug 25;118(8):2138-49
references.pmid: 21734237
references.citation: J Infect Dis. 2011 Mar 15;203(6):765-72
references.pmid: 21343146
references.citation: Immunol Rev. 2011 Jan;239(1):109-24
references.pmid: 21198668
references.citation: Science. 2007 Aug 17;317(5840):944-7
references.pmid: 17641165
references.citation: Nature. 1991 Dec 12;354(6353):453-9
references.pmid: 1721107
references.citation: Nat Immunol. 2002 Nov;3(11):1061-8
references.pmid: 12368910
references.citation: Nat Med. 1996 Apr;2(4):405-11
references.pmid: 8597949
references.citation: AIDS Res Ther. 2009 Jul 01;6:15
references.pmid: 19570221
references.citation: PLoS Pathog. 2010 May 27;6(5):e1000917
references.pmid: 20523897
references.citation: J Virol. 2012 Jan;86(2):919-29
references.pmid: 22090105
references.citation: Immunity. 2013 Mar 21;38(3):425-36
references.pmid: 23521884
references.citation: J Exp Med. 2007 Oct 1;204(10):2473-85
references.pmid: 17893201
references.citation: J Exp Med. 2001 Feb 5;193(3):375-86
references.pmid: 11157057
references.citation: J Virol. 2012 Sep;86(18):9802-16
references.pmid: 22761389
references.citation: Blood. 2006 Jun 15;107(12):4781-9
references.pmid: 16467198
references.citation: Immunity. 2010 Jan 29;32(1):91-103
references.pmid: 20096608
references.citation: J Virol. 2006 Apr;80(7):3617-23
references.pmid: 16537629
references.citation: Blood. 2009 Jun 18;113(25):6351-60
references.pmid: 19389882
references.citation: PLoS Pathog. 2011 Feb;7(2):e1002002
references.pmid: 21383976
references.citation: PLoS Genet. 2009 Dec;5(12):e1000791
references.pmid: 20041166
references.citation: Science. 2002 May 24;296(5572):1439-43
references.pmid: 12029127