title: PD-1 coinhibitory signals: the link between pathogenesis and protection.
abstract: In the majority of HIV-1 infected individuals, the adaptive immune response drives virus escape resulting in persistent viremia and a lack of immune-mediated control. The expression of negative regulatory molecules such as PD-1 during chronic HIV infection provides a useful marker to differentiate functional memory T cell subsets and the frequency of T cells with an exhausted phenotype. In addition, cell-based measurements of virus persistence equate with activation markers and the frequency of CD4 T cells expressing PD-1. High-level expression of PD-1 and its ligands PD-L1 and PD-L2 are found on hematopoietic and non-hematopoietic cells, and are upregulated by chronic antigen stimulation, Type 1 and Type II interferons (IFNs), and homeostatic cytokines. In HIV infected subjects, PD-1 levels on CD4 and CD8 T cells continue to remain high following combination anti-retroviral therapy (cART). System biology approaches have begun to elucidate signal transduction pathways regulated by PD-1 expression in CD4 and CD8 T cell subsets that become dysfunctional through chronic TCR activation and PD-1 signaling. In this review, we summarize our current understanding of transcriptional signatures and signal transduction pathways associated with immune exhaustion with a focus on recent work in our laboratory characterizing the role of PD-1 in T cell dysfunction and HIV pathogenesis. We also highlight the therapeutic potential of blocking PD-1-PD-L1 and other immune checkpoints for activating potent cellular immune responses against chronic viral infections and cancer.
authors.affiliation: Division of Infectious Diseases, Vaccine and Gene Therapy Institute-Florida (VGTI-FL), Port Saint Lucie, FL, United States.
authors.forename: Deanna A
authors.initials: DA
authors.lastname: Kulpa
authors.forename: Mariam
authors.initials: M
authors.lastname: Lawani
authors.forename: Anthony
authors.initials: A
authors.lastname: Cooper
authors.forename: Yoav
authors.initials: Y
authors.lastname: Peretz
authors.forename: Jeff
authors.initials: J
authors.lastname: Ahlers
authors.forename: Rafick-Pierre
authors.initials: RP
authors.lastname: Sékaly
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000628:therapy; D006801:Humans; D057131:Immune Evasion; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D058990:Molecular Targeted Therapy; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D049490:Systems Biology / Q000379:methods*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D061026:Programmed Cell Death 1 Receptor
keywords: PD-1 coinhibitory signals
references.citation: Bioinformatics. 2009 Nov 1;25(21):2855-6
references.pmid: 19706745
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13866-71
references.pmid: 11698646
references.citation: J Immunol. 2003 Jan 1;170(1):477-86
references.pmid: 12496434
references.citation: Nature. 2006 Feb 9;439(7077):682-7
references.pmid: 16382236
references.citation: Immunity. 2012 Dec 14;37(6):1130-44
references.pmid: 23159438
references.citation: J Immunol. 2002 Sep 15;169(6):3447-58
references.pmid: 12218168
references.citation: Nat Immunol. 2009 Jan;10(1):29-37
references.pmid: 19043418
references.citation: Nat Med. 2010 Apr;16(4):452-9
references.pmid: 20208540
references.citation: J Immunol. 2009 Jun 15;182(12):7331-41
references.pmid: 19494254
references.citation: Clin Cancer Res. 2010 Dec 15;16(24):6019-28
references.pmid: 20924130
references.citation: PLoS One. 2012;7(1):e30307
references.pmid: 22276176
references.citation: Immunology. 2012 Apr;135(4):355-63
references.pmid: 22211948
references.citation: Nature. 2001 Mar 1;410(6824):106-11
references.pmid: 11242051
references.citation: N Engl J Med. 2012 Jun 28;366(26):2455-65
references.pmid: 22658128
references.citation: Immunity. 2012 Mar 23;36(3):491-501
references.pmid: 22406268
references.citation: J Virol. 2006 Apr;80(7):3532-40
references.pmid: 16537621
references.citation: Mol Med. 2012 Oct 24;18:1169-82
references.pmid: 22777388
references.citation: EMBO J. 2005 Jul 6;24(13):2331-41
references.pmid: 15933714
references.citation: EMBO Mol Med. 2011 Oct;3(10):581-92
references.pmid: 21739608
references.citation: Immunol Rev. 2009 May;229(1):114-25
references.pmid: 19426218
references.citation: Autophagy. 2012 Apr;8(4):677-89
references.pmid: 22302009
references.citation: Science. 2009 Aug 21;325(5943):1001-5
references.pmid: 19628815
references.citation: Clin Exp Immunol. 2009 Jul;157(1):90-7
references.pmid: 19659774
references.citation: J Infect Dis. 2011 May 1;203(9):1256-63
references.pmid: 21383382
references.citation: Annu Rev Immunol. 2008;26:677-704
references.pmid: 18173375
references.citation: PLoS Pathog. 2012;8(8):e1002840
references.pmid: 22916009
references.citation: Mol Med. 2011 Mar-Apr;17(3-4):229-40
references.pmid: 21103670
references.citation: Blood. 2010 Feb 11;115(6):1280-7
references.pmid: 20007805
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12668-73
references.pmid: 22733744
references.citation: Blood. 2011 Jul 28;118(4):965-74
references.pmid: 21652684
references.citation: J Immunol. 2011 Aug 1;187(3):1113-9
references.pmid: 21697455
references.citation: Immunity. 2011 Oct 28;35(4):583-95
references.pmid: 22018468
references.citation: J Immunol. 2008 Nov 15;181(10):6738-46
references.pmid: 18981091
references.citation: J Virol. 2012 Aug;86(15):8161-70
references.pmid: 22623779
references.citation: Immunol Rev. 2008 Jun;223:317-33
references.pmid: 18613845
references.citation: N Engl J Med. 2012 Jun 28;366(26):2443-54
references.pmid: 22658127
references.citation: Cell Death Differ. 2007 Oct;14(10):1747-58
references.pmid: 17612589
references.citation: BMC Bioinformatics. 2009 Jan 26;10:34
references.pmid: 19171069
references.citation: Sci Signal. 2012 Jun 26;5(230):ra46
references.pmid: 22740686
references.citation: Nat Immunol. 2011 Jun;12(6):536-43
references.pmid: 21572431
references.citation: J Immunol. 2012 Apr 15;188(8):3734-44
references.pmid: 22427637
references.citation: Cell. 1992 Aug 21;70(4):585-93
references.pmid: 1505025
references.citation: J Infect Dis. 2009 Apr 15;199(8):1177-85
references.pmid: 19265479
references.citation: Proc Natl Acad Sci U S A. 2005 May 17;102(20):7239-44
references.pmid: 15872023
references.citation: Blood. 2008 Nov 1;112(9):3679-87
references.pmid: 18728248
references.citation: J Immunol. 2010 Apr 1;184(7):3442-9
references.pmid: 20194714
references.citation: J Exp Med. 2006 Oct 2;203(10):2281-92
references.pmid: 16954372
references.citation: Trends Immunol. 2011 Jan;32(1):1-5
references.pmid: 21190897
references.citation: Blood. 2011 May 19;117(20):5532-40
references.pmid: 21422469
references.citation: J Immunol. 2010 Jan 1;184(1):476-87
references.pmid: 19949078
references.citation: Cell Rep. 2012 May 31;1(5):472-82
references.pmid: 22763434
references.citation: Blood. 2006 Dec 1;108(12):3808-17
references.pmid: 16902147
references.citation: Nat Med. 2010 Oct;16(10):1147-51
references.pmid: 20890291
references.citation: Curr Opin HIV AIDS. 2012 Jan;7(1):17-23
references.pmid: 22134339
references.citation: Genes Dev. 2005 Sep 15;19(18):2100-10
references.pmid: 16166375
references.citation: J Virol. 2009 May;83(9):4386-94
references.pmid: 19211743
references.citation: J Virol. 2007 Apr;81(8):4215-25
references.pmid: 17287266
references.citation: J Exp Med. 2003 Jul 7;198(1):39-50
references.pmid: 12847136
references.citation: J Immunol. 2011 Jun 15;186(12):6871-85
references.pmid: 21562156
references.citation: Nature. 2006 Sep 21;443(7109):350-4
references.pmid: 16921384
references.citation: J Clin Invest. 2010 Nov;120(11):3878-90
references.pmid: 20972331
references.citation: Annu Rev Genet. 2008;42:301-34
references.pmid: 18680434
references.citation: Nat Med. 2006 Oct;12(10):1198-202
references.pmid: 16917489
references.citation: Nature. 2009 Mar 12;458(7235):206-10
references.pmid: 19078956
references.citation: Sci Signal. 2011 Sep 13;4(190):ra59
references.pmid: 21917715
references.citation: J Immunol. 2012 Feb 1;188(3):1156-67
references.pmid: 22210916
references.citation: J Exp Med. 2010 Sep 27;207(10):2175-86
references.pmid: 20819923
references.citation: J Virol. 2010 Jun;84(11):5508-19
references.pmid: 20335254
references.citation: J Immunol. 2011 Apr 1;186(7):4200-12
references.pmid: 21383243
references.citation: J Clin Invest. 2012 May;122(5):1712-6
references.pmid: 22523065
references.citation: Nat Med. 1999 Jun;5(6):677-85
references.pmid: 10371507
references.citation: Gastroenterology. 2008 Jun;134(7):1927-37, 1937.e1-2
references.pmid: 18549878
references.citation: Clin Exp Immunol. 2011 Nov;166(2):208-17
references.pmid: 21985367
references.citation: PLoS One. 2010 Sep 28;5(9):
references.pmid: 20927193
references.citation: J Virol. 2003 Apr;77(8):4911-27
references.pmid: 12663797
references.citation: Blood. 2007 Aug 1;110(3):928-36
references.pmid: 17440051
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13402-7
references.pmid: 20624978
references.citation: Blood. 2012 Oct 25;120(17):3466-77
references.pmid: 22955926
references.citation: Blood. 2011 May 5;117(18):4805-15
references.pmid: 21398582
references.citation: Nat Immunol. 2002 Nov;3(11):1061-8
references.pmid: 12368910
references.citation: Eur J Immunol. 1999 Aug;29(8):2539-50
references.pmid: 10458769
references.citation: Mol Cell Biol. 2005 Nov;25(21):9543-53
references.pmid: 16227604
references.citation: Science. 2012 Apr 27;336(6080):485-9
references.pmid: 22539724
references.citation: Curr HIV/AIDS Rep. 2008 Feb;5(1):13-9
references.pmid: 18417030
references.citation: Nat Biotechnol. 2003 Jan;21(1):89-92
references.pmid: 12483225
references.citation: Curr Opin Immunol. 2007 Aug;19(4):408-15
references.pmid: 17656078
references.citation: J Immunol. 2004 Jul 15;173(2):945-54
references.pmid: 15240681
references.citation: Immunol Rev. 2010 Jul;236:219-42
references.pmid: 20636820
references.citation: J Immunol. 2009 May 15;182(10):5891-7
references.pmid: 19414738
references.citation: J Exp Med. 2004 Sep 20;200(6):701-12
references.pmid: 15381726
references.citation: PLoS Comput Biol. 2012;8(2):e1002375
references.pmid: 22383865
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12674-9
references.pmid: 22733769
references.citation: Cell. 1998 Feb 6;92(3):401-13
references.pmid: 9476899
references.citation: J Exp Med. 2012 Jun 4;209(6):1201-17
references.pmid: 22641383
references.citation: PLoS One. 2011 Mar 07;6(3):e17621
references.pmid: 21408177
references.citation: Cell. 2006 Feb 10;124(3):459-61
references.pmid: 16469690
references.citation: Blood. 2006 Jun 15;107(12):4781-9
references.pmid: 16467198
references.citation: J Exp Med. 2000 Jul 3;192(1):63-75
references.pmid: 10880527
references.citation: AIDS. 2007 Jun 19;21(10):1379-81
references.pmid: 17545722
references.citation: J Immunol. 2011 Aug 1;187(3):1097-105
references.pmid: 21697456
references.citation: Nat Immunol. 2001 Mar;2(3):261-8
references.pmid: 11224527
references.citation: J Virol. 1996 Oct;70(10):7092-102
references.pmid: 8794355
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 17;109(3):881-6
references.pmid: 22223661
references.citation: Nat Immunol. 2011 May 29;12(7):663-71
references.pmid: 21623380
references.citation: PLoS Pathog. 2010 Jun 10;6(6):e1000947
references.pmid: 20548953
references.citation: Nat Chem Biol. 2012 Mar 18;8(5):437-46
references.pmid: 22426112
references.citation: AIDS. 2008 Oct 1;22(15):2035-8
references.pmid: 18784466
references.citation: J Exp Med. 2003 Dec 15;198(12):1909-22
references.pmid: 14676302
references.citation: Immunity. 2008 May;28(5):710-22
references.pmid: 18468462
references.citation: Nat Immunol. 2007 Nov;8(11):1246-54
references.pmid: 17906628
references.citation: J Virol. 2012 May;86(10):5533-40
references.pmid: 22398292
references.citation: Genes Dev. 2006 Dec 1;20(23):3238-43
references.pmid: 17158742
references.citation: J Virol. 2007 Sep;81(17):9249-58
references.pmid: 17567698
references.citation: J Immunol. 2008 Mar 15;180(6):3637-41
references.pmid: 18322167
references.citation: FEBS Lett. 2004 Sep 10;574(1-3):37-41
references.pmid: 15358536
references.citation: J Virol. 2007 Mar;81(6):2545-53
references.pmid: 17182670