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Peptide–MHC multimer-based monitoring of CD8 T-cells in HIV-1 infection and AIDS vaccine development

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References

  • Wherry EJ, Ahmed R. Memory CD8 T-cell differentiation during viral infection. J Virol 2004;78(11):5535-45
  • Virgin HW, Wherry EJ, Ahmed R. Redefining Chronic Viral Infection. Cell 2009;138(1):30-50
  • Belyakov IM, Ahlers JD. What role does the route of immunization play in the generation of protective immunity against mucosal pathogens? J Immunol 2009;183(11):6883-92
  • Zinkernagel RM, Doherty PC. H-2 compatibility requirement for T-cell-mediated lysis of target cells infected with lymphocytic choriomeningitis virus. Different cytotoxic T-cell specificities are associated with structures coded for in H-2K or H-2D. J Exp Med 1975;141(6):1427-36
  • Markovic SN, Nevala WK, Uhl CB, et al. A reproducible method for the enumeration of functional (cytokine producing) versus non-functional peptide-specific cytotoxic T lymphocytes in human peripheral blood. Clin Exp Immunol 2006;145(3):438-47
  • Maecker HT, Hassler J, Payne JK, et al. Precision and linearity targets for validation of an IFN gamma ELISPOT, cytokine flow cytometry, and tetramer assay using CMV peptides. BMC Immunol 2008;9:9
  • Tobery TW, Dubey SA, Anderson K, et al. A comparison of standard immunogenicity assays for monitoring HIV type 1 gag-specific T cell responses in ad5 HIV type 1 gag vaccinated human subjects. AIDS Res Hum Retroviruses 2006;22(11):1081-90
  • Michel N, Ohlschlager P, Osen W, et al. T cell response to human papillomavirus 16 E7 in mice: comparison of Cr release assay, intracellular IFN-gamma production, ELISPOT and tetramer staining. Intervirology 2002;45(4-6):290-9
  • Thakur A, Pedersen LE, Jungersen G. Immune markers and correlates of protection for vaccine induced immune responses. Vaccine 2012;30(33):4907-20
  • Plata F, Autran B, Martins LP, et al. Aids virus-specific cytotoxic lymphocytes-t in lung disorders. Nature 1987;328(6128):348-51
  • Walker BD, Chakrabarti S, Moss B, et al. HIV-specific cytotoxic lymphocytes-t in seropositive individuals. Nature 1987;328(6128):345-8
  • Riviere Y, Tanneausalvadori F, Regnault A, et al. Human immunodeficiency virus-specific cyto-toxic responses of seropositive individuals - distinct types of effector-cells mediate killing of targets expressing gag-proteins and env-proteins. J Virol 1989;63(5):2270-7
  • Castelmur I, Dipaolo C, Bachmann MF, et al. Comparison of the sensitivity of in-vivo and in-vitro assays for detection of antiviral cytotoxic t-cell activity. Cellular Immunology 1993;151(2):460-6
  • Owen JA, Allouche M, Doherty PC. Limiting dilution analysis of the specificity of influenza-immune cytotoxic T cells. Cell Immunol 1982;67(1):49-59
  • Corradin G, Etlinger HM, Chiller JM. Lymphocyte specificity to protein antigens I. Characterization of the antigen-induced in vitro T cell-dependent proliferative response with lymph node cells from primed mice. J Immunol 1977;119(3):1048-53
  • Rosenwasser LJ, Rosenthal AS. Adherent cell function in murine t lymphocyte antigen recognition i. a macrophage-dependent t cell proliferation assay in the mouse. J Immunol 1978;120(6):1991-5
  • Ogg GS, Mcmichael AJ. Quantitation of antigen-specific CD8+ T-cell responses. Immunol Lett 1999;66(1-3):77-80
  • Sun Y, Iglesias E, Samri A, et al. A systematic comparison of methods to measure HIV-1 specific CD8 T cells. J Immunol Methods 2003;272(1-2):23-34
  • Dunbar PR, Ogg GS, Chen J, et al. Direct isolation, phenotyping and cloning of low-frequency antigen-specific cytotoxic T lymphocytes from peripheral blood. Curr Biol 1998;8(7):413-16
  • Sims S, Willberg C, Klenerman P. MHC-peptide tetramers for the analysis of antigen-specific T cells. Expert Rev Vaccines 2010;9(7):765-74
  • Saade F, Gorski SA, Petrovsky N. Pushing the frontiers of T-cell vaccines: accurate measurement of human T-cell responses. Expert Rev Vaccines 2012;11(12):1459-70
  • Hobeika AC, Morse MA, Osada T, et al. Enumerating antigen-specific T-Cell responses in peripheral blood – A comparison of peptide MHC tetramer, ELISpot, and intracellular cytokine analysis. J Immunother 2005;28(1):63-72
  • Altman JD, Moss PaH, Goulder PJR, et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 1996;274(5284):94-6
  • Altman JD. Flow cytometry applications of MHC tetramers. Methods Cell Biol 2004;75:433-52
  • Meidenbauer N, Hoffmann TK, Donnenberg AD. Direct visualization of antigen-specific T cells using peptide-MHC-class I tetrameric complexes. Methods 2003;31(2):160-71
  • Guillaume P, Dojcinovic D, Luescher IF. Soluble MHC-peptide complexes: tools for the monitoring of T cell responses in clinical trials and basic research. Cancer Immun 2009;9:7
  • Luescher IF, Cerottini JC, Romero P. Photoaffinity-labeling of the t-cell receptor on cloned cytotoxic t-lymphocytes by covalent photoreactive ligand. J Biol Chem 1994;269(8):5574-82
  • Luescher IF, Vivier E, Layer A, et al. CD8 modulation of t-cell antigen receptor-ligand interactions on living cytotoxic t-lymphocytes. Nature 1995;373(6512):353-6
  • Dalporto J, Johansen TE, Catipovic B, et al. A soluble divalent class-i major histocompatibility complex molecule inhibits alloreactive t-cells at nanomolar concentrations. Proc Natl Acad Sci USA 1993;90(14):6671-5
  • Gutgemann I, Fahrer AM, Altman JD, et al. Induction of rapid T cell activation and tolerance by systemic presentation of an orally administered antigen. Immunity 1998;8(6):667-73
  • Leisner C, Loeth N, Lamberth K, et al. One-pot, mix-and-read peptide-MHC tetramers. PLoS One 2008;3(2):e1678
  • Schmidt J, Guillaume P, Irving M, et al. Reversible major histocompatibility complex I-peptide multimers containing Ni2+-nitrilotriacetic acid peptides and histidine tags improve analysis and sorting of CD8(+) T cells. J Biol Chem 2011;286(48):41723-35
  • Batard P, Peterson DA, Devevre E, et al. Dextramers: new generation of fluorescent MHC class I/peptide multimers for visualization of antigen-specific CD8(+) T cells. J Immunol Methods 2006;310(1-2):136-48
  • Rodenko B, Toebes M, Hadrup SR, et al. Generation of peptide-MHC class I complexes through UV-mediated ligand exchange. Nat Protoc 2006;1(3):1120-32
  • Schmidt J, Dojcinovic D, Guillaume P, Luescher I. Analysis, Isolation, and Activation of Antigen-Specific CD4(+) and CD8(+) T Cells by Soluble MHC-Peptide Complexes. Fron Immunol 2013;4:218
  • Newell EW, Sigal N, Bendall SC, et al. Cytometry by time-of-flight shows combinatorial cytokine expression and virus-specific cell niches within a continuum of CD8(+) T cell phenotypes. Immunity 2012;36(1):142-52
  • Bendall SC, Nolan GP, Roederer M, Chattopadhyay PK. A deep profiler’s guide to cytometry. Trends Immunol 2012;33(7):323-32
  • Bjornson ZB, Nolan GP, Fantl WJ. Single-cell mass cytometry for analysis of immune system functional states. Curr Opin Immunol 2013;25(4):484-94
  • Cheung RK, Utz PJ. Screening cytof-the next generation of cell detection. Nat Rev Rheumatol 2011;7(9):502-3
  • Haanen J, Van Oijen M, Tirion F, et al. In situ detection of virus- and tumor-specific T-cell immunity. Nat Med 2000;6(9):1056-60
  • Skinner PJ, Daniels MA, Schmidt CS, et al. Cutting edge: in situ tetramer staining of antigen-specific T cells in tissues. J Immunol 2000;165(2):613-17
  • Skinner PJ, Haase AT. In situ tetramer staining. J Immunol Methods 2002;268(1):29-34
  • Vyth-Dreese FA, Kim YH, Dellemijn TaM, et al. In situ visualization of antigen-specific T cells in cryopreserved human tissues. J Immunol Methods 2006;310(1-2):78-85
  • Li QS, Skinner PJ, Ha SJ, et al. Visualizing antigen-specific and infected cells in situ predicts outcomes in early viral infection. Science 2009;323(5922):1726-9
  • Vollers SS, Stern LJ. Class II major histocompatibility complex tetramer staining: progress, problems, and prospects. Immunology 2008;123(3):305-13
  • Reichstetter S, Ettinger RA, Liu AW, et al. Distinct T cell interactions with HLA class II tetramers characterize a spectrum of TCR affinities in the human antigen-specific T cell response. J Immunol 2000;165(12):6994-8
  • Figueiredo S, Charmeteau B, Surenaud M, et al. Memory CD8(+) T cells elicited by HIV-1 lipopeptide vaccines display similar phenotypic profiles but differences in term of magnitude and multifunctionality compared with FLU- or EBV-specific memory T cells in humans. Vaccine 2014;32(4):492-501
  • Belyakov IM, Wang J, Koka R, et al. Activating CTL precursors to reveal CTL function without skewing the repertoire by in vitro expansion. Eur J Immunol 2001;31(12):3557-66
  • Klenerman P, Cerundolo V, Dunbar RR. Tracking T cells with tetramers: new tales from new tools. Nat Rev Immunol 2002;2(4):263-72
  • Lalvani A, Brookes R, Hambleton S, et al. Rapid effector function in CD8(+) memory T cells. J Exp Med 1997;186(6):859-65
  • Rubio-Godoy V, Dutoit V, Rimoldi D, et al. Discrepancy between ELISPOT IFN-gamma secretion and binding of A2/peptide multimers to TCR reveals interclonal dissociation of CTL effector function from TCR-peptide/MHC complexes half-life. Proc Natl Acad Sci USA 2001;98(18):10302-7
  • Goulder PJR, Tang YH, Brander C, et al. Functionally inert. HIV-specific cytotoxic T lymphocytes do not play a major role in chronically infected adults and children. J Exp Med 2000;192(12):1819-31
  • Bousso P. Generation of MHC-peptide tetramers: a new opportunity for dissecting T-cell immune responses. Microbes Infect 2000;2(4):425-9
  • Xu XN, Screaton GR. MHC/peptide tetramer-based studies of T cell function. J Immunol Methods 2002;268(1):21-8
  • Davis MM, Altman JD, Newell EW. Interrogating the repertoire: broadening the scope of peptide-MHC multimer analysis. Nat Rev Immunol 2011;11(8):551-8
  • Fytili P, Dalekos GN, Schlaphoff V, et al. Cross-genotype-reactivity of the immunodominant HCVCD8 T-cell epitope NS3-1073. Vaccine 2008;26(31):3818-26
  • Llano A, Frahm N, Brander C. How to Optimally Define Optimal Cytotoxic T Lymphocyte Epitopes in HIV Infection? HIV Molecular Immunology 2009;3-24
  • Spiegel HML, Ogg GS, Defalcon E, et al. Human immunodeficiency virus type 1-and cytomegalovirus-specific cytotoxic T lymphocytes can persist at high frequency for prolonged periods in the absence of circulating peripheral CD4(+) T cells. J Virol 2000;74(2):1018-22
  • Townsend ARM, Rothbard J, Gotch FM, et al. The epitopes of influenza nucleoprotein recognized by cytotoxic lymphocytes-t can be defined with short synthetic peptides. Cell 1986;44(6):959-68
  • Bakker AH, Hoppes R, Linnemann C, et al. Conditional MHC class I ligands and peptide exchange technology for the human MHC gene products HLA-A1, -A3, -A11 and -B7. Proc Natl Acad Sci USA 2008;105(10):3825-30
  • Shacklett BL, Beadle TJ, Pacheco PA, et al. Isolation of cytomegalovirus-specific cytotoxic T-lymphocytes from gut-associated lymphoid tissue (GALT) of HIV type 1-infected subjects. AIDS Res Hum Retroviruses 2000;16(12):1157-62
  • Monti P, Scirpoli M, Maffi P, et al. Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells. J Clin Invest 2008;118(5):1806-14
  • Bridgeman A, Roshorm Y, Lockett LJ, et al. Ovine atadenovirus, a novel and highly immunogenic vector in prime-boost studies of a candidate HIV-1 vaccine. Vaccine 2009;28(2):474-83
  • Earl PL, Cotter C, Moss B, et al. Design and evaluation of multi-gene, multi-clade HIV-1 MVA vaccines. Vaccine 2009;27(42):5885-95
  • Lecuroux C, Girault I, Urrutia A, et al. Identification of a particular HIV-specific CD8(+) T-cell subset with a CD27(+) CD45RO(-)/RA(+) phenotype and memory characteristics after initiation of HAART during acute primary HIV infection. Blood 2009;113(14):3209-17
  • Koido S, Hara E, Homma S, et al. Dendritic/pancreatic carcinoma fusions for clinical use: comparative functional analysis of healthy- versus patient-derived fusions. Clin Immunol 2010;135(3):384-400
  • Sauce D, Elbim C, Appay V. Monitoring cellular immune markers in HIV infection: from activation to exhaustion. Current Opinion in Hiv and Aids 2013;8(2):125-31
  • Moir S, Chun TW, Fauci AS. Pathogenic Mechanisms of HIV Disease. In: Annual Review of Pathology: Mechanisms of Disease, Vol 6. Abbas AK, Galli SJ, Howley PM, (Editors) 2011. p. 223-48
  • Koup RA, Safrit JT, Cao YZ, et al. Temporal association of cellular immune-responses with the initial control of viremia in primary human-immunodeficiency-virus type-1 syndrome. J Virol 1994;68(7):4650-5
  • Borrow P, Lewicki H, Hahn BH, et al. Virus-specific cd8+ cytotoxic t-lymphocyte activity associated with control of viremia in primary human-immunodeficiency-virus type-1 infection. J Virol 1994;68(9):6103-10
  • Jin X, Bauer DE, Tuttleton SE, et al. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 1999;189(6):991-8
  • Saez-Cirion A, Lacabaratz C, Lambotte O, et al. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci USA 2007;104(16):6776-81
  • Schmitz JE, Kuroda MJ, Santra S, et al. Control of viremia in simian immunodeficiency virus infection by CD8(+) lymphocytes. Science 1999;283(5403):857-60
  • Belyakov IM, Ahlers JD. Mucosal immunity and HIV-1 infection: applications for mucosal AIDS vaccine development. Curr Top Microbiol Immunol 2012;354:157-79
  • Karpenko LI, Bazhan SI, Antonets DV, Belyakov IM. Novel approaches in polyepitope T-cell vaccine development against HIV-1. Expert Rev Vaccines 2014;13(1):155-73
  • Veazey RS, Lifson JD, Schmitz JE, et al. Dynamics of Simian immunodeficiency virus-specific cytotoxic T-cell responses in tissues. J Med Primatol 2003;32(4-5):194-200
  • Cromwell MA, Carville A, Mansfield K, et al. SIV-Specific CD8+T Cells are Enriched in Female Genital Mucosa of Rhesus Macaques and Express Receptors for Inflammatory Chemokines. Am J Reprod Immunol 2011;65(3):242-7
  • Schmitz JE, Veazey RS, Kuroda MJ, et al. Simian immunodeficiency virus (SIV)-specific cytotoxic T lymphocytes in gastrointestinal tissues of chronically SIV-infected rhesus monkeys. Blood 2001;98(13):3757-61
  • Wilson JDK, Ogg GS, Allen RL, et al. Direct visualization of HIV-1-specific cytotoxic T lymphocytes during primary infection. Aids 2000;14(3):225-33
  • Ogg GS, Jin X, Bonhoeffer S, et al. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 1998;279(5359):2103-6
  • Wilson JDK, Ogg GS, Allen RL, et al. Oligoclonal expansions of CD8(+) T cells in chronic HIV infection are antigen specific. J Exp Med 1998;188(4):785-90
  • Ogg GS, Kostense S, Klein MR, et al. Longitudinal phenotypic analysis of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes: correlation with disease progression. J Virol 1999;73(11):9153-60
  • Betts MR, Ambrozak DR, Douek DC, et al. Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: relationship to viral load in untreated HIV infection. J Virol 2001;75(24):11983-91
  • Buseyne F, Burgard M, Teglas JP, et al. Early HIV-specific cytotoxic T lymphocytes and disease progression in children born to HIV-infected mothers. AIDS Res Hum Retroviruses 1998;14(16):1435-44
  • Aldhous MC, Watret KC, Mok JYQ, et al. Cytotoxic t-lymphocyte activity and cd8 subpopulations in children at risk of hiv-infection. Clin Exp Immunol 1994;97(1):61-7
  • Mcfarland EJ, Harding PA, Luckey D, et al. High-frequency of gag-specific and envelope-specific cytotoxic t-lymphocyte precursors in children with vertically acquired human-immunodeficiency-virus type-1 infection. J Infect Dis 1994;170(4):766-74
  • Walker CM, Moody DJ, Stites DP, Levy JA. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 1986;234(4783):1563-6
  • Yang OO, Kalams SA, Trocha A, et al. Suppression of human immunodeficiency virus type 1 replication by CD8(+) cells: evidence for HLA class I-restricted triggering of cytolytic and noncytolytic mechanisms. J Virol 1997;71(4):3120-8
  • Klein MR, Vanbaalen CA, Holwerda AM, et al. Kinetics of gag-specific cytotoxic t-lymphocyte responses during the clinical course of hiv-1 infection - a longitudinal analysis of rapid progressors and long-term asymptomatics. J Exp Med 1995;181(4):1365-72
  • Klein MR, Van Der Burg SH, Pontesilli O, Miedema F. Cytotoxic T lymphocytes in HIV-1 infection: a killing paradox? Immunol Today 1998;19(7):317-24
  • Borrow P, Lewicki H, Wei XP, et al. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med 1997;3(2):205-11
  • Gea-Banacloche JC, Migueles SA, Martino L, et al. Maintenance of large numbers of virus-specific CD8(+) T cells in HIV-infected progressors and long-term nonprogressors. J Immunol 2000;165(2):1082-92
  • Addo MM, Yu XG, Rathod A, et al. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J Virol 2003;77(3):2081-92
  • Betts MR, Nason MC, West SM, et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8(+) T cells. Blood 2006;107(12):4781-9
  • Belyakov IM, Kuznetsov VA, Kelsall B, et al. Impact of vaccine-induced mucosal high-avidity CD8(+)CTLs in delay of AIDS viral dissemination from mucosa. Blood 2006;107(8):3258-64
  • Propato A, Schiaffella E, Vicenzi E, et al. Spreading of HIV-specific CD8(+) T-cell repertoire in long-term nonprogressors and its role in the control of viral load and disease activity. Hum Immunol 2001;62(6):561-76
  • Frahm N, Korber BT, Adams CM, et al. Consistent cytotoxic-T-lymphocyte targeting of immunodominant regions in human immunodeficiency virus across multiple ethnicities. J Virol 2004;78(5):2187-200
  • Goulder PJR, Altfeld MA, Rosenberg ES, et al. Substantial differences in specificity of HIV-specific cytotoxic T cells in acute and chronic HIV infection. J Exp Med 2001;193(2):181-93
  • Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006;439(7077):682-7
  • Zajac AJ, Blattman JN, Murali-Krishna K, et al. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 1998;188(12):2205-13
  • Saez-Cirion A, Sinet M, Shin SY, et al. Heterogeneity in HIV Suppression by CD8 T Cells from HIV Controllers: association with Gag-Specific CD8 T Cell Responses. J Immunol 2009;182(12):7828-37
  • Zimmerli SC, Harari A, Cellerai C, et al. HIV-1-specific IFN-gamma/IL-2-secreting CD8 T cells support CD4-independent proliferation of HIV-1-specific CD8 T cells. Proc Natl Acad Sci USA 2005;102(20):7239-44
  • Jin X, Ogg G, Bonhoeffer S, et al. An antigenic threshold for maintaining human immunodeficiency virus type 1-specific cytotoxic T lymphocytes. Molecular Medicine 2000;6(9):803-9
  • Nehete PN, Lewis DE, Tang DN, et al. Presence of HLA-C-restricted cytotoxic T-lymphocyte responses in long-term nonprogressors infected with human immunodeficiency virus. Viral Immunol 1998;11(3):119-29
  • Migueles SA, Laborico AC, Shupert WL, et al. HIV-specific CD8(+) T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 2002;3(11):1061-8
  • Shin H, Wherry EJ. CD8 T cell dysfunction during chronic viral infection. Curr Opin Immunol 2007;19(4):408-15
  • Blank C, Kuball J, Voelkl S, et al. Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro. Int J Cancer 2006;119(2):317-27
  • Yamamoto R, Nishikori M, Kitawaki T, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood 2008;111(6):3220-4
  • Sakuishi K, Apetoh L, Sullivan JM, et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 2010;207(10):2187-94
  • Gallimore A, Glithero A, Godkin A, et al. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I peptide complexes. J Exp Med 1998;187(9):1383-93
  • Appay V, Nixon DF, Donahoe SM, et al. HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 2000;192(1):63-75
  • Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006;443(7109):350-4
  • Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8(+) T cells leads to reversible immune dysfunction. Nat Med 2006;12(10):1198-202
  • Urbani S, Amadei B, Tola D, et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 2006;80(22):11398-403
  • Boni C, Fisicaro P, Valdatta C, et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 2007;81(8):4215-25
  • Chang J, Srikiatkhachorn A, Braciale TJ. Visualization and characterization of respiratory syncytial virus F-specific CD8(+) T cells during experimental virus infection. J Immunol 2001;167(8):4254-60
  • Xiong YL, Luscher MA, Altman JD, et al. Simian immunodeficiency virus (SIV) infection of a rhesus macaque induces SIV-specific CD8(+) T cells with a defect in effector function that is reversible on extended interleukin-2 incubation. J Virol 2001;75(6):3028-33
  • Welsh RM. Assessing CD8 T cell number and dysfunction in the presence of antigen. J Exp Med 2001;193(5):F19-22
  • Wherry EJ. T cell exhaustion. Nat Immunol 2011;12(6):492-9
  • Streeck H, Brumme ZL, Anastario M, et al. Antigen load and viral sequence diversification determine the functional profile of HIV-1-specific CD8(+) T cells. PLoS Med 2008;5(5):790-804
  • Mueller SN, Ahmed R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc Natl Acad Sci USA 2009;106(21):8623-8
  • Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol 2005;6(4):353-60
  • Khaitan A, Unutmaz D. Revisiting immune exhaustion during HIV infection. Curr HIV/AIDS Rep 2011;8(1):4-11
  • Youngblood B, Wherry EJ, Ahmed R. Acquired transcriptional programming in functional and exhausted virus-specific CD8 T cells. Curr Opin HIV AIDS 2012;7(1):50-7
  • Kulpa DA, Lawani M, Cooper A, et al. PD-1 coinhibitory signals: the link between pathogenesis and protection. Semin Immunol 2013;25(3):219-27
  • Hofmeyer KA, Jeon H, Zang XX. The PD-1/PD-L1 (B7-H1) Pathway in Chronic Infection-Induced Cytotoxic T Lymphocyte Exhaustion. J Biomed Biotechnol 2011;2011:451694
  • Porichis F, Kaufmann DE. Role of PD-1 in HIV pathogenesis and as target for therapy. Curr HIV/AIDS Rep 2012;9(1):81-90
  • Zhang JY, Zhang Z, Wang XC, et al. PD-1 up-regulation is correlated with HIV-specific memory CD8(+) T-cell exhaustion in typical progressors, but not in long-terrn nonprogressors. Blood 2007;109(11):4671-8
  • Fisicaro P, Valdatta C, Massari M, et al. Antiviral Intrahepatic T-Cell Responses Can Be Restored by Blocking Programmed Death-1 Pathway in Chronic Hepatitis B. Gastroenterology 2010;138(2):682-U348
  • Petrovas C, Price DA, Mattapallil J, et al. SIV-specific CD8(+) T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection. Blood 2007;110(3):928-36
  • Kaufmann DE, Walker BD. Programmed death-1 as a factor in immune exhaustion and activation in HIV infection. Curr Opin HIV AIDS 2008;3(3):362-7
  • D’souza M, Fontenot AP, Mack DG, et al. Programmed death 1 expression on HIV-specific CD4(+) T cells is driven by viral replication and associated with T cell dysfunction. J Immunol 2007;179(3):1979-87
  • Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192(7):1027-34
  • Carter LL, Fouser LA, Jussif J, et al. PD-1: PD-L inhibitory pathway affects both CD4(+)and CD8(+) T cells and is overcome by IL-2. Eur J Immunol 2002;32(3):634-43
  • Petrovas C, Casazza JP, Brenchley JM, et al. PD-1 is a regulator of virus-specific CD8(+) T cell survival in HIV infection. J Exp Med 2006;203(10):2281-92
  • Velu V, Titanji K, Zhu BG, et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 2009;458(7235):206-U205
  • Seung E, Dudek TE, Allen TM, et al. PD-1 Blockade in Chronically HIV-1-Infected Humanized Mice Suppresses Viral Loads. PLoS One 2013;8(10):e77780
  • Raziorrouh B, Schraut W, Gerlach T, et al. The Immunoregulatory Role of CD244 in Chronic Hepatitis B Infection and its Inhibitory Potential on Virus-Specific CD8+ T-cell Function. Hepatology 2010;52(6):1934-47
  • Bengsch B, Seigel B, Ruhl M, et al. Coexpression of PD-1, 2B4, CD160 and KLRG1 on Exhausted HCV-Specific CD8+ T Cells Is Linked to Antigen Recognition and T Cell Differentiation. PLoS Pathog 2010;6(6):e1000947
  • Shankar EM, Che KF, Messmer D, et al. Expression of a Broad Array of Negative Costimulatory Molecules and Blimp-1 in T Cells following Priming by HIV-1 Pulsed Dendritic Cells. Molecular Medicine 2011;17(3-4):229-40
  • Blackburn SD, Crawford A, Shin H, et al. Tissue-Specific Differences in PD-1 and PD-L1 Expression during Chronic Viral Infection: implications for CD8 T-Cell Exhaustion. J Virol 2010;84(4):2078-89
  • Yamamoto T, Price DA, Casazza JP, et al. Surface expression patterns of negative regulatory molecules identify determinants of virus-specific CD8(+) T-cell exhaustion in HIV infection. Blood 2011;117(18):4805-15
  • Ha SJ, Mueller SN, Wherry EJ, et al. Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection. J Exp Med 2008;205(3):543-55
  • Snyder JT, Alexander-Miller MA, Berzofsky JA, Belyakov IM. Molecular mechanisms and biological significance of CTL avidity. Curr HIV Res 2003;1(3):287-94
  • Belyakov IM, Isakov D, Zhu Q, et al. A novel functional CTL avidity/activity compartmentalization to the site of mucosal immunization contributes to protection of macaques against simian/human immunodeficiency viral depletion of mucosal CD4(+) T cells. J Immunol 2007;178(11):7211-21
  • Yee C, Savage PA, Lee PP, et al. Isolation of high avidity melanoma-reactive CTL from heterogeneous populations using peptide-MHC tetramers. J Immunol 1999;162(4):2227-34
  • Dzutsev AH, Belyakov IM, Isakov DV, et al. Avidity of CD8 T cells sharpens immunodominance. Int Immunol 2007;19(4):497-507
  • Bullock TNJ, Mullins DW, Colella TA, Engelhard VH. Manipulation of avidity to improve effectiveness of adoptively transferred CD8(+) T cells for melanoma immunotherapy in human MHC class I-transgenic mice. J Immunol 2001;167(10):5824-31
  • Derby MA, Wang J, Margulies DT, Berzofsky JA. Two intermediate-avidity cytotoxic T lymphocyte clones with a disparity between functional avidity and MHC tetramer staining. Int Immunol 2001;13(6):817-24
  • Echchakir H, Dorothee G, Vergnon I, et al. Cytotoxic T lymphocytes directed against a tumor-specific mutated antigen display similar HLA tetramer binding but distinct functional avidity and tissue distribution. Proc Natl Acad Sci USA 2002;99(14):9358-63
  • Cawthon AG, Lu HP, Alexander-Miller MA. Peptide requirement for CTL activation reflects the sensitivity to CD3 engagement: correlation with CD8 alpha beta versus CD8 alpha alpha expression. J Immunol 2001;167(5):2577-84
  • Belyakov IM, Berzofsky JA. Immunobiology of mucosal HIV infection and the basis for development of a new generation of mucosal AIDS vaccines. Immunity 2004;20(3):247-53
  • Berzofsky JA, Ahlers JD, Belyakov IM. Strategies for designing and optimizing new generation vaccines. Nat Rev Immunol 2001;1(3):209-19
  • Decrausaz L, Revaz V, Bobst M, et al. Induction of human papillomavirus oncogene-specific CD8 T-cell effector responses in the genital mucosa of vaccinated mice. Int J Cancer 2010;126(10):2469-78
  • Koup RA, Douek DC. Vaccine Design for CD8 T Lymphocyte Responses. Cold Spring Harbor Perspectives in Medicine 2011;1(1):a007252
  • Mudd PA, Martins MA, Ericsen AJ, et al. Vaccine-induced CD8(+) T cells control AIDS virus replication. Nature 2012;491(7422):129-U152
  • Hulot SL, Cale EM, Korber BT, Letvin NL. Vaccine-Induced CD8(+) T Lymphocytes of Rhesus Monkeys Recognize Variant Forms of an HIV Epitope but Do Not Mediate Optimal Functional Activity. J Immunol 2011;186(10):5663-74
  • Vojnov L, Martins MA, Bean AT, et al. The Majority of Freshly Sorted Simian Immunodeficiency Virus (SIV)-Specific CD8(+) T Cells Cannot Suppress Viral Replication in SIV-Infected Macrophages. J Virol 2012;86(8):4682-7
  • Hong JJ, Reynolds MR, Mattila TL, et al. Localized Populations of CD8(low/-) MHC Class I Tetramer(+) SIV-Specific T Cells in Lymphoid Follicles and Genital Epithelium. PLoS One 2009;4(1):e4131
  • Mascola JR, Lewis MG, Vancott TC, et al. Cellular immunity elicited by human immunodeficiency virus type 1/simian immunodeficiency virus DNA vaccination does not augment the sterile protection afforded by passive infusion of neutralizing antibodies. J Virol 2003;77(19):10348-56
  • Novitsky V, Rybak N, Mclane MF, et al. Identification of human immunodeficiency virus type 1 subtype C Gag-, Tat-, Rev-, and Nef-specific Elispot-based cytotoxic T-lymphocyte responses for AIDS vaccine design. J Virol 2001;75(19):9210-28
  • Westrop SJ, Grageda N, Imami N. Novel approach to recognition of predicted HIV-1 Gag B*3501-restricted CD8 T-cell epitopes by HLA-B*3501(+) patients: Confirmation by quantitative ELISpot analyses and characterisation using multimers. J Immunol Methods 2009;341(1-2):76-85
  • Livingston BD, Newman M, Crimi C, et al. Optimization of epitope processing enhances immunogenicity of multiepitope DNA vaccines. Vaccine 2001;19(32):4652-60
  • Rodriguez F, Harkins S, Redwine JM, et al. CD4(+) T cells induced by a DNA vaccine: immunological consequences of epitope-specific lysosomal targeting. J Virol 2001;75(21):10421-30
  • Goldoni AL, Maciel MJr, Rigato PO, et al. Mucosal and systemic anti-GAG immunity induced by neonatal immunization with HIV LAMP/gag DNA vaccine in mice. Immunobiology 2011;216(4):505-12
  • Rigato PO, Maciel M, Goldoni AL, et al. Immunization of neonatal mice with LAMP/p55 HIV gag DNA elicits robust immune responses that last to adulthood. Virology 2010;406(1):37-47
  • Peters C, Peng XH, Douven D, et al. The induction of HIV gag-specific CD8(+) T cells in the spleen and gut-associated lymphoid tissue by parenteral or mucosal immunization with recombinant Listeria monocytogenes HIV gag. J Immunol 2003;170(10):5176-87
  • Caivano A, Doria-Rose NA, Buelow B, et al. HIV-1 Gag p17 presented as virus-like particles on the E2 scaffold from Geobacillus stearothermophilus induces sustained humoral and cellular immune responses in the absence of IFN gamma production by CD4+T cells. Virology 2010;407(2):296-305
  • Belyakov IM, Wyatt LS, Ahlers JD, et al. Induction of a mucosal cytotoxic T-lymphocyte response by intrarectal immunization with a replication-deficient recombinant vaccinia virus expressing human immunodeficiency virus 89.6 envelope protein. J Virol 1998;72(10):8264-72
  • Roshorm Y, Hong JP, Kobayashi N, et al. Novel HIV-1 clade B candidate vaccines designed for HLA-B*5101(+) patients protected mice against chimaeric ecotropic HIV-1 challenge. Eur J Immunol 2009;39(7):1831-40
  • Ratto-Kim S, Currier JR, Cox JH, et al. Heterologous Prime-Boost Regimens Using rAd35 and rMVA Vectors Elicit Stronger Cellular Immune Responses to HIV Proteins Than Homologous Regimens. PLoS One 2012;7(9):e45840
  • Shen YJ, Shephard E, Douglass N, et al. A novel candidate HIV vaccine vector based on the replication deficient Capripoxvirus, Lumpy skin disease virus (LSDV). Virol J 2011;8:265
  • Belyakov IM, Derby MA, Ahlers JD, et al. Mucosal immunization with HIV-1 peptide vaccine induces mucosal and systemic cytotoxic T lymphocytes and protective immunity in mice against intrarectal recombinant HIV-vaccinia challenge. Proc Natl Acad Sci USA 1998;95(4):1709-14
  • Belyakov IM, Hel Z, Kelsall B, et al. Mucosal AIDS vaccine reduces disease and viral load in gut reservoir and blood after mucosal infection of macaques. Nat Med 2001;7(12):1320-6
  • Strbo N, Vaccari M, Pahwa S, et al. Gp96(SIV)Ig immunization induces potent polyepitope specific, multifunctional memory responses in rectal and vaginal mucosa. Vaccine 2011;29(14):2619-25
  • Kaufman DR, Liu JY, Carville A, et al. Trafficking of antigen-specific CD8(+) T lymphocytes to mucosal surfaces following intramuscular vaccination. J Immunol 2008;181(6):4188-98
  • Liard C, Munier S, Arias M, et al. Targeting of HIV-p24 particle-based vaccine into differential skin layers induces distinct arms of the immune responses. Vaccine 2011;29(37):6379-91
  • Korsholm KS, Karlsson I, Tang ST, et al. Broadening of the T-Cell Repertoire to HIV-1 Gag p24 by Vaccination of HLA-A2/DR Transgenic Mice with Overlapping Peptides in the CAF05 Adjuvant. PLoS One 2013;8(5):e63575
  • Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. The Lancet 2008;372(9653):1881-93
  • Mcelrath MJ, De Rosa SC, Moodie Z, et al. HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case–cohort analysis. The Lancet 2008;372(9653):1894-905
  • Hansen SG, Piatak M, Ventura AB, et al. Immune clearance of highly pathogenic SIV infection. Nature 2013;502(7469):100
  • De Rosa SC. Vaccine applications of flow cytometry. Methods 2012;57(3):383-91
  • Ru ZT, Xiao WJ, Pajot A, et al. Development of a Humanized HLA-A2.1/DP4 Transgenic Mouse Model and the Use of This Model to Map HLA-DP4-Restricted Epitopes of HBV Envelope Protein. PLoS One 2012;7(3):e32247
  • Taneja V, David CS. HLA Transgenic mice as humanized mouse models of disease and immunity. J Clin Invest 1998;101(5):921-6
  • Karpenko LI, Ilyichev AA, Eroshkin AM, et al. Combined virus-like particle-based polyepitope DNA/protein HIV-1 vaccine - Design, immunogenicity and toxicity studies. Vaccine 2007;25(21):4312-23
  • Bazhan SI, Belavin PA, Seregin SV, et al. Designing and engineering of DNA-vaccine construction encoding multiple CTL-epitopes of major HIV-1 antigens. Vaccine 2004;22(13-14):1672-82
  • Bazhan SI, Karpenko LI, Lebedev LR, et al. A synergistic effect of a combined bivalent DNA-protein anti-HIV-1 vaccine containing multiple T- and B-cell epitopes of HIV-1 proteins. Mol Immunol 2008;45(3):661-9
  • Karpenko LI, Bazhan SI, Eroshkin AM, et al. CombiHIVvac vaccine which contains polyepitope B and T- cell immunogens of HIV-1. Dokl Biochem Biophys 2007;413:65-7

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