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Stanford BIO 230 - Study Notes

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PD-1 expression on HIV-specific T cells isassociated with T-cell exhaustion and diseaseprogressionCheryl L. Day1,2,3*, Daniel E. Kaufmann2*, Photini Kiepiela1, Julia A. Brown4, Eshia S. Moodley1, Sharon Reddy1,Elizabeth W. Mackey2, Joseph D. Miller5, Alasdair J. Leslie3, Chantal DePierres1, Zenele Mncube1,Jaikumar Duraiswamy5, Baogong Zhu4, Quentin Eichbaum2, Marcus Altfeld2, E. John Wherry6,Hoosen M. Coovadia1, Philip J. R. Goulder1,2,3, Paul Klenerman3, Rafi Ahmed5, Gordon J. Freeman4& Bruce D. Walker1,2,7Functional impairment of T cells is characteristic of many chronicmouse and human viral infections. The inhibitory receptor pro-grammed death 1 (PD-1; also known as PDCD1), a negativeregulator of activated T cells1–4, is markedly upregulated on thesurface of exhausted virus-specific CD8 T cells in mice5. Blockadeof this pathway using antibodies against the PD ligand 1 (PD-L1,also known as CD274) restores CD8 T-cell function and reducesviral load5. To investigate the role of PD-1 in a chronic human viralinfection, we examined PD-1 expression on human immuno-deficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infectedpeople who were naive to anti-HIV treatments, using ten majorhistocompatibility complex (MHC) class I tetramers specific forfrequently targeted epitopes. Here we report that PD-1 is signifi-cantly upregulated on these cells, and expression correlates withimpaired HIV-specific CD8 T-cell function as well as predictors ofdisease progression: positively with plasma viral load and inverselywith CD4 T-cell count. PD-1 expression on CD4 T cells likewiseshowed a positive correlation with viral load and an inversecorrelation with CD4 T-cell count, and blockade of the pathwayaugmented HIV-specific CD4 and CD8 T-cell function. These dataindicate that the immunoregulatory PD-1/PD-L1 pathway isoperative during a persistent viral infection in humans, and definea reversible defect in HIV-specific T-cell function. Moreover, thispathway of reversible T-cell impairment provides a potentialtarget for enhancing the function of exhausted T cells in chronicHIV infection.Recent evidence from experimental lymphocytic choriomeningitisvirus (LCMV) infection indicates a crucial role of the PD-1/PD-L1pathway in inhibiting the function of virus-specific CD8 T cells inchronic viral infections in mice5. To address the potential role of thispathway in a chronic human viral infection associated with persistentviraemia and impaired T-cell function6–13, we examined peripheralblood from a cohort14of over 500 people with chronic untreated HIVinfection in KwaZulu Natal Province in South Africa, where sero-prevalence rates are in excess of 30% in certain age groups.A panel of ten MHC class I tetramers—based on prevalent humanleukocyte antigen (HLA) alleles and frequently targeted HIV-1 cladeC epitopes14—was synthesized (Supplementary Table 1), allowing thedirect visualization of surface PD-1 expression on tetramer-positive(tetramerþ) cells (Fig. 1a). A subset of 71 people naive for anti-retroviral therapy was studied on the basis of expression of relevantHLA alleles, and a total of 126 individual tetramer responses wereexamined (Fig. 1b). PD-1 expression was readily apparent on thesetetramerþcells, and was significantly higher than in the total CD8 T-cell population (P , 0.0001). In turn, PD-1 expression on bothtetramerþCD8 T cells and the total CD8 T-cell population wassignificantly higher than in HIV-seronegative controls. Significantlyless PD-1 was expressed on cytomegalovirus (CMV)-specific cellscompared with HIV-specific CD8 T cells (P ¼ 0.0002), whereas PD-1expression on cells specific for a single lytic Epstein–Barr virus (EBV)epitope tested was also at high levels.PD-1 expression was also analysed on CMV-specific, EBV-specificand vaccinia-virus-specific CD8 T cells from HIV-seronegative con-trols, and found to be intermediate on CMV-specific cells, high for alytic EBV epitope, and low on vaccinia-virus-specific CD8 T cells in18 healthy individuals (Fig. 1c), indicating a relationship betweenongoing antigen exposure andPD-1expression.HighPD-1expression on HIV-specific CD8 T cells was unique as we did notsee upregulation of the inhibitory receptor CTLA-4 (cyt otoxicT-lymphocyte-associated protein 4; data no t shown), consistentwith previous reports15.Next, we determined whether there was evidence for epitope-specific differences in PD-1 expression. Each HIV tetramer was usedto stain peripheral blood mononuclear cells (PBMCs) from 3 to 29individuals of the appropriate HLA type, revealing a range of PD-1expression levels on tetramerþcells (Fig. 1d); for a given epitope, themedian percentage of PD-1-expressing tetramerþcells ranged from68% to 94% (Fig. 1e). Of the 71 people examined, 16 individualshad multiple tetramer responses—13 of whom showed differentpatterns of PD-1 expression depending on the epitope (Fig. 1f).These data indicate that PD-1 may be differentially expressed oncontemporaneous epitope-specific CD8 T cells from a single person,perhaps consistent with data indicating epitope-specific differencesin antiviral efficacy16–18.Because HIV-specific CD8 T cells also show impaired proliferativecapacity6,7, we stimulated carboxyfluorescein diacetate succinimidylLETTERS1HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu Natal, Durban 4013, South Africa.2Partners AIDS Research Center, MassachusettsGeneral Hospital and Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115, USA.3Nuffield Department of Medicine, The Peter Medawar Building forPathogen Research, Oxford University, Oxford OX1 3SY, UK.4Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School,Boston, Massachusetts 02115, USA.5Emory Vaccine Center and Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.6Immunology Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.7Howard Hughes Medical Institute, Chevy Chase, Maryland 20185, USA.*These authors contributed equally to this work.Vol 443|21 September 2006|doi:10.1038/nature05115350© 2006 Nature Publishing Groupester (CFSE)-labelled PBMC with HIV peptides for 6 days to analyseHIV-specific CD8 T-cell proliferation in relation to PD-1 expressionon HIV tetramerþcells (Supplementary Fig. 1). We found a signifi-cant inverse correlation between the percentage of proliferating


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