title: Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection.
abstract: The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of 'exhaustion' or 'immune checkpoint' markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches.
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.|Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital, St. Gallen, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Department of Hygiene, Epidemiology & Medical Statistics, Athens University Medical School, Athens, Greece.|MRC Clinical Trials Unit at UCL Institute of Clinical Trials & Methodology, London, United Kingdom.
authors.forename: Nikos
authors.initials: N
authors.lastname: Pantazis
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.
authors.forename: Genevieve E
authors.initials: GE
authors.lastname: Martin
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hickling
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.|The Oxford Martin School, Oxford, United Kingdom.
authors.forename: Jacob
authors.initials: J
authors.lastname: Hurst
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.
authors.forename: Jodi
authors.initials: J
authors.lastname: Meyerowitz
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.|Oxford National Institute of Health Research Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Christian B
authors.initials: CB
authors.lastname: Willberg
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.|Oxford National Institute of Health Research Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Robinson
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.|Oxford National Institute of Health Research Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Brown
authors.affiliation: Brighton and Sussex University Hospitals, Brighton, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Fisher
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kinloch
authors.affiliation: MRC Clinical Trials Unit at UCL Institute of Clinical Trials & Methodology, London, United Kingdom.
authors.forename: Abdel
authors.initials: A
authors.lastname: Babiker
authors.affiliation: Division of Medicine, Wright Fleming Institute, Imperial College, London, United Kingdom.
authors.forename: Jonathan
authors.identifier: http://orcid.org/0000-0001-5696-0340
authors.initials: J
authors.lastname: Weber
authors.affiliation: Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: Nneka
authors.initials: N
authors.lastname: Nwokolo
authors.affiliation: Department of Genitourinary Medicine and Infectious Disease, Guys and St Thomas' NHS Trust, London, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Fox
authors.affiliation: Division of Medicine, Wright Fleming Institute, Imperial College, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Fidler
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.|The Oxford Martin School, Oxford, United Kingdom.|Oxford National Institute of Health Research Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Rodney
authors.initials: R
authors.lastname: Phillips
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.|The Oxford Martin School, Oxford, United Kingdom.|Oxford National Institute of Health Research Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Frater
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D015703:Antigens, CD / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology; D015415:Biomarkers / Q000032:analysis*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D044966:Anti-Retroviral Agents; D015703:Antigens, CD; D015415:Biomarkers; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000093322:Lymphocyte Activation Gene 3 Protein