Temporal Dynamics of CD8+ T Cell Effector Responses during Primary HIV Infection

PLoS Pathogens

Michael A. Eller¹  Chris K. Li²  Marcus Buggert³  Korey R. Demers³  George Makedonas³  Mark K. Slifka⁴  Andrew J. McMichael⁵  Nicole F. Bernard⁶  Merlin L. Robb⁷  Nilu Goonetilleke⁸  Sorachai Nitayaphan⁸  Barton F. Haynes⁹  Jean-Pierre Routy^1,10  Kathleen Rono^1,11  Leigh Anne Eller^1,11  Michael R. Betts^1,12  Lucas Maganga^1,13  Sarah J. Ratcliffe^1,13  Hannah Kibuuka^1,14 

[1] Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Karolinksa University Hospital Huddinge, Stockholm, Sweden;Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Department of Retrovirology, United States Army Medical Component, Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS), Bangkok, Thailand;Division of Hematology & Chronic Viral Illness Service, McGill University Health Centre, Montréal, Québec, Canada;Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America;Duke Human Vaccine Institute, Duke University, Durham, North Carolina, United States of America;Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, United States of America;Makerere University Walter Reed Project, Makerere University Medical School, Kampala, Uganda;Mbeya Medical Research Centre, Mbeya, Tanzania;Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, England;NDM Research Building, Old Road Campus, University of Oxford, Oxford, United Kingdom;U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America;Walter Reed Project-Kenya, Kenya Medical Research Institute, Kericho, Kenya

关键词: T cells;    Cytotoxic T cells;    HIV infections;    Memory T cells;    Viral load;    HIV;    Cloning;    Viremia;   

DOI  :  10.1371/journal.ppat.1005805

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The loss of HIV-specific CD8+ T cell cytolytic function is a primary factor underlying progressive HIV infection, but whether HIV-specific CD8+ T cells initially possess cytolytic effector capacity, and when and why this may be lost during infection, is unclear. Here, we assessed CD8+ T cell functional evolution from primary to chronic HIV infection. We observed a profound expansion of perforin+ CD8+ T cells immediately following HIV infection that quickly waned after acute viremia resolution. Selective expression of the effector-associated transcription factors T-bet and eomesodermin in cytokine-producing HIV-specific CD8+ T cells differentiated HIV-specific from bulk memory CD8+ T cell effector expansion. As infection progressed expression of perforin was maintained in HIV-specific CD8+ T cells with high levels of T-bet, but not necessarily in the population of T-betLo HIV-specific CD8+ T cells that expand as infection progresses. Together, these data demonstrate that while HIV-specific CD8+ T cells in acute HIV infection initially possess cytolytic potential, progressive transcriptional dysregulation leads to the reduced CD8+ T cell perforin expression characteristic of chronic HIV infection.

【 授权许可】

CC BY