title: Temporal Dynamics of CD8+ T Cell Effector Responses during Primary HIV Infection.
abstract: 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.
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Korey R
authors.initials: KR
authors.lastname: Demers
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Makedonas
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Karolinksa University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Buggert
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.|Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eller
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Ratcliffe
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, England.
authors.forename: Nilu
authors.initials: N
authors.lastname: Goonetilleke
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, England.
authors.forename: Chris K
authors.initials: CK
authors.lastname: Li
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.|Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, United States of America.
authors.forename: Leigh Anne
authors.initials: LA
authors.lastname: Eller
authors.affiliation: Walter Reed Project-Kenya, Kenya Medical Research Institute, Kericho, Kenya.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Rono
authors.affiliation: Mbeya Medical Research Centre, Mbeya, Tanzania.
authors.forename: Lucas
authors.initials: L
authors.lastname: Maganga
authors.affiliation: Department of Retrovirology, United States Army Medical Component, Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS), Bangkok, Thailand.
authors.forename: Sorachai
authors.initials: S
authors.lastname: Nitayaphan
authors.affiliation: Makerere University Walter Reed Project, Makerere University Medical School, Kampala, Uganda.
authors.forename: Hannah
authors.initials: H
authors.lastname: Kibuuka
authors.affiliation: Division of Hematology & Chronic Viral Illness Service, McGill University Health Centre, Montréal, Québec, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Slifka
authors.affiliation: Duke Human Vaccine Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: NDM Research Building, Old Road Campus, University of Oxford, Oxford, United Kingdom.
authors.forename: Andrew J
authors.identifier: 0000-0002-9101-7478
authors.initials: AJ
authors.lastname: McMichael
authors.affiliation: Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Bernard
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.|Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, United States of America.
authors.forename: Merlin L
authors.initials: ML
authors.lastname: Robb
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D002908:Chronic Disease; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D008875:Middle Aged; D054353:Perforin / Q000276:immunology; D020825:T-Box Domain Proteins / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D054353:Perforin