title: Cooperativity of HIV-Specific Cytolytic CD4 T Cells and CD8 T Cells in Control of HIV Viremia.
abstract: CD4+ T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4+ T cell functions beyond helper effects have been described, and a role for cytolytic CD4+ T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4+ T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4+ T cells revealed a distinct transcriptional signature compared to Th1 CD4+ cells but shared similar features with HIV-specific cytolytic CD8+ T cells. Furthermore, HIV-specific cytolytic CD4+ T cells showed comparable killing activity relative to HIV-specific CD8+ T cells and worked cooperatively in the elimination of virally infected cells. Interestingly, we found that cytolytic CD4+ T cells emerge early during acute HIV infection and tightly follow acute viral load trajectory. This emergence was associated to the early viral set point, suggesting an involvement in early control, in spite of CD4 T cell susceptibility to HIV infection. Our data suggest cytolytic CD4+ T cells as an independent subset distinct from Th1 cells that show combined activity with CD8+ T cells in the long-term control of HIV infection.
  
  
  OBJECTIVE
  The ability of the immune system to control chronic HIV infection is of critical interest to both vaccine design and therapeutic approaches. Much research has focused on the effect of the ability of CD8+ T cells to control the virus, while CD4+ T cells have been overlooked as effectors in HIV control due to the fact that they are preferentially infected. We show here that a subset of HIV-specific CD4+ T cells cooperate in the cytolytic control of HIV replication. Moreover, these cells represent a distinct subset of CD4+ T cells showing significant transcriptional and phenotypic differences compared to HIV-specific Th1 cells but with similarities to CD8+ T cells. These findings are important for our understanding of HIV immunopathology.
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Johnson
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Eller
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Teigler
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Sebastien M
authors.initials: SM
authors.lastname: Maloveste
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Schultz
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
authors.forename: Damien Z
authors.initials: DZ
authors.lastname: Soghoian
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Lu
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Oster
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Agnès-Laurence
authors.initials: AL
authors.lastname: Chenine
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
authors.affiliation: Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Marovich
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Merlin L
authors.initials: ML
authors.lastname: Robb
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Nelson L
authors.initials: NL
authors.lastname: Michael
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Bolton
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA Institute for Medical Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany hendrik.streeck@uk-essen.de.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Streeck
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D006801:Humans; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019562:Viral Load; D014766:Viremia / Q000276:immunology* / Q000821:virology