title: Transcriptional and posttranscriptional regulation of cytokine gene expression in HIV-1 antigen-specific CD8+ T cells that mediate virus inhibition.
abstract: The ability of CD8+ T cells to effectively limit HIV-1 replication and block HIV-1 acquisition is determined by the capacity to rapidly respond to HIV-1 antigens. Understanding both the functional properties and regulation of an effective CD8+ response would enable better evaluation of T cell-directed vaccine strategies and may inform the design of new therapies. We assessed the antigen specificity, cytokine signature, and mechanisms that regulate antiviral gene expression in CD8+ T cells from a cohort of HIV-1-infected virus controllers (VCs) (<5,000 HIV-1 RNA copies/ml and CD4+ lymphocyte counts of >400 cells/μl) capable of soluble inhibition of HIV-1. Gag p24 and Nef CD8+ T cell-specific soluble virus inhibition was common among the VCs and correlated with substantial increases in the abundance of mRNAs encoding the antiviral cytokines macrophage inflammatory proteins MIP-1α, MIP-1αP (CCL3L1), and MIP-1β; granulocyte-macrophage colony-stimulating factor (GM-CSF); lymphotactin (XCL1); tumor necrosis factor receptor superfamily member 9 (TNFRSF9); and gamma interferon (IFN-γ). The induction of several of these mRNAs was driven through a coordinated response of both increased transcription and stabilization of mRNA, which together accounted for the observed increase in mRNA abundance. This coordinated response allows rapid and robust induction of mRNA messages that can enhance the CD8+ T cells' ability to inhibit virus upon antigen encounter.
  
  
  OBJECTIVE
  We show that mRNA stability, in addition to transcription, is key in regulating the direct anti-HIV-1 function of antigen-specific memory CD8+ T cells. Regulation at the level of RNA helps enable rapid recall of memory CD8+ T cell effector functions for HIV-1 inhibition. By uncovering and understanding the mechanisms employed by CD8+ T cell subsets with antigen-specific anti-HIV-1 activity, we can identify new strategies for comprehensive identification of other important antiviral genes. This will, in turn, enhance our ability to inhibit virus replication by informing both cure strategies and HIV-1 vaccine designs that aim to reduce transmission and can aid in blocking HIV-1 acquisition.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA Duke Human Vaccine Institute, Duke University, Durham, North Carolina, USA.
authors.forename: Tamika L
authors.initials: TL
authors.lastname: Payne
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Blackinton
authors.affiliation: Duke Human Vaccine Institute, Duke University, Durham, North Carolina, USA.
authors.forename: Alyse
authors.initials: A
authors.lastname: Frisbee
authors.affiliation: Department of Surgery, Duke University, Durham, North Carolina, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Pickeral
authors.affiliation: Duke Human Vaccine Institute, Duke University, Durham, North Carolina, USA.
authors.forename: Sheetal
authors.initials: S
authors.lastname: Sawant
authors.affiliation: Duke Human Vaccine Institute, Duke University, Durham, North Carolina, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Vandergrift
authors.affiliation: Department of Surgery, Duke University, Durham, North Carolina, USA Duke Human Vaccine Institute, Duke University, Durham, North Carolina, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Freel
authors.affiliation: Department of Surgery, Duke University, Durham, North Carolina, USA Duke Human Vaccine Institute, Duke University, Durham, North Carolina, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Ferrari
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Keene
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA Department of Surgery, Duke University, Durham, North Carolina, USA Department of Immunology, Duke University, Durham, North Carolina, USA Duke Human Vaccine Institute, Duke University, Durham, North Carolina, USA gdt@duke.edu.
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015488:HIV Antigens / Q000276:immunology*; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; D015488:HIV Antigens; D012333:RNA, Messenger