title: Dendritic cells restore CD8+ T cell reactivity to autologous HIV-1.
abstract: Recall T cell responses to HIV-1 antigens are used as a surrogate for endogenous cellular immune responses generated during infection. Current methods of identifying antigen-specific T cell reactivity in HIV-1 infection use bulk peripheral blood mononuclear cells (PBMC) yet ignore professional antigen-presenting cells (APC) that could reveal otherwise hidden responses. In the present study, peptides representing autologous variants of major histocompatibility complex (MHC) class I-restricted epitopes from HIV-1 Gag and Env were used as antigens in gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) and polyfunctional cytokine assays. Here we show that dendritic cells (DC) enhanced T cell reactivity at all stages of disease progression but specifically restored T cell reactivity after combination antiretroviral therapy (cART) to early infection levels. Type 1 cytokine secretion was also enhanced by DC and was most apparent late post-cART. We additionally show that DC reveal polyfunctional T cell responses after many years of treatment, when potential immunotherapies would be implemented. These data underscore the potential efficacy of DC immunotherapy that aims to awaken a dormant, autologous, HIV-1-specific CD8+ T cell response.
  
  
  OBJECTIVE
  Assessment of endogenous HIV-1-specific T cell responses is critical for generating immunotherapies for subjects on cART. Current assays ignore the ability of dendritic cells to reveal these responses and may therefore underestimate the breadth and magnitude of T cell reactivity. As DC do not prime new responses in these assays, it can be assumed that the observed responses are not detected without appropriate stimulation. This is important because dogma states that HIV-1 mutates to evade host recognition and that CD8+ cytotoxic T lymphocyte (CTL) failure is due to the inability of T cells to recognize the autologous virus. The results presented here indicate that responses to autologous virus are generated during infection but may need additional stimulation to be effective. Detecting the breadth and magnitude of HIV-1-specific T cell reactivity generated in vivo is of the utmost importance for generating effective DC immunotherapies.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA kellie@jhmi.edu.
authors.forename: Kellie N
authors.initials: KN
authors.lastname: Smith
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Robbie B
authors.initials: RB
authors.lastname: Mailliard
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Brendan B
authors.initials: BB
authors.lastname: Larsen
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Wong
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Phalguni
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Rinaldo
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008297:Male; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology
chemical_list: D016207:Cytokines; D054299:env Gene Products, Human Immunodeficiency Virus; D054301:gag Gene Products, Human Immunodeficiency Virus