title: CD40 ligand trimer and IL-12 enhance peripheral blood mononuclear cells and CD4+ T cell proliferation and production of IFN-gamma in response to p24 antigen in HIV-infected individuals: potential contribution of anergy to HIV-specific unresponsiveness.
abstract: It has been suggested that CD4+ T cell proliferative responses to HIV p24 Ag may be important in the control of HIV infection. However, these responses are minimal or absent in many HIV-infected individuals. Furthermore, while in vitro and in vivo responses to non-HIV recall Ags improve upon administration of highly active antiretroviral therapy, there does not appear to be a commensurate enhancement of HIV-specific immune responses. It is possible that CD4+ p24-specific T cells are deleted early in the course of infection. However, it is also possible that a discrete unresponsiveness, or anergy, contributes to the lack of proliferation to p24. To evaluate the possible contribution of unresponsiveness to the lack of CD4+ T cell proliferation to p24 in HIV-infected individuals, we attempted to overcome unresponsiveness. CD40 ligand trimer (CD40LT) and IL-12 significantly increased PBMC and CD4+ T cell proliferative responses to p24 Ag in HIV-infected, but not uninfected, individuals. No increase in proliferative response to CMV Ag was observed. CD40LT exerted its effect through B7-CD28-dependent and IL-12- and IL-15-independent mechanisms. Finally, the increase in proliferation with CD40LT and IL-12 was associated with an augmented production of IFN-gamma in most, but not all, individuals. These data suggest the possible contribution of HIV-specific unresponsiveness to the lack of CD4+ T cell proliferation to p24 Ag in HIV-infected individuals and that clonal deletion alone does not explain this phenomenon. They also indicate the potential for CD40LT and IL-12 as immune-based therapies for HIV infection.
authors.affiliation: Laboratory of Immunoregulation and Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, and Warren Magneson Clinical Research Center, National Institutes of Health, Bethesda, MD 20892, USA. mdybul@nih.gov
authors.forename: M
authors.initials: M
authors.lastname: Dybul
authors.forename: G
authors.initials: G
authors.lastname: Mercier
authors.forename: M
authors.initials: M
authors.lastname: Belson
authors.forename: C W
authors.initials: CW
authors.lastname: Hallahan
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: C
authors.initials: C
authors.lastname: Perry
authors.forename: B
authors.initials: B
authors.lastname: Herpin
authors.forename: L
authors.initials: L
authors.lastname: Ehler
authors.forename: R T
authors.initials: RT
authors.lastname: Davey
authors.forename: J A
authors.initials: JA
authors.lastname: Metcalf
authors.forename: J M
authors.initials: JM
authors.lastname: Mican
authors.forename: R A
authors.initials: RA
authors.lastname: Seder
authors.forename: A S
authors.initials: AS
authors.lastname: Fauci
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology*; D019380:Anti-HIV Agents / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000502:physiology; D018106:CD28 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D000939:Epitopes / Q000276:immunology; D016655:HIV Core Protein p24 / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000502:physiology* / Q000627:therapeutic use; D019409:Interleukin-15 / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000502:physiology* / Q000627:therapeutic use
chemical_list: D000276:Adjuvants, Immunologic; D019380:Anti-HIV Agents; D018122:B7-1 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; D000939:Epitopes; D016655:HIV Core Protein p24; D019409:Interleukin-15; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma