title: Decreased stimulation of CD4+ T cell proliferation and IL-2 production by highly enriched populations of HIV-infected dendritic cells.
abstract: APC infection and dysfunction may contribute to the immunopathogenesis of HIV disease. In this study, we examined immunologic function of highly enriched populations of HIV-infected monocyte-derived dendritic cells (DC). Compared with uninfected DC, HIV-infected DC markedly down-regulated surface expression of CD4. HIV p24(+) DC were then enriched by negative selection of CD4(+)HIV p24(-) DC and assessed for cytokine secretion and immunologic function. Although enriched populations of HIV-infected DC secreted increased IL-12p70 and decreased IL-10, these cells were poor stimulators of allogeneic CD4(+) T cell proliferation and IL-2 production. Interestingly, HIV-infected DC secreted HIV gp120 and the addition of soluble (s) CD4 (a known ligand for HIV gp120) to DC-CD4(+) T cell cocultures restored T cell proliferation in a dose-dependent manner. By contrast, addition of antiretroviral drugs did not affect CD4(+) T cell proliferation. Furthermore, recombinant HIV gp120 inhibited proliferation in uninfected cocultures of allogeneic DC and CD4(+) T cells, an effect that was also reversed by addition of sCD4. In summary, we show that HIV gp120 produced by DC infected by HIV in vitro impairs normal CD4(+) T cell function and that sCD4 completely reverses HIV gp120-mediated immunosuppression. We hypothesize that HIV-infected DC may contribute to impaired CD4(+) T cell-mediated immune responses in vivo and that agents that block this particular immunosuppression may be potential immune adjuvants in HIV-infected individuals.
authors.affiliation: Dermatology Branch and Experimental Retrovirology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Tatsuyoshi
authors.initials: T
authors.lastname: Kawamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.forename: Debra L
authors.initials: DL
authors.lastname: Borris
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.forename: Andrew
authors.initials: A
authors.lastname: Blauvelt
mesh_terms: D000328:Adult; D017951:Antigen Presentation / Q000187:drug effects; D015704:CD4 Antigens / Q000096:biosynthesis / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D002455:Cell Division / Q000276:immunology; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology*; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000096:biosynthesis / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007519:Isoantigens / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D012995:Solubility; D015854:Up-Regulation / Q000276:immunology
chemical_list: D015704:CD4 Antigens; D006131:Growth Inhibitors; D015699:HIV Envelope Protein gp120; D017320:HIV Protease Inhibitors; D007376:Interleukin-2; D007519:Isoantigens; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D016753:Interleukin-10; D018664:Interleukin-12