title: Impaired monocyte maturation in response to CpG oligodeoxynucleotide is related to viral RNA levels in human immunodeficiency virus disease and is at least partially mediated by deficiencies in alpha/beta interferon responsiveness and production.
abstract: The biological activity of CpG oligodeoxynucleotide 2216 (ODN2216), a Toll-like receptor 9 agonist, was investigated with monocytes from human immunodeficiency virus (HIV)-negative and HIV-positive (HIV+) donors. Exposure of peripheral blood mononuclear cells to CpG ODN2216 led to decreased expression of the monocyte marker CD14 and increased expression of the dendritic cell marker CD83, as well as increased expression of HLA-DR, CD40, CD80, and CD86 among the monocytes. Several features of the CpG ODN-induced maturation were diminished in monocytes from HIV+ donors, and these deficiencies were related to increased viremia but not to CD4 cell counts. Alpha interferon (IFN-alpha) was implicated as at least a partial mediator of the CpG ODN-induced monocyte maturation. Reduced production of IFN-alpha in response to CpG ODN and reduced frequencies of plasmacytoid dendritic cells, the principal IFN-alpha-producing cell type in peripheral blood, were observed in peripheral blood mononuclear cells from HIV+ donors. These deficiencies also were related to levels of plasma HIV RNA. Responses of monocytes from HIV+ donors to direct stimulation with IFN-alpha also were partially impaired. Thus, reduced production of IFN-alpha and reduced IFN-alpha responsiveness may contribute to diminished functional responses to CpG ODN in HIV disease. Application of CpG ODNs in HIV disease for adjuvant or immunoregulatory purposes may be particularly useful for HIV+ donors without high-level viremia.
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, Department of Medicine, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
authors.forename: Janelle R
authors.initials: JR
authors.lastname: Salkowitz
authors.forename: Benigno
authors.initials: B
authors.lastname: Rodriguez
authors.forename: Clifford V
authors.initials: CV
authors.lastname: Harding
authors.forename: Scott F
authors.initials: SF
authors.lastname: Sieg
mesh_terms: D000276:Adjuvants, Immunologic; D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D018791:CD4 Lymphocyte Count; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006678:HIV / Q000502:physiology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D007136:Immunoglobulins / Q000032:analysis; D016898:Interferon-alpha / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology* / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D012367:RNA, Viral / Q000097:blood; D014766:Viremia; D000097802:CD83 Antigen
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D006684:HLA-DR Antigens; D007136:Immunoglobulins; D016898:Interferon-alpha; D016899:Interferon-beta; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D012367:RNA, Viral; D000097802:CD83 Antigen; C408982:CPG-oligonucleotide