Differential effects of P-class versus other CpG oligodeoxynucleotide classes on the impaired innate immunity of plasmacytoid dendritic cells in HIV type 1 infection.
Abstract Human plasmacytoid dendritic cells (PDC) are the major producers of type I interferons (IFN) after stimulation with CpG oligodeoxynucleotides (ODN). HIV-1-infected patients show a deficit in PDC numbers and function with progression of disease. CpG ODN appear to be attractive therapeutics to support the impaired innate immunity in HIV-1 infection. PDC counts, phenotype, and function were analyzed in 23 HIV-infected untreated individuals and 16 controls. Markers for migration (CCR7), activation (CD80), maturation (CD83), and endocytosis (BDCA2) were evaluated at baseline and 20 h after in vitro stimulation with class A, B, C, and P ODN. PDC counts and the expression of BDCA2 on these cells were significantly lower in HIV-1-infected subjects compared to controls (both p < 0.001). After stimulation with CpG ODN, CD80 and CD83 were upregulated to a similar extent in patients and controls, whereas CCR7 was upregulated more efficiently by CpG-P and CpG-C than CpG-A in HIV-1-infected individuals compared to controls. The IFN-alpha induction significantly differed for the CpG ODN classes (A > P > C > B) in patients and controls (p < 0.05). Functional PDC deficits in IFN-alpha and TNF-alpha induction were particularly evident in subjects with less than 500 CD4(+) cells/mul. CpG-P ODNs not only induced remarkable IFN-alpha production in patient PBMCs, but also significantly upregulated the antibacterial and antiviral CXC chemokine IP-10. In conclusion, PDC counts, phenotype, and function are significantly impaired in HIV-1-infected subjects. Optimized P-class ODN may be effective in reversing this innate immune defect, which should be further evaluated in vivo.
German National Reference Centre for Retroviruses, University of Erlangen-Nürnberg , Erlangen, Germany .
Norbert
N
Donhauser
Martin
M
Helm
Kathrin
K
Pritschet
Philipp
P
Schuster
Moritz
M
Ries
Klaus
K
Korn
Jörg
J
Vollmer
Barbara
B
Schmidt
D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D018122:B7-1 Antigen / Q000032:analysis; D003713:Dendritic Cells / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology / Q000821:virology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007136:Immunoglobulins / Q000032:analysis; D007155:Immunologic Factors / Q000494:pharmacology*; D016898:Interferon-alpha / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000032:analysis; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D054400:Receptors, CCR7 / Q000032:analysis; D011971:Receptors, Immunologic / Q000032:analysis; D000097802:CD83 Antigen
D015703:Antigens, CD; D018122:B7-1 Antigen; D007136:Immunoglobulins; D007155:Immunologic Factors; D016898:Interferon-alpha; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D054400:Receptors, CCR7; D011971:Receptors, Immunologic; D000097802:CD83 Antigen; C515370:CCR7 protein, human; C443299:CLEC4C protein, human; C408982:CPG-oligonucleotide