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. 2007 Apr;120(4):526-35.
doi: 10.1111/j.1365-2567.2007.02530.x.

Impact of class A, B and C CpG-oligodeoxynucleotides on in vitro activation of innate immune cells in human immunodeficiency virus-1 infected individuals

Jeffrey A Martinson  1 , Allan R Tenorio, Carlos J Montoya, Lena Al-Harthi, Carolyne N Gichinga, Arthur M Krieg, Linda L Baum, Alan L Landay
Affiliations

Impact of class A, B and C CpG-oligodeoxynucleotides on in vitro activation of innate immune cells in human immunodeficiency virus-1 infected individuals

Jeffrey A Martinson et al. Immunology. 2007 Apr.

Abstract

Oligodeoxynucleotides (ODN) with unmethylated deoxycytidyl-deoxyguanosine dinucleotides (CpG-ODNs) stimulate Toll-like receptor 9 (TLR9) in plasmacytoid dendritic cells (pDC) and B cells and activate innate and adaptive immunity. Three classes of synthetic CpG-ODNs, class A, B and C, activate cells through TLR9; our goal was to evaluate their effect on cells from human immunodeficiency virus (HIV)-1(+) individuals. We compared the frequencies and the unstimulated activation status of immune effector cells in HIV-1(+) and HIV-1(-) individuals. Fewer pDC, myeloid dendritic cells (mDC), B cells, natural killer (NK) cells and invariant natural killer T cells (iNKT) were present in HIV-1(+) peripheral blood mononuclear cells (PBMC) and their baseline activation status was higher than HIV-1(-) PBMC. Exposure of HIV-1(+) PBMC to all classes of CpG-ODNs led to activation and maturation of pDC based on CD86, CD80, and CD83 expression similar to that of cells from HIV-1(-) individuals. The percentage of CpG-ODN stimulated pDC that express CD40 was dramatically higher when cells were obtained from HIV-1(+) than from HIV-1(-) individuals. B-lymphocytes were activated similarly in HIV-1(+) and HIV-1(-) individuals. mDC, NK and iNKT cell, which lack TLR9, were indirectly activated. Interferon-alpha (IFN-alpha) and interferon inducible protein 10 (IP-10) secretion was induced by class A or C but not class B CpG-ODN, but the concentrations were less than those produced by HIV-1(-) PBMC. HIV-1 infected individuals have fewer innate effector cells that are chronically activated, but these cells can be further activated by CpG-ODN, which suggests that synthetic CpG-ODNs could be used to enhance the immune system in HIV-1 infected individuals.

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Figures

Figure 1
Figure 1
Impact of viral load on frequency of pDC, mDC, iNKT and NK cell subpopulations in HIV-1+ individuals. Cell frequency in the peripheral blood was evaluated by flow cytometry. Each point represents one individual. Percentages of the following were evaluated: (a) pDC (Lin1–/CD123+/HLA-DR+) (b) mDC (Lin1–/CD11c+/HLA-DR+) (c) iNKT (6B11+/CD3+), and (d) NK (CD3–/CD56 16+). Groups included: HIV-1– (n = 25), HIV-1+ individuals treated with antiretroviral therapy who had a viral load <50 copies/ml (HIV-1+ART VL < 50) (n = 21), HIV-1+ individuals treated with antiretroviral therapy who had a viral load >50 copies/ml (HIV-1+ART VL > 50) (n = 26), or HIV-1+ treatment-naive (HIV-1+ No ART) (n = 5). The horizontal bar corresponds to mean percentage of cells. Statistical comparisons were made using the Student's t-test. *Significance at P < 0·05.
Figure 2
Figure 2
Impact of HIV-1 on activation of pDC stimulated with CpG-ODN. PBMC from 10 HIV-1+ and 10 HIV-1– individuals were incubated for 24 hr with control CpG-ODN, class A, class B or class C CpG-ODN or media alone. Flow cytometry was used to determine expression of: (a) CD86, (b) CD40 and (c) CD80 and CD83 on pDC. Results are expressed as the mean ± standard deviation of the percentage of cells that express each cell surface marker. Statistical comparisons were made between the media control and the corresponding class A, B, or C CpG-ODN stimulated cultures using Student's t-test; values were considered significant if P < 0·05. *Significantly different from HIV-1+ controls; **significantly different from HIV-1– controls.
Figure 3
Figure 3
Impact of HIV-1 on activation of B cells, iNKT cells and NK cells stimulated with CpG-ODN. PBMC from 10 HIV-1+ and 10 HIV-1– individuals were incubated for 24 hr with control CpG-ODN, class A, class B or class C CpG-ODN or media alone. Flow cytometry was used to determine expression of: (a) CD86 on B cells, (b) CD69 on iNKT cells and (c) CD69 on NK cells. Cell populations were defined using the cell surface markers described in Figure 1. PBMC were evaluated by flow cytometry. Results are expressed as the mean ± standard deviation of the percentage of cells expressing the indicated cellular activation marker. Statistical comparisons were made using Student's t-test; values were considered significant if P < 0·05. *Significantly different from HIV-1+ controls; **significantly different from HIV-1– controls.
Figure 4
Figure 4
CpG-ODN induced IFN-α and IP-10 secretion by PBMC from HIV–1+ individuals. PBMC from 10 HIV-1+ and 10 HIV-1– individuals were incubated for 24 hr with control CpG-ODN, class A, class B or class C CpG-ODN or media alone. Culture supernatants were collected and concentrations of IFN-α and IP-10 were measured by ELISA. Results are expressed as mean ± standard deviation: (a) IFN-α and (b) IP-10. Statistical comparisons between groups were made using the Student's t-test. *P < 0·05 greater than the HIV+ CpG control; **P < 0·05 greater than the HIV− CpG control.
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