Modulation of HIV-1-induced activation of plasmacytoid dendritic cells by 6-desfluoroquinolones.
Chronic activation of plasmacytoid dendritic cells (pDCs) is an important contributor to the immunopathogenesis of HIV infection. The quinolone derivative chloroquine (CQ) prevents endosomal acidification, required for toll-like receptor sensing of HIV by pDCs, and is currently under clinical trial as an immunotherapeutic approach. We tested three different 6-desfluoroquinolones (6-DFQs), structurally related to CQ and endowed with antiretroviral activity, for their ability to inhibit HIV-induced pDC activation and interferon (IFN)-α production in peripheral blood mononuclear cells (PBMCs) in vitro. PBMCs from six healthy donors were cultured overnight with aldrithiol-2 (AT-2)-inactivated HIV-1MN in the presence or absence of 6-DFQs or CQ. IFN-α production was measured by ELISA; pDC and monocyte activation was analyzed by flow cytometry. Incubation with HIV labeled with the fluorescent dye DyLight-488 (DL488) was used to test virus uptake by flow cytometry. We found that the 6-DFQs effectively inhibited HIV-induced IFN-α similar to CQ, but only 6-DFQs also inhibited the upregulation of the pDC activation marker CD83. Interestingly, HIV-induced expression of the costimulatory molecule CD80 and, to a lesser extent CD86, was further enhanced on pDCs by 6-DFQs, but not CQ. Conversely, 6-DFQs and CQ had similar inhibitory effects on HIV-induced monocyte activation, consistent with the primary mechanism being associated with IFN-α signaling. Finally, 6-DFQs interfered with HIV interaction with pDCs and monocytes, but not myeloid DCs. Our data indicate that 6-DFQs may interfere with pDC-mediated and IFN-α-dependent immunopathogenesis while supporting pDC differentiation into mature antigen-presenting cells by favoring expression of costimulatory molecules.
1 Immunology Section, Chelsea and Westminster Hospital , Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Imperial College, London, United Kingdom .
Caroline M
CM
Royle
Ming-Han
MH
Tsai
Oriana
O
Tabarrini
Serena
S
Massari
David R
DR
Graham
Veronica N
VN
Aquino
Adriano
A
Boasso
D015703:Antigens, CD / Q000032:analysis; D018122:B7-1 Antigen / Q000032:analysis; D051940:B7-2 Antigen / Q000032:analysis; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D024841:Fluoroquinolones / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007136:Immunoglobulins / Q000032:analysis; D007155:Immunologic Factors / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000032:analysis; D000097802:CD83 Antigen
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D024841:Fluoroquinolones; D007136:Immunoglobulins; D007155:Immunologic Factors; D007371:Interferon-gamma; D008562:Membrane Glycoproteins; D000097802:CD83 Antigen; C497964:CD86 protein, human