Modulation of HIV-1-Induced Activation of Plasmacytoid Dendritic Cells by 6-Desfluoroquinolones

Abstract

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.

Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS

“…In this case, the in vitro effect is in line with the results of two in vivo studies [53,60]. The use of chloroquine-related compounds with increased potency is yielding promising results in vitro [66], and it will be interesting to test the best-performing candidates in the simian AIDS model. The effects of chloroquine/hydroxychloroquine on viral replication have been repeatedly shown in vitro at lower drug levels than those inducing the cellular effects [35,36,63,65].…”

“…In this case, the in vitro effect is in line with the results of two in vivo studies [ 53 , 60 ]. The use of chloroquine-related compounds with increased potency is yielding promising results in vitro [ 66 ], and it will be interesting to test the best-performing candidates in the simian AIDS model.…”

Quinolone derivatives: Potential anti‐HIV agent—development and application

“…Hydrogen, amino, fluoro, hydroxyl, and methyl are tolerated at this position. Up to date, hydrogen is optimal for the antiviral activity. Several substituents such as fluoro, amino, and various substituted benzyl have been introduced into C‐6 position of 4‐quinolone core, and fluoro is the most common substituent for the antibacterial agents since fluoro facilitates the penetration of 4‐quinolone into the microbial.…”