Mechanisms of HIV-1 Inhibition by the Lipid Mediator N-Arachidonoyldopamine

Abstract

Several linear fatty acid dopamides (N-acyldopamines) have been identified recently in the brain. Among them, N-arachidonoyldopamine (NADA) is an endogenous lipid mediator sharing endocannabinoid and endovanilloid biological activities. We have reported previously that NADA exerts some of its biological activities through inhibition of the NF-κB pathway and, because this transcription factor plays a key role in HIV-1-long terminal repeat (LTR) trans activation, we have evaluated the anti-HIV-1 activity of NADA. In this study, we show that NADA inhibits vesicular stomatitis virus-pseudotyped HIV-1 infection in the human leukemia T cell line Jurkat, in primary T cells, and in the human astrocytic cell line U373-MG. Other endocannabinoids such as anandamide, 2-arachidonoylglycerol, and noladin ether did not show inhibitory activity in the HIV-1 replication assays. The anti-HIV-1 activity of NADA was independent of known cannabinoid and vanilloid receptor activation. In addition, NADA did not affect reverse transcription and integration steps of the viral cycle, and its inhibitory effect was additive with that of the reverse transcriptase inhibitor azidothymidine. NADA inhibited both TNF-α and HIV-1 trans activator protein-induced HIV-1-LTR activation. We also show that NADA counteracts the TNF-α-mediated trans activation capacity of the p65 NF-κB subunit without affecting its physical association to the HIV-1-LTR promoter. Moreover, NADA inhibited the p65 transcriptional activity by specifically targeting the phosphorylation of this NF-κB subunit at Ser536. These findings provide new mechanistic insights into the biological activities of NADA, and highlight the potential of lipid mediators for the management of AIDS.

N-Octanoyl dopamine transiently inhibits T cell proliferation via G1 cell-cycle arrest and inhibition of redox-dependent transcription factors

“…We are aware of the studies performed by Sancho et al [27,28]. who demonstrate that N-oleoyl-and N-arachidonoyl dopamine inhibit proliferation of Jurkat T cells.…”

N-acyl dopamine derivates as lead compound for implementation in transplantation medicine

“…Because of their redox active catechol structure NADD have the propensity to inhibit the activation of redox dependent proinflammatory transcription factors, e.g. NF-κB, AP-1 and NFAT [64,65], and therefore they largely inhibit the expression of inflammatory mediators produced by endothelial cells [66] and proliferation of T cells [64][65][66][67].…”

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells

“…Additionally, NADA has been observed to suppress inflammatory activation of human Jurkat T-cells and to inhibit the release of prostaglandin E 2 (PGE 2 ) from LPS-activated astrocytes, microglia and mouse brain ECs (46 -48). NADA also displays inhibitory activity in HIV-1 replication assays (49). Finally, a recent report suggests that NADA can prevent the degranulation and release of TNF␣ from RBL-2H3 mast cells treated with an IgE-antigen complex (50).…”