Inhibition of HIV-1-mediated syncytium formation and virus replication by the lipophosphoglycan fromLeishmania donovaniis due to an effect on early events in the virus life cycle

Abstract

Previous findings have indicated that the major surface molecule of Leishmania, lipophosphoglycan (LPG), could abrogate HIV‐1‐induced syncytium formation and virus replication. In the present work, we were interested in characterizing this inhibitory process. Data from a new luciferase‐based semiquantitative assay for syncytium formation, relying on the coincubation of a T‐cell line containing an HIV‐1 LTR‐driven luciferase construct with a cell line chronically infected with HIV‐1, confirmed that LPG was indeed a strong inhibitor of HIV‐1‐dependent syncytium formation and that this inhibition was dose‐dependent. As determined by flow cytometric analyses, this inhibition was not apparently due to downregulation of CD4, CXCR4 or LFA‐1, three distinct surface glycoproteins known to be important in HIV‐1 mediated syncytium formation. Furthermore, LPG did not seem to affect signal transduction pathways in T cells as judged by measurement of HIV‐1 LTR‐driven reporter gene activity upon treatment with different stimuli. However, pretreatment of either of the cell lines used in the assay with LPG led to a significant decrease of virus‐mediated syncytium formation, which was further accentuated when both cell lines were pretreated. LPG inhibition of HIV‐1 replication was next assessed. When measuring either infection with luciferase‐encoding recombinant HIV‐1 particles or multinucleated giant cell formation following an acute virus infection, we again observed that LPG was efficient at blocking HIV‐1 replication. Specific assays probing different steps of viral entry demonstrated that attachment was not hindered by LPG but that viral entry was modulated, suggesting that LPG targets a postbinding step. Hence, incorporation of LPG into a target cell membrane could influence its fluidity and diminish both the virus‐cell and cell‐to‐cell fusion processes initiated by HIV‐1.

Inhibitory effect of aqueous dandelion extract on HIV-1 replication and reverse transcriptase activity

“…Shikonin from the dried root of Lithospermum erythrorhizon is a pan-chemokine receptor inhibitor [ 16 ]. Lipophosphoglycan (LPG) from Leishmania donovani has been shown to inhibit the early stage of the HIV-1 life cycle by influencing the membrane fluidity of target cells and diminishing both the virus-cell and cell-to-cell fusion processes initiated by HIV-1 [ 17 ].…”

Leishmania infantumPromastigotes Reduce Entry of HIV‐1 into Macrophages through a Lipophosphoglycan‐Mediated Disruption of Lipid Rafts

“…It is thus less likely to act simultaneously on incoming new viruses. Nevertheless, LPG inhibits HIV-1 syncytium formation between infected CD4 ϩ T cells [10,11], possibly also as a consequence of its effect on the plasma membrane lipid microdomains. Finally, our results showing that axenic amastigotes do not inhibit virus entry indicate that Leishmania infection will most likely increase the overall viral load in HIV-1-infected patients.…”

“…Interestingly, LPG has been shown to exert a dual effect with respect to HIV-1. Indeed, it can promote HIV-1 production in both CD4 ϩ T cells and macrophages [6,9], and it can also inhibit syncytium formation and virus entry at a postbinding step in CD4 ϩ T cells [10,11].…”