The Low-Cost Compound Lignosulfonic Acid (LA) Exhibits Broad-Spectrum Anti-HIV and Anti-HSV Activity and Has Potential for Microbicidal Applications

Abstract

ObjectivesLignosulfonic acid (LA), a low-cost lignin-derived polyanionic macromolecule, was extensively studied for its anti-HIV and anti-HSV activity in various cellular assays, its mechanism of viral inhibition and safety profile as potential microbicide.ResultsLA demonstrated potent inhibitory activity of HIV replication against a wide range of R5 and X4 HIV strains and prevented the uptake of HIV by bystander CD4+ T cells from persistently infected T cells in vitro (IC50: 0.07 – 0.34 μM).LA also inhibited HSV-2 replication in vitro in different cell types (IC50: 0.42 – 1.1 μM) and in rodents in vivo. Furthermore, LA neutralized the HIV-1 and HSV-2 DC-SIGN-mediated viral transfer to CD4+ T cells (IC50: ∼1 μM). In addition, dual HIV-1/HSV-2 infection in T cells was potently blocked by LA (IC50: 0.71 μM). No antiviral activity was observed against the non-enveloped viruses Coxsackie type B4 and Reovirus type 1.LA is defined as a HIV entry inhibitor since it interfered with gp120 binding to the cell surface of T cells. Pretreatment of PBMCs with LA neither increased expression levels of cellular activation markers (CD69, CD25 and HLA-DR), nor enhanced HIV-1 replication. Furthermore, we found that LA had non-antagonistic effects with acyclovir, PRO2000 or LabyA1 (combination index (CI): 0.46 – 1.03) in its anti-HSV-2 activity and synergized with tenofovir (CI: 0.59) in its anti-HIV-1 activity. To identify mechanisms of LA resistance, we generated in vitro a mutant HIV-1 NL4.3LAresistant virus, which acquired seven mutations in the HIV-1 envelope glycoproteins: S160N, V170N, Q280H and R389T in gp120 and K77Q, N113D and H132Y in gp41. Additionally, HIV-1 NL4.3LAresistant virus showed cross-resistance with feglymycin, enfuvirtide, PRO2000 and mAb b12, four well-described HIV binding/fusion inhibitors. Importantly, LA did not affect the growth of vaginal Lactobacilli strains.ConclusionOverall, these data highlight LA as a potential and unique low-cost microbicide displaying broad anti-HIV and anti-HSV activity.

Lignin for Nano‐ and Microscaled Carrier Systems: Applications, Trends, and Challenges

“…Ag NPs and fullerene derivatives have been used for antiviral studies. In sharp contrast, no studies on nano‐ or microscaled antiviral lignin materials have been published, although antiviral properties have been reported for different types of lignins . Ag NPs are well known for their antibacterial effects .…”

Antimicrobial Activity of Lignin-Derived Polyurethane Coatings Prepared from Unmodified and Demethylated Lignins

“…For textiles, there are special requirements such as non-toxicity to the consumer, namely cytotoxicity, allergy or irritation and sensitization. In other recent studies, lignosulfonic acid is reported to exhibit broad-spectrum anti-HIV (human immunodeficiency virus) and anti-HSV (herpes simplex virus) properties [22,23]. Thus, Qiu investigated the anti-HIV-1 activity-potential of lignosulfonates as a microbicide to prevent HIV-1 sexual transmission [23].…”

Lignin-Derived Biomaterials for Drug Release and Tissue Engineering

“…investigated lignosulfonic acid regarding HIV antiviral activity revealing lignosulfonic acid to be a potent inhibitor of the HIV replication. They also prevent an uptake of the virus by CD4T cells from persistently infected T cells in vitro [56]. The antiviral activity of lignin products is also shown for CMV and HSV-1 and HSV-2.…”