title: The Low-Cost Compound Lignosulfonic Acid (LA) Exhibits Broad-Spectrum Anti-HIV and Anti-HSV Activity and Has Potential for Microbicidal Applications.
abstract: OBJECTIVE
  Lignosulfonic 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.
  
  
  RESULTS
  LA 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.
  
  
  CONCLUSIONS
  Overall, these data highlight LA as a potential and unique low-cost microbicide displaying broad anti-HIV and anti-HSV activity.
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Gordts
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Férir
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: D'huys
authors.affiliation: Centre of Microbial and Plant Genetics, University of Leuven, Leuven, Belgium; Department of Bioscience Engineering, Antwerp University, Antwerp, Belgium.
authors.forename: Mariya I
authors.initials: MI
authors.lastname: Petrova
authors.affiliation: Centre of Microbial and Plant Genetics, University of Leuven, Leuven, Belgium; Department of Bioscience Engineering, Antwerp University, Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lebeer
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000187:drug effects; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000635:transmission; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006558:Herpes Genitalis / Q000188:drug therapy / Q000635:transmission; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear; D008031:Lignin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; C001545:lignosulfuric acid; D008031:Lignin