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Title
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The low-cost compound lignosulfonic acid (LA) exhibits broad-spectrum anti-HIV and anti-HSV activity and has potential for microbicidal applications
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Author
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Abstract
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| Objectives 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 mu M). LA also inhibited HSV-2 replication in vitro in different cell types (IC50: 0.42 - 1.1 mu M) and in rodents in vivo. Furthermore, LA neutralized the HIV-1 and HSV-2 DC-SIGN-mediated viral transfer to CD4(+) T cells (IC50:similar to 1 mu M). In addition, dual HIV-1/HSV-2 infection in T cells was potently blocked by LA (IC50: 0.71 mu M). 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 NL4.3(LAresistant) 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 NL4.3(LAresistant) 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. Conclusion Overall, these data highlight LA as a potential and unique low-cost microbicide displaying broad anti-HIV and anti-HSV activity. |
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Language
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English
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Source (journal)
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PLoS ONE
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Publication
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2015
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ISSN
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1932-6203
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DOI
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10.1371/JOURNAL.PONE.0131219
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Volume/pages
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10
:7
(2015)
, 30 p.
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Article Reference
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e0131219
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ISI
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000358153000105
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Pubmed ID
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26132818
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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Full text (open access)
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