title: Lignosulfonic acid exhibits broadly anti-HIV-1 activity--potential as a microbicide candidate for the prevention of HIV-1 sexual transmission.
abstract: Some secondary metabolites from plants show to have potent inhibitory activities against microbial pathogens, such as human immunodeficiency virus (HIV), herpes simplex virus (HSV), Treponema pallidum, Neisseria gonorrhoeae, etc. Here we report that lignosulfonic acid (LSA), a polymeric lignin derivative, exhibits potent and broad activity against HIV-1 isolates of diverse subtypes including two North America strains and a number of Chinese clinical isolates values ranging from 21.4 to 633 nM. Distinct from other polyanions, LSA functions as an entry inhibitor with multiple targets on viral gp120 as well as on host receptor CD4 and co-receptors CCR5/CXCR4. LSA blocks viral entry as determined by time-of-drug addiction and cell-cell fusion assays. Moreover, LSA inhibits CD4-gp120 interaction by blocking the binding of antibodies specific for CD4-binding sites (CD4bs) and for the V3 loop of gp120. Similarly, LSA interacts with CCR5 and CXCR4 via its inhibition of specific anti-CCR5 and anti-CXCR4 antibodies, respectively. Interestingly, the combination of LSA with AZT and Nevirapine exhibits synergism in viral inhibition. For the purpose of microbicide development, LSA displays low in vitro cytotoxicity to human genital tract epithelial cells, does not stimulate NF-κB activation and has no significant up-regulation of IL-1α/β and IL-8 as compared with N-9. Lastly, LSA shows no adverse effect on the epithelial integrity and the junctional protein expression. Taken together, our findings suggest that LSA can be a potential candidate for tropical microbicide.
authors.affiliation: Center for Public Health Research, School of Medicine, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Qiu
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Chu
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Yuan
authors.forename: Hongyong
authors.initials: H
authors.lastname: Song
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Chen
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wu
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D000918:Antibody Specificity / Q000187:drug effects; D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004357:Drug Synergism; D004848:Epithelium / Q000187:drug effects / Q000821:virology; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control* / Q000635:transmission*; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D008031:Lignin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D019829:Nevirapine / Q000494:pharmacology / Q000627:therapeutic use; D017433:Protein Structure, Secondary; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D016209:Interleukin-8; D016328:NF-kappa B; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015215:Zidovudine; C001545:lignosulfuric acid; D008031:Lignin; D019829:Nevirapine