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.
Highlights
Since the advent of AIDS pandemic, efforts have been directed to the search of viral inhibitory molecules to either block virus at the entry portal or disrupt viral life cycle after the entry
The infection of human immunodeficiency virus (HIV)-1 is initiated by the viral envelop interaction with its cellular receptor CD4, which leads to further interaction with viral co-receptor CCR5 or CXCR4 [1,2]
lignosulfonic acid (LSA) exhibited inhibitory activities against a panel of diverse clinical isolates derived from infected Chinese patients [19], with EC50 values ranging from 0.171 mg/ml to 5.060 mg/ml (Table 1)
Summary
Since the advent of AIDS pandemic, efforts have been directed to the search of viral inhibitory molecules to either block virus at the entry portal or disrupt viral life cycle after the entry. It is well established that sulfated polyanions (SPs) are potent inhibitors of HIV infection by either competing with cell surface molecules for virus binding or directly interacting with cell surface molecules that are required for the virion attachment or entry [4]. These negatively charged molecules can bind HIV-1 envelop glycoproteins, and cell surface molecules, such as CD4 on the lymphocytes, through charge-charge interactions and disrupt viral binding or fusion process [5,6,7]. SPs’ binding to cell-associated molecules were reported and considered to play roles in viral inhibition as well [5,6,7,17,18]
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