Inhibition of human immunodeficiency virus infection by heparin derivatives

Heparin (Hep) and sulfated polysaccharides (SPs) have been reported to inhibit HIV infection in vitro. In vivo, anticoagulant activity and reduced bioavailability were found to limit the antiviral effects of Hep. In this investigation, three nonanticoagulant N-acylated Hep conjugates [OI1:3Hep, Pal1:5Hep, and Pal1:5Hep(SO4)] were compared to Hep for their ability to interact with HIV replication in CD4-positive cell lines and PBMCs. Resulfated palmitoyl-Hep [Pal1:5Hep(SO4)] exhibited the strongest anti-HIV effects. For instance, no provirus HIV DNA was detected in the genome of HIV-1-LAI-infected PBMCs treated with this heparin derivative. Cell-to-cell fusion and RT activity were explored to explain these differences. Hep and Pal1:5Hep(SO4) derivative exerted identical effects on cell-to-cell fusion. On the other hand, Pal1:5Hep(SO4) displayed the strongest inhibitory effects in the acellular RT inhibition assay. This suggests that RT might be a second target for N-acylated Hep, even though SP uptake and the preferential effects of SPs on RT as opposed to DNA polymerase have not yet been demonstrated. Nevertheless, considering the anticoagulant, antiviral, and antiinflammatory effects of N-acylated Hep, the N-acylated Hep derivatives might be excellent candidates as new anti-HIV pharmacological tools.