Broad spectrum inhibition of HIV-1 infection by sulfated K5 Escherichia coli polysaccharide derivatives.
OBJECTIVE
HIV-1 entry into CD4 cells represents a main target for developing novel antiretroviral agents and microbicides.


METHODS
Sulfated derivatives of the K5 polysaccharide have a backbone structure resembling the heparin precursor, but are devoid of the anticoagulant activity. The derivatives were chemically sulfated in the N position after N-deacetylation, in the O position, or in both sites.


METHODS
HIV replication in human T cell blasts, monocyte-derived macrophages and cell lines was studied in the presence of sulfated K5 derivatives.


RESULTS
O-sulfated [K5-OS(H)] and N,O-sulfated [K5-N,OS(H)] K5 derivatives with high degree of sulfation inhibited the replication of an HIV strain using CXCR4 as entry co-receptor (X4 virus) in both cell lines and T-cell blasts. K5 derivatives also strongly inhibited the multiplication of CCR5-dependent HIV (R5 virus) in cell lines, T-cell blasts and primary monocyte-derived macrophages. Their 50% inhibitory concentration was between 0.07 and 0.46 microM, without evidence of cytotoxicity even at the maximal concentration tested (9 microM). In addition, both K5-N,OS(H) and K5-OS(H) potently inhibited the replication of several primary HIV-1 isolates in T-cell blasts, with K5-N,OS(H) being more active than K5-OS(H) on dual tropic R5X4 strains. K5 derivatives inhibited the early steps of virion attachment and/or entry.


CONCLUSIONS
Because K5 derivatives are unlikely to penetrate into cells they may represent potential topical microbicides for the prevention of sexual HIV-1 transmission.
Vicenzi
Elisa
E
AIDS Immunopathogenesis Unit, San Raffaele Scientific Institute, and the Glycores 2000 S.r.l., Milano, Italy.
Gatti
Alessandra
A
Ghezzi
Silvia
S
Oreste
Pasqua
P
Zoppetti
Giorgio
G
Poli
Guido
G
D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D016667:Bacterial Capsules; D002478:Cells, Cultured; D004926:Escherichia coli; D015726:Giant Cells / Q000187:drug effects; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000821:virology; D011135:Polysaccharides, Bacterial / Q000627:therapeutic use*; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D013601:T-Lymphocytes / Q000821:virology; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D011135:Polysaccharides, Bacterial; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011991:Receptors, Virus; C050673:capsular polysaccharide K5