Cellulose sulfate, a polyanionic compound derived from cotton, has been proposed as a topical
microbicide to reduce the sexual transmission of HIV. However, a phase III clinical trial of a
vaginal gel formulation of
cellulose sulfate (
Ushercell) had to be prematurely closed after early data indicated
microbicide users had a higher rate of
HIV infection than women using a placebo. The unexpected results of the
cellulose sulfate trail prompted us to reexamine and attempt to replicate the available preclinical data for this compound and other
polyanions. We show here that
cellulose sulfate has a biphasic effect on
HIV infection in vitro: at high concentrations it inhibits
infection but at low concentrations it significantly and reproducibly increases
HIV infection. This stimulatory effect is evident for the R5-tropic strains of virus responsible for sexual transmission, reflects the rate of
infection rather than viral growth, and occurs at clinically relevant concentrations of the compound. An examination of published studies shows that the biphasic effect of
cellulose sulfate was evident in previous research by independent laboratories and is also found for other
polyanions such as
dextrin sulfate and
PRO2000. These data help in understanding the failure of the
Ushercell clinical trial and indicate that
cellulose sulfate is not safe for mucosal application in humans.