Abstract
BackgroundContinued efforts are being directed toward the development of microbicides that will be used to reduce or eliminate the risk of HIV-1 sexual transmission. Unfortunately, clinical trials involving polyanion-containing microbicide formulations, including Carraguard (λ-carrageenan [LC]) and Ushercell (cellulose sulfate [CS]) demonstrated that these products were ineffective and may have, in some circumstances, increased the risk of HIV-1 infection. These findings prompted reassessments of the in vitro activities of these agents to determine whether variables that can affect agent safety and efficacy had been overlooked during preclinical testing. One such variable is product retention and loss following topical application.ResultsIn the present studies involving an HIV-1-susceptible cell line and primary human immune cells, product loss was mimicked by introducing and then removing polyanionic compounds prior to HIV-1 infection. In these in vitro "washout" experiments, LC and CS significantly enhanced HIV-1 infection, despite potent antiviral activity when introduced simultaneously with the virus. The presence and magnitude of this effect were dependent on compound identity and concentration; target cell; interval between compound removal and virus challenge; and coreceptor usage. Levels of enhancement (relative to controls) were considerable, exceeding a 200% increase (CS) in P4-R5 MAGI cells and a 300% increase (LC) in human peripheral blood mononuclear cells.ConclusionsThese studies, which demonstrate significant increases in HIV-1 infection subsequent to application and removal of LC and CS, support plausible explanations for the failures of microbicides formulated from these compounds. Detailed studies are now underway to determine the mechanism responsible for this enhancement effect and to assess the potential contribution of this effect to the clinical failures of these agents.
Highlights
Continued efforts are being directed toward the development of microbicides that will be used to reduce or eliminate the risk of HIV-1 sexual transmission
Polyanionic compounds effectively inhibit infection by HIV-1 BaL and IIIB To establish compound concentrations to be used in the washout assays, P4-R5 MAGI cells and peripheral blood mononuclear cells (PBMCs) were exposed to each compound and simultaneously infected with HIV-1
Preexposure to cellulose sulfate (CS) or LC enhances P4-R5 MAGI infection by R5 HIV-1 In the washout infection experiments, antiviral compounds were removed from the culture media before introduction of virus
Summary
Continued efforts are being directed toward the development of microbicides that will be used to reduce or eliminate the risk of HIV-1 sexual transmission. Clinical trials involving polyanion-containing microbicide formulations, including Carraguard (l-carrageenan [LC]) and Ushercell (cellulose sulfate [CS]) demonstrated that these products were ineffective and may have, in some circumstances, increased the risk of HIV1 infection. These findings prompted reassessments of the in vitro activities of these agents to determine whether variables that can affect agent safety and efficacy had been overlooked during preclinical testing. In the present AIDS pandemic, approximately 50% of the 33.4 million people infected with HIV-1 are women [1] This fact highlights the urgent need for female-controlled and female-centric prevention methods that can effectively reduce or eliminate the risk of infection in women. Among the potential microbicide agents advanced through clinical trials were two compounds classified as polyanions: carrageenan and cellulose sulfate (CS). l-Carrageenan (LC) was thought to be especially promising as an antiviral agent because its demonstrated in vitro IC50 (the concentration at which 50% virus inhibition is achieved) was more than 100-fold lower than its anticoagulant threshold, suggesting a margin of safety for use at concentrations capable of inhibiting infection [7]
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