Application and removal of polyanionic microbicide compounds enhances subsequent infection by HIV-1

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.

A Single Dose of a MIV-150/Zinc Acetate Gel Provides 24 h of Protection Against Vaginal Simian Human Immunodeficiency Virus Reverse Transcriptase Infection, with More Limited Protection Rectally 8–24 h After Gel Use

“…Moreover, knowing that a vaginal gel does not exacerbate rectal infection is important. Despite in vitro data suggesting a potential enhancing effect of CG on HIV infection, 4,24,25 we have found no evidence of CG-mediated enhancement in macaques following vaginal or rectal application, even when challenging up to 24 h after gel dosing (data herein and unpublished observations). 4,10,11,26 This also supports the earlier findings from the Phase 3 trial testing the efficacy of CG against HIV infection, where the HIV infection frequency was reduced, albeit not significantly, in the CG arm 27 and that HIV shedding was not enhanced in HIVinfected women using CG.…”

The Low-Cost Compound Lignosulfonic Acid (LA) Exhibits Broad-Spectrum Anti-HIV and Anti-HSV Activity and Has Potential for Microbicidal Applications

“…As a vaginal or rectal microbicide may not be toxic nor stimulate HIV target cells, we showed that LA did not activate PBMCs, nor increased their susceptibility for HIV-1 infection as our control agents tenofovir, PRO2000 or acyclovir ( Fig 7 ). In contrast, application and removal of cellulose sulfate and carrageenan, resulted in an enhanced subsequent HIV-1 infection in vitro [ 70 ]. Further studies pointed out that cellulose sulfate altered the epithelial architecture by affecting junctional proteins (e.g.…”

A Modified Zinc Acetate Gel, a Potential Nonantiretroviral Microbicide, Is Safe and Effective against Simian-Human Immunodeficiency Virus and Herpes Simplex Virus 2 Infection In Vivo

“…VivaGel has shown anti-SHIV activity when applied only 20 min before challenge with 2,500 TCID 50 SHIV 89.6P (60), and the anti-HSV-2 window of protection shows 75% to 88% protection when applied up to 30 min before and 27% protection when applied 1 h before HSV-2 at 10 4 PFU (63). VivaGel is also claimed to exhibit anti-HPV activity, but there are no published reports available to compare its activity with the strong in vitro and in vivo anti-HPV activity of carrageenan (32)(33)(34).…”

“…CG represents an excellent delivery vehicle for ZA. It has been shown to be safe and acceptable in numerous preclinical and clinical studies (7,19,22,(25)(26)(27)(28)(29)(30)(31)(32) despite contradictory observations using in vitro systems that CG can enhance HIV infection (22,33). Additionally, CG may have activity against HPV (34)(35)(36).…”