title: Application and removal of polyanionic microbicide compounds enhances subsequent infection by HIV-1.
abstract: BACKGROUND
  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. 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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Department of Microbiology and Immunology, and Center for Molecular Therapeutics and Resistance, Center for Sexually Transmitted Disease, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pirrone
authors.forename: Shendra
authors.initials: S
authors.lastname: Passic
authors.forename: Brian
authors.initials: B
authors.lastname: Wigdahl
authors.forename: Fred C
authors.initials: FC
authors.lastname: Krebs
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002482:Cellulose / Q000031:analogs & derivatives / Q000494:pharmacology; D015497:HIV-1 / Q000254:growth & development* / Q000472:pathogenicity; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000821:virology*; D000071228:Polyelectrolytes; D011108:Polymers / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D002482:Cellulose; D000071228:Polyelectrolytes; D011108:Polymers; D014227:Triazines; C013431:caragard; C020254:cellulose sulfate