title: Combinations of griffithsin with other carbohydrate-binding agents demonstrate superior activity against HIV Type 1, HIV Type 2, and selected carbohydrate-binding agent-resistant HIV Type 1 strains.
abstract: Carbohydrate-binding agents (CBAs) are potential HIV microbicidal agents with a high genetic barrier to resistance. We wanted to evaluate whether two mannose-specific CBAs, recognizing multiple and often distinct glycan structures on the HIV envelope gp120, can interact synergistically against HIV-1, HIV-2, and HIV-1 strains that were selected for resistance against particular CBAs [i.e., 2G12 mAb and microvirin (MVN)]. Paired CBA/CBA combinations mainly showed synergistic activity against both wild-type HIV-1 and HIV-2 but also 2G12 mAb- and MVN-resistant HIV-1 strains as based on the median effect principle with combination indices (CIs) ranging between 0.29 and 0.97. Upon combination, an increase in antiviral potency of griffithsin (GRFT) up to ∼12-fold (against HIV-1), ∼8-fold (against HIV-2), and ∼6-fold (against CBA-resistant HIV-1) was observed. In contrast, HHA/GNA combinations showed additive activity against wild-type HIV-1 and HIV-2 strains, but remarkable synergy with HHA and GNA was observed against 2G12 mAb- and MVN-resistant HIV-1 strains (CI, 0.64 and 0.49, respectively). Overall, combinations of GRFT and other CBAs showed synergistic activity against HIV-1, HIV-2, and even against certain CBA-resistant HIV-1 strains. The CBAs tested appear to have distinct binding patterns on the gp120 envelope and therefore do not necessarily compete with each other's glycan binding sites on gp120. As a result, there might be no steric hindrance between two different CBAs in their competition for glycan binding (except for the HHA/GNA combination). These data are encouraging for the use of paired CBA combinations in topical microbicide applications (e.g., creams, gels, or intravaginal rings) to prevent HIV transmission.
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Férir
authors.forename: Dana
authors.initials: D
authors.lastname: Huskens
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Palmer
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Boudreaux
authors.forename: Michael D
authors.initials: MD
authors.lastname: Swanson
authors.forename: David M
authors.initials: DM
authors.lastname: Markovitz
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology*; D050260:Carbohydrate Metabolism; D015195:Drug Design; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000187:drug effects* / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D008297:Male; D037121:Plant Lectins / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D015699:HIV Envelope Protein gp120; D037121:Plant Lectins; C499654:griffithsin protein, Griffithsia