Abstract
Carbohydrate-binding agents (CBAs), such as the plant lectins Hippeastrum hybrid agglutinin (HHA) and Urtica dioica agglutinin (UDA), but also the nonpeptidic antibiotic pradimicin A (PRM-A), inhibit entry of HIV into its target cells by binding to the glycans of gp120. Given the high sequence identity and similarity between the envelope gp120 glycoproteins of HIV and simian immunodeficiency virus (SIV), the inhibitory activity of a variety of CBAs were evaluated against HIV-1, HIV-2, and SIV. There seemed to be a close correlation for the inhibitory potential of CBAs against HIV-1, HIV-2, and SIV replication in cell culture and syncytia formation in cocultures of persistently SIV-infected HUT-78 cell cultures and uninfected CEM cells. CBAs also inhibit transmission of the SIV to T lymphocytes after capture of the virus by dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN)-expressing cells. A total of 8 different SIV strains were isolated after prolonged HHA, UDA, and PRM-A exposure in virus-infected cell cultures. Each virus isolate consistently contained at least 2 or 3 glycan deletions in its gp120 envelope and showed decreased sensitivity to the CBAs and cross-resistance toward all CBAs. Our data revealed that CBAs afford SIV and HIV-1 inhibition in a similar manner regarding prevention of virus infection, DC-SIGN-directed virus capture-related transmission, and selection of drug-resistant mutant virus strains. Therefore, SIVmac251-infected monkeys might represent a relevant animal model to study the efficacy of CBAs in vivo.
Footnotes
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This work was supported by the European Commission (René Descartes Prize-2001, Krediet no. HPAW-2002-90001; and EMPRO 503558 of the 6th Frame Work Programme), the Fonds for Wetenschappelijk Onderzoek (FWO) Krediet nr. G-0485-08 and the Centers of Excellence of the Katholieke Universiteit Leuven (Krediet no. EF/05/015).
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ABBREVIATIONS: SIV, simian immunodeficiency virus; CBA, carbohydrate-binding agent; PRM-A, pradimicin A; HHA, Hippeastrum hybrid agglutinin; GNA, Galanthus nivalis agglutinin; UDA, Urtica dioica agglutinin; PVAS, polyvinyl alcohol sulfate; DC-SIGN, dendritic cell-specific ICAM3-grabbing nonintegrin; dNTP, deoxynucleotide triphosphate; PCR, polymerase chain reaction; FCS, fetal calf serum.
- Received March 31, 2008.
- Accepted May 8, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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Simian Immunodeficiency Virus Is Susceptible to Inhibition by Carbohydrate-Binding Agents in a Manner Similar to That of HIV: Implications for Further Preclinical Drug Development
