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.
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, SIV(mac251)-infected monkeys might represent a relevant animal model to study the efficacy of CBAs in vivo.
François
Katrien O
KO
Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Auwerx
Joeri
J
Schols
Dominique
D
Balzarini
Jan
J
D000818:Animals; D018943:Anthracyclines / Q000378:metabolism / Q000494:pharmacology; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D050260:Carbohydrate Metabolism / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000639:trends*; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000502:physiology*; D006678:HIV / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D037121:Plant Lectins / Q000493:pharmacokinetics / Q000494:pharmacology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000378:metabolism*; D000095643:Pradimicins and Benanomicins
D018943:Anthracyclines; D000998:Antiviral Agents; D037121:Plant Lectins; C058036:pradimicin A; D000095643:Pradimicins and Benanomicins