Carbohydrate-Binding Agents: A Potential Future Cornerstone for the Chemotherapy of Enveloped Viruses?

Abstract

Carbohydrate-binding agents (CBAs) inhibit HIV-1 and it is proposed that therapy with such agents may have important implications for the future of anti-HIV therapy. Examples of CBAs include the procaryotic cyanovirin-N (CV-N), plant lectins such as HHA, GNA, NPA, CA and UDA, the monoclonal antibody 2G12 directed against a glycan-containing epitope on HIV envelope gp120, and the mannose-specific non-peptidic antibiotic Pradimicin A, which inhibits the entry of HIV-1 into its target cells. CBAs prevent not only virus infection of susceptible cells, but also inhibit syncytia formation between persistently HIV-infected cells and uninfected lymphocytes. In addition, CBAs may also prevent DC-SIGN-mediated transmission of HIV to T-lymphocytes. Therefore, CBAs qualify as potential microbicide drugs. Long-term exposure of HIV to CBAs in cell culture results in the progressive deletion of N-glycans of HIV gpl20 in an attempt of the virus to escape drug pressure. In this respect, the CBAs are endowed with a high genetic barrier. Multiple mutations at N-glycosylation sites are required before pronounced phenotypic drug resistance development becomes evident. CBA treatment of HIV may consist of a novel chemotherapeutic concept with a dual mechanism of antiviral action: a direct antiviral activity by preventing HIV entry and transmission to its target cells, and an indirect antiviral activity by forcing HIV to delete glycans in its gpl20 envelope. The latter phenomenon will result in creating 'holes' in the protective glycan shield of the HIV envelope, whereby the immune system may become triggered to produce neutralizing antibodies against previously hidden immunogenic epitopes of gp120. If this concept can be proven in in vivo, low-molecular-weight non-peptidic CBAs such as Pradimycin A may become the cornerstone for the efficient treatment of infections of those viruses that require a glycosylated envelope (that is, HIV, but also hepatitis C virus) for entry into its target cells. In addition, influenza virus and coronavirus infections may also qualify to be treated by CBAs.