DESCRIPTION (provided by applicant): Dendritic cells (DCs) found in dermal and mucosal tissue express the lectin, DC-specific intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN), a mannose binding, calcium dependent, lectin. Because DCs are found at mucosal surfaces, they are one of the first cell types exposed to HIV-1 and their cell surface DC-SIGN binds it by adhering to mannose residues present on gp120. While binding and uptake mediated by DC-SIGN is considered to play an important role in the immune response, in some instances it facilitates viral infection. Its interaction with HIV-1 and 2 is an example of this. DC-SIGN has been found to bind other viruses including Ebola, hepatitis C virus, cytomegalovirus and Dengue virus, as well as different bacteria. In studies of infection of DC-SIGN expressing cells by Ebola, it was found that a hyperbranched dendritic polymer (dendrimer) derivatized with mannose residues was able to inhibit the receptor function of the DC lectin . Similar studies have not been carried out with HIV. This is a glaring deficit since mannose- specific lectins were found to inhibit infection of T lymphocytes by HIV-1, presumably by binding the mannose residues and blocking DC-SIGN binding to gp120. These observations provide a solid base for the hypothesis that mannosylated dendrimers might inhibit infection by HIV as well. Proposed experiments are designed to determine whether mannosylated dendrimers are effective ligands for DC-SIGN and if so whether they inhibit the interaction of DC-SIGN with gp120. Once an effective inhibitor is identified, experiments will be carried out to determine whether it is taken up by cells. If as anticipated, mannosylated dendrimers are effective inhibitors of the binding of rgp120 by DC-SIGN-expressing target cells, it will provide a new potential therapeutic approach for the prevention of HIV-1, and would support the hypothesis that multivalent mannosylated compounds might be effective at inhibiting the interaction of other pathogens that utilize the DC-SIGN pathway. It is these possibilities that make this research worth the risk.
|Effective start/end date||9/15/07 → 8/31/10|
- National Institutes of Health: $222,197.00
- National Institutes of Health: $183,650.00
Cell Adhesion Molecules