Viral envelope glycoproteins are highly glycosylated structures that interact with various cell surface receptors. Dr. Benhur Lee's lab studies the mechanisms of HIV entry and membrane fusion, focusing on the interaction of the viral envelope with cell surface receptors. DC-SIGN is such a viral attachment molecule specifically expressed on dendritic cells (DCs) and is thought to mediate the transfer of HIV virions from the mucosa to secondary lymphoid organs.
Lee and his colleagues have determined that a very high affinity viral Env attachment molecule (DC-SIGN) could markedly enhance the efficiency of viral entry. DC-SIGN is also thought to be responsible for the transfer of HIV from DCs in the mucosa to permissive T-cells in secondary lymphoid organs. The researchers are now studying the cell biological, immunological and structural basis for DC-SIGN's ability to facilitate infection in cis- and in trans-. Understanding the intracellular trafficking behavior of DC-SIGN, the factors regulating its expression on dendritic cells and downstream signaling events upon contact with its cognate ligands and the structural interactions between HIV Env and DC-SIGN will allow future exploitation of this DC-HIV interface as a novel target for therapeutic interventions. In addition, the research on DC-SIGN has focused Lee's attention on the family of C-type lectins present on DCs; he and his colleagues are presently studying the functional consequence of their differential regulation on DC subsets.
Due to the recent redirection of national research priorities into the area of bioterrorism, Lee and his colleagues have begun to use their expertise to study the entry mechanism of some emergent viruses like Nipah/Hendra, a new genus of paramyxovirus that can cause fatal encephalitis in greater than 40 percent of infected subjects. Nipah virus is categorized as a Category C priority Pathogen in the National Institutes of Health Biodefense Research Agenda, and is listed as a BSL-4 pathogen (same biosafety class as the Ebola virus). The researchers have generated reagents and systems to study the mechanics underlying the envelope mediated fusion process using the HIV envelope and the Nipah virus envelope as two model systems. The researchers also are generating a minigenome system for the Nipah virus, so that reverse genetics experiments can be performed on the virus under less than BSL-4 conditions. Finally, Lee and his associates are looking at the role of endogenous lectins (as part of the innate immune defense) in modulating the entry of this virus.
Selected Cancer-Related Publications:
Hong PW, Nguyen S, Young S, Su SV, Lee B. Optimal DC-SIGN binding to HIV-1 gp120 involves specific N-glycans within the 2G12 epitope. J Virol. 2007.
Lee B. Envelope-receptor interactions in Nipah virus pathobiology. Ann N Y Acad Sci. 2007; 1102: 51-65.
Aguilar HC, Matreyek KA, Choi DY, Filone CM, Young S, Lee B. Polybasic KKR motif in the cytoplasmic tail of Nipah virus fusion protein modulates membrane fusion by inside-out signaling. J Virol. 2007; 81(9): 4520-32.
de Parseval A, Su SV, Elder JH, Lee B. Specific interaction of feline immunodeficiency virus surface glycoprotein with human DC-SIGN. J Virol. 2004; 78(5): 2597-600.
Su SV, Gurney KB, Lee B. Sugar and spice: viral envelope-DC-SIGN interactions in HIV pathogenesis. Curr HIV Res. 2003; 1(1): 87-99.