Viral Attachment and Entry - HIV and Emerging Viruses

Viral envelope glycoproteins are highly glycosylated structures that interact with various cell surface receptors. My lab places emphasis on the mechanisms of viral entry and membrane fusion, focusing on the interaction of the viral envelope with cell surface receptors.

Immunobiology of DC-SIGN mediated transfer of HIV-1. DC-SIGN is a viral attachment molecule specifically expressed on dendritic cells (DCs), and is though to mediate the sexual mucosal transmission of HIV. Our DC-SIGN work focuses on the structure-function of DC-SIGN/HIV envelope interactions and characterizing the biology of these DC-SIGN+ DCs in human rectal mucosa (Gurney et. al., (2005) J.Virol.) The ultimate aim of these studies is to develop microbicides that can prevent sexual mucosal transmission of HIV, and engineer a vaccine that can elicit antibodies that target this initial viral-DC interaction.

Glycobiology of Nipah virus entry. Nipah virus is a Priority Pathogen in the NIH Biodefense Research Agenda and can cause up to a 70% mortality rate. We are focused on the glycan structures on the Nipah viral envelope that mediate target cell binding and membrane fusion. These glycan structures also "shield" the Nipah viral envelope from neutralizing antibodies, our studies are generating selectively deglycosylated Envs that are more neutralization sensitive and may lead to design of a better immunogen. Our lab has also recently identified the bona fide receptor for Nipah virus entry (Negrete et. al. (2005) Nature). We will further characterize the interaction between NiV envelope and its cognate recetpor with the goal of developing therapeutics that can block Nipah virus entry. These studies will complement our studies into the glycobiology of HIV entry.

Novel innate immune system functions of galectin-1. Galectin-1 is an immune system lectin that can induce a marked upregulation of proinflammatory cytokines from dendritic cells. It also has direct anti-viral activities for several viruses including Nipah virus (Levroney et. al., (2005) J. Immunol.). Recently, gal-1 has also been shown to enhance HIV entry. We intend to study gal-1's differential modulation of infection by various viruses. To further understand the basis of gal-1's effect on DC maturation, we will identify the bona fide gal-1 ligands on DCs and characterize the signaling pathways induced by gal-1 interacting with DCs using biophysical and bioinformatics approaches.