The EBV gp350 polypeptide (907 residues) contains an 18-residue peptide at the C terminus that is located inside the viral membrane, a membrane-spanning domain and a large N-terminal segment (860 residues) predicted to extend outside the viral membrane. The extreme N-terminal region (residues 1–470) of gp350 is sufficient to bind receptor CR2. The gp350-binding region on CR2 has been mapped to N-terminal short consensus repeats (SCRs) 1 and 2, which also bind C3d. A soluble N-terminal gp350 fragment (residues 1–470) can prevent EBV attachment to cells by blocking receptor binding, and soluble SCR1 and SCR2 from CR2 can block EBV infection and EBV-induced lymphoproliferation. Furthermore, gp350 is a primary target of neutralizing antibody in human hosts, and immunization with gp350 has been shown to provide protection from EBV challenge in an animal model20–23. Thus, the interaction of gp350 with CR2 is an important step for intervention against virus infection and virus-associated cancer development.