Receptor binding is a key step in the life cycles of all animal viruses, and in many cases the virus-receptor interactions determine both the host susceptibility and tissue tropism. Receptors for different viruses include carbohydrates and proteins, and in some cases multiple receptors work in concert to mediate cell binding and infection (33,37,66,71,73). For nonenveloped viruses the interaction with the receptor initiates a series of steps that leads to capsid endocytosis, sorting of the particle into an endosomal compartment for penetration into the cytoplasm, disassembly to allow release of the infectious material, and transport of the genome and associated proteins within the cell to allow replication (37,39,42,60,61,70). Infection of cells by most viruses involves complex interactions and structural changes induced by receptor binding, low pH, or endosomal proteolysis that allow membrane penetration and intracellular delivery (39,66,89,90).Our studies of the viral-cell interactions and intracellular trafficking pathways of canine and feline parvoviruses have shown that the specific interactions between viral capsids and host transferrin receptors (TfR) are critical to infection (24-26, 48, 50). Canine parvovirus (CPV) and the closely related feline panleukopenia virus (FPV) are small nonenveloped viruses that, depending on the strain of virus, infect cats and/or dogs. They provide a model for the process of cell infection and also for the control of viral host range through capsid-receptor interactions (reviewed in reference 27). CPV emerged as a pandemic virus in dogs during the 1970s, and the strain of virus that spread widely in 1978 was designated CPV type-2 (CPV-2) to distinguish it from a previously known but distinct parvovirus, minute virus of canines (57, 67). CPV-2 differs from FPV or closely related viruses in only a small number of sequence changes (68, 81), and the ability to infect dogs or dog cells is controlled by changes in a raised region of the capsid surrounding the threefold axis of icosahedral symmetry (the threefold spike) (1). Amino acids affecting host range in natural variants or laboratory-derived mutants included VP2 residues 93 (Lys in FPV; Asn in CPV), 323 (Asp in FPV; Asn in CPV), 299 (Gly in wild-type CPV-2; Glu in the host range mutant CPV-2-G299E), and 300 (Ala in wild-type CPV; Asp in the mutant CPV-2-A300D) (12,23,24,36,51).During 1979 a variant strain of CPV, CPV type-2a (CPV2a), emerged in dogs and within 1 year had replaced CPV-2 worldwide (56, 58); the variant contained differences of VP2 residues 87, 101, 300, and 305 (53-55). CPV-2a had regained the host range for cats and was also antigenically variant (29,46,58,80). Additional single mutations of CPV-2a that have become widely distributed since 1980 include the substitution of VP2 residue 426 (Asn to Asp) to give the antigenic variant designated CPV-2b, which appears to be the same as CPV-2a in host range and other properties (74,81).FPV and CPV both bind the feline TfR and use that receptor for cell infection; ...