The restriction factor TRIM5α binds to the capsid protein of the retroviral core 
and blocks retroviral replication. The affinity of TRIM5α for the capsid is a 
major host tropism determinant of HIV and other primate immunodeficiency 
viruses, but the molecular interface involved in this host-pathogen interaction 
remains poorly characterized. Here we use NMR spectroscopy to investigate 
binding of the rhesus TRIM5α SPRY domain to a selection of HIV capsid 
constructs. The data are consistent with a model in which one SPRY domain 
interacts with more than one capsid monomer within the assembled retroviral 
core. The highly mobile SPRY v1 loop appears to span the gap between neighboring 
capsid hexamers making interhexamer contacts critical for restriction. The 
interaction interface is extensive, involves mobile loops and multiple epitopes, 
and lacks interaction hot spots. These properties, which may enhance resistance 
of TRIM5α to capsid mutations, result in relatively low affinity of the 
individual SPRY domains for the capsid, and the TRIM5α-mediated restriction 
depends on the avidity effect arising from the oligomerization of TRIM5α.