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TRIM5 is a member of a broad family of otherwise unrelated proteins defined by the presence of a tripartite motif containing a RING domain, a B-box type 1, and a B-box type 2, followed by a coiled-coil region. TRIM5 has six alternately spliced isoforms, the longest of which is the α variant which also contains a carboxy-terminal B30.2 (SPRY) domain. Expression of TRIM5α variants from humans, rhesus monkeys, and African green monkeys enabled resistance to infection by various retroviruses including HIV-1, albeit at differing efficiencies. All TRIM5α variants could inhibit at least two different retroviruses, but not from those viruses isolated from the same species, suggesting that TRIM5α acts as a natural barrier to cross-species retrovirus transmission.