Chance favors a prepared genome.

D uring evolution, all vertebrates have been exposed to multiple waves of crossspecies infection by retroviruses. A number of defensive strategies have developed, among them the spontaneous expression, throughout the body, of restriction factors, antiviral proteins that will bind to the capsid (CA) protein of incoming virions and interfere with virus replication (1). One example of such a protein is TRIM5 , first described in 2004, that provides species-specific retrovirus restriction and can prevent HIV-1 infection (2). TRIM5 can block retrovirus replication either before or after reverse transcription seemingly dependent on proteasome engagement (3). It comprises an N-terminal RBCC domain made up of RING (R), B-box (B), and coiled-coil (CC) modules and a Cterminal B30.2 domain (4). The B30.2 domain mediates virus binding and determines which viruses a given TRIM5 will restrict, whereas the RBCC domain is important for TRIM5 multimerization and appears responsible for communicating with the proteasome. Shortly after the initial description of Trim5 , a novel restriction protein was reported in Aotus trivirgatus (owl monkey). Insertion of a cyclophilin A (CypA) pseudogene between exons 7 and 8 of the TRIM5 gene resulted in formation of a fusion protein where the CypA has replaced the B30.2 domain (5, 6). Because CypA can bind CA from various lentiviruses (7), this fusion protein can act as a restriction factor for a number of viruses including HIV-1. Remarkably, it now appears that the owl monkey fusion protein is not unique. Three articles in this issue of PNAS, by Wilson et al. (8), Virgen et al. (9), and Brennan et al. (10), and two articles published elsewhere (11, 12) provide a description of the second, independent case of the generation of a Trim5CypA fusion protein.