Cyclophilin A is important for the inhibition of HIV-1 by TRIM5α in Old World monkey species. The "specificity" of restriction, that is, whether a given retrovirus can be targeted by TRIM5α, is entirely determined by the amino acid sequence of the C-terminal domain of the protein, called the B30.2/PRY-SPRY domain. Amino acid 332, which occurs within this domain, seems to play a critical role in determining the specificity of retrovirus restriction. TRIM5α may have played a critical role in the human immune defense system about 4 million years ago, when the retrovirus PtERV1 was infecting the ancestors of modern chimpanzees. While no trace of PtERV1 has yet been found in the human genome, about 130 traces of PtERV1 DNA have been found in the genome of modern chimpanzees. After recreating part of the PtERV1 retrovirus, it was reported that TRIM5α prevents the virus from entering human cells in vitro. While this cellular defense mechanism may have been very useful 4 million years ago when facing a PtERV1 epidemic, it has the side effect of leaving cells more susceptible to attack by the HIV-1 retrovirus. Recently, doubt has been cast over these conclusions. By using a PtERV1 capsid, which produces higher titer virus-like particles, Perez-Caballero et al. reported that PtERV1 is not restricted by either human or chimpanzee TRIM5α. Clinical significance Rhesus macaques, a species of Old World monkeys, appeared to be almost completely resistant to HIV-1, the virus that causes AIDS in humans. The Rhesus macaques version of TRIM5α was very quick and had a high enough affinity to the incoming HIV capsule that it could bind and degrade it quickly so that the virus was neutralized. Humans also have a TRIM5α, but it is not well enough tuned to mediate a sufficient response. However, the human version of TRIM5α can inhibit strains of the murine leukemia virus (MLV) as well as equine infectious anemia virus (EIAV). Prior to the discovery of TRIM5α as an antiviral protein, the inhibition phenotype had been described and coined Ref1 (in human cells) and Lv1 (in monkey cells). This terminology is now largely abandoned. A related protein, named TRIMCyp (or TRIM5-CypA), was isolated in the owl monkey, a species of New World monkey, and shown to potently inhibit infection by HIV-1. A similar protein has arisen independently in Old World monkeys and has been identified in several species of macaque. It was recently described