Background:  Trim5a is a host antiretroviral gene that interacts with retroviral capsids and has been evolving under extreme positive selection in the primate lineage throughout the last 30 million years. Presumably, this rapid evolution is due to episodic conflicts with retroviruses in a lineage-specific manner. Retroviruses in general have potential to invade and fix into the genomes of their host. Recently, it was discovered that about 150 copies of a g-retrovirus called PtERV is now present as an endogenous retrovirus in chimpanzees, but is completely absent from the human genome. This virus was estimated to be active as an exogenous virus approximately 3million to 4 million years ago. The absence of any relic of PtERV in the human genome may be an indication that early humans had an active mechanism of restriction of this virus. Thus, we tested whether or not Trim5a could have protected humans from infection by PtERV.

Methods:  We reconstructed the p12 and CA genes of an extinct and inactive endogenous retrovirus called PtERV, which is found in the chimpanzee genomes, but not in the human genome. The PtERV ancestor was determined by in silico techniques and site-directed mutagenesis was used to reconstruct the CA ancestor from the genomic DNA of chimpanzees and gorillas. A chimeric virus of MLV/PtERV was then used to functionally test the restriction of PtERV CA by different Trim5a’s cloned from various hominoids in a heterologous cell line.

Results:  We resurrected the ancestral p12 and CA genes of an extinct endogenous retrovirus and constructed a chimeric virus encoding the PtERV p12 and CA along with the remainder of murine leukemia virus (MLV). This chimeric virus generated infectious virus particles. In functional assays, human Trim5a potently restricts PtERV capsid. Restriction of PtERV is controlled by a single amino acid in the interaction domain of Trim5a. This amino acid is also critical for the ability of Trim5a to restrict HIV-1. Mutations that lose the ability to restrict PtERV gain restriction of HIV-1 and vice versa.

Conclusions:  The ability of human Trim5a to restrict either HIV-1 or PtERV is mutually exclusive. If PtERV did exert selective pressure for a selective sweep of Trim5a in the human lineage 4 million years ago, then it has left humans with a version of Trim5a that now is limited in its ability to prevent or restrict HIV-1.