Speaker
Description
Human endogenous retroviruses (HERVs) comprise about 8% of our genome and provide us with a valuable fossil record of host-retrovirus interaction in our primate ancestors. The most recently active HERV-K(HML-2) 5Hs group, although now apparently extinct as an infectious agent, has some members that entered our ancestral genome less than 1 million years ago and retain one or more viral ORFs,. Members of this clade are known to be transcriptionally and translationally active in healthy tissue, malignancies, and early developmental states. Here, we report the likely functional activity of a specific provirus, at 3q12.3, which integrated into a common ancestor of humans and gorillas, some 8-12 million years ago, yet retains an intact gag ORF and, due to a human-specific 4-nucleotide duplication in the 5’ LTR is the most widely expressed HML-2 provirus in normal human tissues. Its sequence shows a clear sign of purifying selection in humans with very little diversity across >5000 alleles, especially in a segment encompassing CA (capsid) and NC (nicleocapsid) proteins derived by recombination with an older LTR5B provirus. Coexpression of 3q12.3 Gag with consensus HML-2 Gag reveals a block to oligomerization and viral budding, leading to aberrantly-formed particles. The critical determinant of restriction activity was the CA protein, specifically a single amino acid deletion in the linker between the N- and C-terminal domains. Together, these findings suggest that 3q12.3 gag has been maintained as a retroviral restriction factor and may have contributed to its apparent extinction within the last million years. This mechanism of viral restriction appears to extend beyond HERV-K(HML-2), as the 3q12.3 Gag shows significant inhibition against the egress of HIV-1, but not ALV (an alpharetrovirus), MLV (a gammaretrovirus), or MPMV (a betaretrovirus). These findings illuminate Important aspects of the evolutionary history of the association of retroviruses and our ancestors.
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