An Endogenous Retrovirus from Human Hookworm Encodes an Ancient Phlebovirus-Like Class II Envelope Fusion Protein ^†

Abstract

Within the parasitic nematode Ancylostoma ceylanicum, a ~20 million-year-old Bel/Pao LTR retrotransposon encodes an ancient viral class II envelope fusion protein termed Atlas Gc. Typically, retroviruses and related degenerate retrotransposons encode a hemagglutinin-like class I envelope fusion protein. A subset of Bel/Pao LTR retrotransposons within the phylum Nematoda have acquired a phlebovirus-like envelope gene and utilized the encoded fusion machinery to escape the genome as intact exogenous retroviruses. This includes C. elegans retroelement 7 virus which was recently reclassified as a member of the genus Semotivirus. A 3.76 Å cryoEM reconstruction confirms Atlas Gc as a closely related phleboviral homologue and class II fusion protein in a novel case of gene exaptation. Preliminary biophysical and biochemical characterization indicate Atlas Gc functions under specific physiological conditions targeting late-endosomal membranes, much like modern viral class II envelope fusion proteins. Phylogenetic analyses support the reclassification of the Atlas endogenous retrovirus and five other A. ceylanicum ERVs as novel semotiviruses of Belpaoviridae of the new viral order of reverse-transcribing viruses Ortervirales.