A bioactive phlebovirus-like envelope protein in a hookworm endogenous retrovirus

Endogenous retroviruses (ERVs), accounting for 14% of our genome, serve as a genetic reservoir from which new genes can emerge. Nematode ERVs are particularly diverse and informative of retrovirus evolution. We identify Atlas virus – a novel, intact ERV in the human hookworm Ancylostoma ceylanicum with an envelope protein genetically related to G N -G C glycoproteins from phleboviruses. A cryo-EM structure of Atlas G C reveals a class II viral membrane fusion protein fold not previously seen in retroviruses. Atlas G C has the structural hallmarks of an active fusogen. Atlas G C trimers insert into membranes with endosomal lipid compositions and low pH. When expressed on the plasma membrane, Atlas G C has cell-cell fusion activity. Atlas virus is transcriptionally active at specific stages of hookworm development. The preserved activities and expression pattern of Atlas G C suggest it has acquired a cellular function. Our work reveals an unexpected degree of structural and genetic plasticity in retroviruses.