Editors' ChoiceInfectious Disease

Gamete fusion gone viral

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Science Translational Medicine  15 Mar 2017:
Vol. 9, Issue 381, eaam9866
DOI: 10.1126/scitranslmed.aam9866


Enveloped virus infection may be linked to the origin of sexual reproduction.

Sexual reproduction and enveloped virus infection have many similarities, including a requirement for membrane fusion. Enveloped viruses, such as flaviviruses (e.g., Zika virus and dengue virus) and alphaviruses (e.g., chikungunya virus), fuse with host cells by utilizing virus-encoded class II fusion proteins. These specialized envelope proteins contain a fusion loop, which undergoes a conformational change to insert itself into the host cell membrane and to subsequently promote membrane fusion. Neutralizing antiviral antibodies that are readily generated against the class II fusion proteins of these enveloped viruses are able to block viral entry into target cells, thereby producing protective and sometimes even therapeutic antiviral immunity.

HAP2 is a male gamete (sperm)–specific transmembrane protein that is expressed in multiple taxa, including plants, arthropods, and protists, but not vertebrates. HAP2 was first identified more than a decade ago and was subsequently found to be necessary for gamete fusion. In order to better define mechanisms of HAP2-mediated membrane fusion, Fédry et al. set out to crystalize and further characterize HAP2 from the green alga Chlamydomonas reinhardtii, and what they found was unexpected and remarkable: the structure of HAP2 bears a striking resemblance to the class II fusion proteins expressed by enveloped viruses. Crystallographic analysis revealed that HAP2 also has a fusion loop, much like flavivirus and alphavirus class II fusion proteins. Next, the authors generated HAP2 fusion loop mutants and an anti-HAP2 fusion loop antibody, which prevented gamete fusion in functional studies.

The implications of Fédry et al.’s findings are stunning. Indeed, the fact that male gametes from multiple taxa utilize a virus-like class II fusion protein to facilitate membrane fusion and fertilization suggests that a virus infection of an ancient eukaryote resulted in integration of a viral class II fusion protein into the host genome in an event that may have occurred at the very origin of sexual reproduction. Furthermore, this discovery has major implications for the generation of novel therapies. Since HAP2 is also expressed by parasitic microorganisms, including Plasmodium (malaria), Toxoplasma, and Trypanosoma, antibodies and vaccines that target the fusion loop of HAP2 may have the capacity to prevent or cure these infectious diseases.

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