Abstract
Intrinsic immunity relies on specific recognition of viral epitopes to mount a cell-autonomous defense against viral infections. Viral recognition determinants in intrinsic immunity genes are expected to evolve rapidly as host genes adapt to changing viruses, resulting in a signature of adaptive evolution. Zinc-finger antiviral protein (ZAP) from rats was discovered to be an intrinsic immunity gene that can restrict murine leukemia virus, and certain alphaviruses and filoviruses. Here, we used an approach combining molecular evolution and cellular infectivity assays to address whether ZAP also acts as a restriction factor in primates, and to pinpoint which protein domains may directly interact with the virus. We find that ZAP has evolved under positive selection throughout primate evolution. Recurrent positive selection is only found in the poly(ADP-ribose) polymerase (PARP)–like domain present in a longer human ZAP isoform. This PARP-like domain was not present in the previously identified and tested rat ZAP gene. Using infectivity assays, we found that the longer isoform of ZAP that contains the PARP-like domain is a stronger suppressor of murine leukemia virus expression and Semliki forest virus infection. Our study thus finds that human ZAP encodes a potent antiviral activity against alphaviruses. The striking congruence between our evolutionary predictions and cellular infectivity assays strongly validates such a combined approach to study intrinsic immunity genes.
Highlights
Recent discoveries have highlighted the role of intrinsic immunity genes in primate host defense against viral infections [1,2,3]
This ‘‘back-and-forth’’ evolution is predicted to result in rapid changes of both host and viral proteins, which results in an evolutionary signature of positive selection, especially at the direct interaction interface
We queried the primate orthologs of zinc-finger antiviral protein (ZAP) to ascertain both whether they have evolved under positive selection, and whether they have antiviral activity
Summary
Recent discoveries have highlighted the role of intrinsic immunity genes in primate host defense against viral infections [1,2,3] These genes are predicted to be locked in ancient, ongoing genetic conflicts with an ever-changing repertoire of viral infections [4,5,6]. Consistent with this prediction, the primate genes that encode for intrinsic immunity have been found to be evolving under positive selection, wherein they accumulate an excess number of nonsynonymous substitutions (protein-altering, dN) compared to synonymous substitutions (no effect on protein, dS). A signature of positive selection has provided information about the antiviral activity and age of these ‘‘restriction’’ genes, but has helped to identify protein domains at the direct interface of the host– virus interaction [4]
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