Evolution-Guided Identification of Antiviral Specificity Determinants in the Broadly Acting Interferon-Induced Innate Immunity Factor MxA

SummaryMxA is an interferon-induced dynamin-like GTPase with wide-ranging antiviral activity, which hinges upon detection of unique viral structures that differ across virus families. Despite elucidation of its structure, the basis of MxA antiviral specificity remains enigmatic. We used an evolution-guided approach to identify the loop L4 of MxA as a hotspot for recurrent positive selection in primates. Further, we show that single amino acid changes in L4 are necessary and sufficient to explain dramatic differences in species-specific antiviral activity of primate MxA proteins against the orthomyxoviruses Thogoto virus and influenza A virus. Taken together, our findings identify a genetic determinant of MxA target recognition and suggest a model by which MxA achieves antiviral breadth without compromising viral specificity.

► The unstructured loop L4 in primate MxA evolves under strong positive selection
► Loop L4 is the determinant of MxA antiviral specificity against orthomyxoviruses
► A single amino acid confers MxA antiviral specificity for Thogoto virus (THOV)
► MxA antiviral specificity for influenza A virus is also mediated by L4