Patrick Mitchell

Interdisciplinary Training

Patrick Mitchell

"Evolution of antiviral specificity and function of the primate Mx GTPases"

Interferon-stimulated genes (ISGs) represent a critical molecular barrier to prevent viral infections
including HIV-1. The Malik/Emerman labs have pioneered a combined evolutionary and functional
virology approach that leverages the natural variation of ISGs in primates to study host/virus
interactions, which has provided unique and important insights into human disease susceptibility, cross-
species transmission and virus emergence/spillover events. I intend to use this approach to understand
the unusually broad antiviral activity of MxA, and the newly identified anti-HIV-1/SIV function of its
paralog, MxB.

The large GTPase MxA acts against a wide spectrum of both RNA and DNA viruses, but not retroviruses
such as HIV-1. In contrast the function of the MxA paralog MxB has long been enigmatic, despite sharing
numerous characteristics with MxA including induction by interferon. Recently, human MxB was found
to inhibit HIV-1 replication. This suggests that MxA and MxB have evolved distinct antiviral specificities. I
have found that surfaces on MxA and MxB are rapidly evolving under positive selection consistent with a
role for these surfaces in the interaction between MxA and MxB with their viral targets. I have
previously used this signature to characterize the molecular basis for MxA antiviral specificity against
orthomyxoviruses (such as influenza). This proposal aims to determine how other rapidly evolving MxA
surfaces contribute to its restriction of multiple viruses, thereby providing a molecular basis for the
antiviral breadth of MxA. Using a similar strategy I will characterize the evolution and function of the
newly identified host restriction factor MxB against HIV-1.