# Evolution and mechanism of restriction of herpesviruses by MxB

> **NIH NIH R21** · FRED HUTCHINSON CANCER CENTER · 2024 · $220,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Herpesviruses cause a substantial worldwide burden on human health. In response to infections by these and
other pathogens, host cells express thousands of interferon-stimulated genes. One such gene encodes the
myxovirus resistance protein B (MxB) that potently restricts several herpesviruses, including herpes simplex
virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), and cytomegalovirus (CMV). MxB has been undergoing rapid
evolution in primates, as reflected in genetic signatures of positive selection, suggesting that MxB has been
engaged in arms races with viruses over millions of years. Intriguingly, unlike human MxB, the MxB alleles from
several non-human primates do not inhibit HSV-1 replication. In contrast, all tested orthologs retain antiviral
activity against CMV. These results suggest that human MxB, but not non-human primate orthologs, including
the closely related chimpanzee gene, has evolved to restrict HSV-1. This scenario appears to be a rare example
of the host side “winning” during an evolutionary arms race with a virus. To dissect the mechanism MxB utilizes
to restrict HSV-1, studies in Aim 1 will define the role of specific residues that are necessary and sufficient to
explain differing restrictive phenotypes of human and chimpanzee MxB orthologs. Experiments aiming to identify
viral factors that are the targets of MxB, as well as which host co-factors are potentially required, will employ
proximity ligation assays coupled with mass spectrometry. Building on the observation that HSV-2 strains vary
in their sensitivity to human and chimpanzee MxB, Aim 2 will identify which other primate MxB orthologs restrict
which strains of HSV-2, which will help elucidate the evolutionary trajectory of the development of the phenotype.
Additionally, because human MxB restricts only a subset of HSV-2 strains, analyses of sequence differences
among the strains will aid in the identification of viral determinants of MxB sensitivity. Together, this proposal will
reveal the critical factors mediating the arms races between MxB and herpes simplex viruses and will aid in
elucidating the anti-herpesvirus mechanism of MxB.

## Key facts

- **NIH application ID:** 10911144
- **Project number:** 5R21AI171353-02
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** ADAM P. GEBALLE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $220,000
- **Award type:** 5
- **Project period:** 2023-08-21 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911144

## Citation

> US National Institutes of Health, RePORTER application 10911144, Evolution and mechanism of restriction of herpesviruses by MxB (5R21AI171353-02). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10911144. Licensed CC0.

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