# Evolution and mechanisms of cytomegalovirus antagonism of host cell defenses

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2022 · $440,057

## Abstract

Project Summary/Abstract
Human cytomegalovirus (HCMV) causes life-threatening diseases in patients with poor immune system
function and long-lasting neurological disabilities in congenitally-infected newborns. In addition to its medical
importance, HCMV and related viruses provide a powerful experimental model for investigating how viruses
evolve to elude host cell defense systems. The long-term goal of this research is to discover evolutionary and
molecular mechanisms by which viruses like HCMV control the host cell's protein synthesis machinery to allow
viral replication. One of the defense systems that inhibits many viruses is mediated by protein kinase R (PKR).
HCMV encodes two protein antagonists of PKR, TRS1 and IRS1, at least one of which is absolutely essential
for the virus to replicate in human cells. Aim 1 seeks to understand why HCMV, like several other large DNA
viruses, has two genes that serve the same function. Studies of mutant viruses that have only one of the genes
will be used to determine why viruses lacking TRS1 have a replication defect not observed with viruses lacking
just IRS1. Other experiments will reveal whether the combination of both genes confers a benefit to the virus
under conditions that more closely model natural infections than previous studies, such as when clinical strains
of HCMV infect different types of cells, and when they encounter an inflammatory environment. Aim 2 will
elucidate mechanisms by which CMV can adapt to overcome PKR using gene duplication and horizontal
gene transfer, two processes that have had major impacts on the evolution of large DNA viruses. Aim 3 will
dissect how a domain in PKR that is critical for its activity has adapted to maintain its function in
defending the host, while changing enough to evade viral factors. Comparisons of variants of this domain
in humans, Old World monkeys, and New World monkeys, using the powerful technique of “deep mutational
scanning” in which each amino acid in a protein is mutated to all of the other 19 alternatives, will reveal how this
region of PKR has evolved and how in turn CMVs have evolved to adapt to the changes. These studies will
reveal insights into the mechanisms and evolution of both viral and host factors that are in conflict and that
determine whether the virus replicates or is successfully blocked by host defenses.

## Key facts

- **NIH application ID:** 10376227
- **Project number:** 6R01AI145945-03
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** ADAM P. GEBALLE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $440,057
- **Award type:** 6
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376227

## Citation

> US National Institutes of Health, RePORTER application 10376227, Evolution and mechanisms of cytomegalovirus antagonism of host cell defenses (6R01AI145945-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10376227. Licensed CC0.

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