# Adenovirus manipulation of cellular chromatin to overcome host responses

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $542,364

## Abstract

PROJECT SUMMARY
The need to evade antiviral immune responses has driven evolution of viral strategies to manipulate host cell
chromatin, to control gene expression and subvert cellular defenses. Adenoviruses are ubiquitous viruses that
have provided both important model systems for understanding fundamental cellular processes, as well as
vectors for therapeutic purposes. Infections by Adenovirus and derived vectors elicit strong innate immune
responses, which impact both the course of disease and their effectiveness as vectors for gene delivery and
vaccination. Therefore understanding viral proteins that subvert host responses is important for treating
infections and improving therapeutic vector applications. Here we focus on Adenovirus protein VII, the major
core protein that was previously thought to function exclusively for packaging viral genomes. We discovered
that protein VII has unexpected roles on both viral and host genomes during Adenovirus infection. The long-
term goal of this project is to decipher how this histone-like viral protein overcomes innate host responses and
promotes production of infectious viral progeny. We recently showed that protein VII binds DNA and
nucleosomes, possesses post-transcriptional modifications (PTMs) analogous to histones, and accumulates in
chromatin during infection. We demonstrated that protein VII can alter the composition of host proteins
associated with viral genomes in the nuclei of infected cells, and also sequesters host factors in cellular
chromatin. Our central hypothesis is that Adenovirus protein VII mimics histones as part of an insidious
strategy that manipulates both viral and cellular chromatin to subvert innate host responses. This novel
hypothesis has been formulated on the basis of extensive preliminary data produced in our lab with new tools
we have generated to study how protein VII is necessary and sufficient to counter cellular immune responses.
The two integrated Specific Aims are designed to test our hypothesis by studying functions of protein VII on
viral and cellular genomes. Aim 1 will define functions of protein VII on the viral genome during infection.
Biochemical and molecular experiments will address how protein VII exploits host machinery to promote
production of infectious progeny. Aim 2 will examine the impacts of protein VII on cellular chromatin and
genome architecture. Genomic and cellular approaches will determine how association of protein VII with
cellular proteins and the chromatinized genome serves to counteract antiviral host responses. We have
assembled an interdisciplinary collaborative team to determine this core viral histone-like protein subverts
cellular innate immune responses in a project that has broader implications for understanding how viruses elicit
changes in chromatin to overcome host defenses.

## Key facts

- **NIH application ID:** 9979734
- **Project number:** 5R01AI121321-03
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Matthew D. Weitzman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $542,364
- **Award type:** 5
- **Project period:** 2018-09-24 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979734

## Citation

> US National Institutes of Health, RePORTER application 9979734, Adenovirus manipulation of cellular chromatin to overcome host responses (5R01AI121321-03). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/9979734. Licensed CC0.

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