# Mechanism of Viral Genome Delivery into Cells

> **NIH NIH R35** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $323,216

## Abstract

Project Summary
Nearly 120 years since the discovery of the first virus, our understanding of how viruses deliver genomes into
cells overcoming the complexity of biological membranes remains limited. While a vast scientific literature
exists on viral surface proteins and their interaction with host receptors, and the immune system, little
emphasis has been devoted to studying the delivery of entire viral genomes into cells. For instance, how do
bacteriophages eject DNA through the cell envelope of Gram-negative bacteria? Or, in humans, how do
herpesviruses deliver ~200 kb genome through the Nuclear Pore Complex (NPC) into the cell nucleus?
 For a quarter of a century, first as a trainee (1995-2003), and since 2004 as a principal investigator, I have
investigated the mechanisms of nucleocytoplasmic transport and viral genome packaging. My work has
resulted in close to 85 publications that contributed to elucidating the atomic structure and regulation of crucial
factors implicated in nuclear import, and viral genome packaging. In this R35, I propose to combine the study
of these two seemingly distinct biological processes by focusing on the mechanisms of viral genome delivery
into living cells. Specifically, I will ask two biological questions that seek to compare and contrast how simple
bacterial viruses (or bacteriophages) eject their DNA into bacteria with how Herpesviruses deliver their
complex genomes into the nucleus of eukaryotic cells. The first question explores how bacteriophages
eject ~45 kb genomes through the cell envelope of gram-negative bacteria. Long-thought to be a simple
pressure-driven injection, this process uses a virus-encoded nanomachine, which we have begun to study in
my laboratory. The second question explores how Herpesviruses deliver their large genome through the
Nuclear Pore Complex (NPC) of human cells into the cell nucleus. This is a signal- and energy-mediated
process that uses host importins and the GTPase Ran, exploiting the cellular transport machinery to promote
entry of an exogenous genome into the nucleus. Overall, understanding how viruses transfer genetic
information through biological membranes into cells and organelles is vital for deciphering the molecular
mechanisms of virulence as well as the development of novel therapeutic approaches. The common
denominator of this R35 lies in our interest in the structure and transport mechanisms of biological
macromolecules. Our research approach marries established sciences like protein biochemistry and X-ray
crystallography with the power of cryo-electron microscopy (cryo-EM) to visualize biological macromolecules in
near-native conditions. We believe that this R35 MIRA funding mechanism will fuel the creative and diligent
pursuit of answers to the questions we pose, permitting our research program to achieve significant
advancements in structural biology.

## Key facts

- **NIH application ID:** 11013985
- **Project number:** 7R35GM140733-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Gino Cingolani
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $323,216
- **Award type:** 7
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11013985

## Citation

> US National Institutes of Health, RePORTER application 11013985, Mechanism of Viral Genome Delivery into Cells (7R35GM140733-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11013985. Licensed CC0.

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