# Defining the Impact of Entry Pathways on the Outcome of Human Cytomegalovirus Infection

> **NIH NIH F31** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $36,073

## Abstract

ABSTRACT
 Human cytomegalovirus (HCMV), like all herpesviruses, has two phases of its infectious cycle that enable
lifelong infection in its host. Lytic infection occurs in differentiated cells and produces infectious virions. Latent
infection occurs in undifferentiated cells and is characterized by limited viral gene expression, lack of virion
production, and the potential for reactivation. HCMV virions have a tegument layer around the capsid containing
proteins important for initial events in infection. In differentiated cells, tegument-delivered viral transactivator
pp71 traffics to the nucleus, degrades the cellular repressor DAXX, activates lytic immediate early (IE) genes,
and lytic infection is initiated. In undifferentiated cells, tegument-delivered pp71 does not reach the nucleus,
DAXX is not degraded, IE transcription is silenced, and latent infection is established. This is because in
undifferentiated cells, pp71 and some other tegument proteins remain colocalized with endosomes, while the
genome-containing capsid and capsid-associated tegument proteins reach the nucleus. However, the
mechanism leading to tegument disassembly and the nuclear localization of tegument-delivered pp71 in
differentiated cells and why it does not occur in undifferentiated cells is unknown. Because HCMV enters
fibroblasts (where tegument-delivered pp71 reaches the nucleus) by virion fusion at the plasma membrane, but
enters myeloid cells (where tegument-delivered pp71 remains cytoplasmic) by endocytosis, I hypothesize that
entry by fusion drives pp71 nuclear localization. Here I will test this hypothesis by chemically and biologically
inducing HCMV to fuse into myeloid cells and then monitor tegument-delivered pp71 subcellular localization, IE
transcription, and infection outcome.

## Key facts

- **NIH application ID:** 10996481
- **Project number:** 1F31AI186494-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Esther Lynne Wisdom
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $36,073
- **Award type:** 1
- **Project period:** 2024-09-22 → 2026-09-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996481

## Citation

> US National Institutes of Health, RePORTER application 10996481, Defining the Impact of Entry Pathways on the Outcome of Human Cytomegalovirus Infection (1F31AI186494-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10996481. Licensed CC0.

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