# Viral entry shapes HCMV latency establishment

## TL;DR

This study shows that the efficiency of HCMV entering monocytes affects whether the virus becomes latent or productive, adding a new layer to understanding viral persistence.

## Contribution

The study identifies viral entry efficiency as a previously unrecognized factor in HCMV latency establishment.

## Key findings

- Monocytes have lower viral transcription due to inefficient viral entry compared to macrophages.
- Enhanced viral entry in monocytes enables productive infection, showing they can support lytic replication.
- Integrin β3 contributes to HCMV entry into macrophages, explaining differences in entry efficiency.

## Abstract

Human cytomegalovirus (HCMV) infection results in either productive or latent infection, the latter enabling life-long viral persistence. Monocytes support latent infection but become permissive to productive infection upon differentiation into macrophages. These differentiation-driven differences have been largely attributed to chromatin-mediated repression of the viral genome. Using metabolic labeling of newly synthesized RNA, we observe markedly lower viral transcription at early stages of infection in monocytes compared to macrophages. Unbiased comparison reveals that this difference is partly explained by inefficient viral entry in monocytes: fewer viruses enter, and correspondingly, fewer genomes reach the nucleus. Indeed, ectopic expression of known HCMV entry receptors in monocytes enhances viral entry and enables productive infection, demonstrating that these cells can support full lytic replication if entry is efficient. We further identify integrin β3 as a differentiation-induced surface protein playing an important role in HCMV entry into macrophages, partially accounting for the observed differences in entry efficiency. Finally, we show that cells receiving fewer viral genomes are the ones that establish latent infection and have the capacity to reactivate. Overall, our findings reveal that entry is a previously unrecognized factor contributing to latent infection in monocytes, adding a critical layer to the paradigm of HCMV latency.

HCMV infection can become productive or latent. Here the authors show that variations in the number of incoming viral particles across cell types is a key factor of this decision, identifying entry efficiency as a key regulator of latency.