# SARS-CoV-2 encoded ORF3a interacts with YY1 to promote latent HCMV reactivation

## TL;DR

This study shows how SARS-CoV-2 can reactivate latent HCMV by interacting with a protein called YY1, offering new insights for treating co-infections.

## Contribution

The study identifies ORF3a as a novel SARS-CoV-2 protein that promotes HCMV reactivation by degrading YY1.

## Key findings

- SARS-CoV-2 ORF3a interacts with YY1 to activate the HCMV major immediate early promoter.
- ORF3a causes ubiquitin-dependent degradation of YY1, promoting HCMV reactivation and replication.
- This mechanism provides a new theoretical basis for preventing and treating SARS-CoV-2 and HCMV co-infections.

## Abstract

Human Cytomegalovirus (HCMV) is a commonly infected double-stranded DNA virus of the β-herpesviridae subfamily that typically establishes lifelong latency or persistent infection following primary infection. The regulation of HCMV latency and reactivation is governed by the chromatin structure at the viral major immediate early promoter (MIEP) within myeloid cells. Both cellular and viral factors play a role in regulating the reactivation of latent HCMV. Recently, it has been found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) promotes HCMV reactivation in the clinic; however, the mechanism remains unclear. In this study, we found that SARS-CoV-2 ORF3a can activate HCMV MIEP by interacting with Yin Yang 1 (YY1), an inhibitor of MIEP. This interaction leads to YY1 ubiquitin-dependent degradation and subsequently promotes the reactivation of latent HCMV, as well as the replication and proliferation of the virus. These findings reveal the molecular mechanism underlying the interaction between SARS-CoV-2 and HCMV during co-infection, providing a new theoretical basis for future prevention and treatment strategies against the co-infection of these two viruses.

Although the WHO has declared the COVID-19 pandemic over, the impact of the pandemic on people still exists, especially the long-term symptoms known as post-acute sequelae or long COVID found in some individuals. Studies have shown that co-infection with other viruses may be an important factor in the development of long COVID. In clinical practice, SARS-CoV-2 may also lead to the reactivation of latent HCMV, a prevalent herpesvirus. Meanwhile, reactivation from latency plays a crucial role in recurrent HCMV infection. However, previous research has primarily focused on understanding the mechanisms that establish viral latency. In this study, we discovered that the SARS-CoV-2 ORF3a protein activates the HCMV major immediate-early promoter (MIEP) by interacting with the MIEP inhibitor Yin Yang 1 (YY1). This interaction leads to ubiquitin-dependent proteasomal degradation of YY1, thus promoting the reactivation of latent HCMV. These findings provide the first direct laboratory evidence and elucidate the specific mechanism by which SARS-CoV-2 promotes HCMV reactivation from latency, highlighting ORF3a as a potential therapeutic target and providing new insights for therapeutic interventions for COVID-19 complications.