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Neurons: The perfect hiding spot for herpes virus

Herpes simplex virus hides in neurons for life, evading the immune system and periodically reactivating to cause recurrent infections.

Herpes simplex virus (HSV), encompassing HSV-1 and HSV-2, is a widespread human pathogen responsible for various conditions, from cold sores and genital herpes to severe encephalitis. These infections are incurable because, after affecting peripheral tissues such as the lips and genitals, the virus infiltrates neurons in the peripheral nervous system and remains there for life.

During this latent infection phase, the virus does not replicate; its DNA genome persists in the nuclei of neurons. Periodically, the virus reactivates, travelling back to the peripheral tissues and causing recurrent outbreaks. This sophisticated “hit-and-run” strategy enables the virus to evade the immune system while retaining the ability to spread, presenting a significant challenge for the prevention and treatment of herpes-related diseases.

How herpes simplex virus hide in your body? Herpes simplex virus utilizes neuron-specific microRNAs to facilitate latent infection by repressing both viral replication and host transcription factors essential for viral gene expression, thereby creating an optimal environment for the virus to hide and periodically reactivate.

Dongli Pan

MicroRNAs in neurons facilitate herpes virus hiding

Herpes simplex virus (HSV) can infect various cell types but becomes latent in neurons. This suggests that certain molecules in neurons aid the virus in hiding. For the virus to evade the immune system, its replication and gene expression must be silenced. MicroRNAs, small RNA molecules that silence target genes, play a role in this process.

A neuron-specific microRNA, miR-138, has been shown to promote HSV latency by silencing viral and host molecules critical for virus replication. Research screened numerous microRNAs abundant in neuronal tissues to identify others that could facilitate latent infection. Among these, miR-9 was highlighted for its ability to repress virus replication and gene expression. Experiments with different cellular and animal models demonstrated that miR-9 could inhibit virus reactivation from latent infection. These findings suggest that miR-9, like miR-138, helps the herpes simplex virus maintain latency by repressing virus replication and gene expression.

Figure 1. Model of regulation of the lytic/latent balance by host neuronal miRNAs and their targets.Β 
Credit. Nature communication

Repression of host transcription factors involved in virus gene expression

Virus gene expression is a complex process involving both viral and host molecules. Transcription factors are proteins that bind to DNA to regulate gene expression. A crucial host transcription factor in herpes simplex virus (HSV) replication is OCT-1, which partners with a viral protein, VP16, to bind the viral genome and initiate gene expression.

Recent research has identified another family of host transcription factors essential for HSV replication and gene expression: the ONECUT family proteins, comprising ONECUT1, ONECUT2, and ONECUT3. These proteins bind directly to the viral genome, significantly upregulating viral gene expression. By doing so, the ONECUT proteins enhance virus replication and reactivation from latent infection. Additionally, all three ONECUT genes and the OCT-1 gene are targeted by miR-9, leading to a substantial reduction in their abundance when miR-9 levels are high. Consequently, miR-9 promotes latent herpes virus infection by repressing the host transcription factors OCT-1 and the ONECUT family.

Epigenetic regulation of herpes virus gene expression

Epigenetic regulation refers to the control of gene expression through chemical modifications of genes or gene-associated proteins. Herpes viruses, as double-stranded DNA viruses replicating in the cell nucleus, are subject to this type of regulation. Upon entering the nucleus, the herpes virus DNA genome binds with histone proteins to form viral chromatin. The structure of this viral chromatin determines the expression of viral genes. Generally, an open chromatin structure activates gene expression, while a compact structure suppresses it. Certain histone modifications promote compact chromatin.

Recent findings reveal that ONECUT2 reduces the association of these compacting histone modifications with viral genes, while miR-9 has the opposite effect. Using ATAC-seq, a technique that analyses chromatin accessibility, it has been shown that ONECUT2 significantly increases chromatin openness across the viral genome. Consequently, ONECUT proteins epigenetically enhance herpes simplex virus gene expression, whereas miR-9 represses it by targeting ONECUT genes.

Conclusions

This research offers a new explanation for why the herpes simplex virus tends to hide in nerve cells. For effective replication, the virus depends not only on its molecules but also on host transcription factors that increase viral chromatin accessibility. After the virus enters neurons, these host transcription factors are present at very low levels. This reduction is partly due to high levels of certain neuron-specific microRNAs that repress the expression of these transcription factors. This cellular environment provides an ideal hiding place for the virus.

This significant research uncovers a network of molecular interactions that control herpes simplex virus latent infection. While the mechanisms of herpes virus latency are a popular topic, examining cell-type-specific factors is an uncommon approach to understanding these processes. Many questions remain, such as whether these mechanisms are conserved across similar herpes virus species and how the virus overcomes the repressive molecular network during reactivation. Further research is needed to fully understand the molecular networks governing herpes virus latency and reactivation. Insights from this work could lead to therapeutic interventions, potentially offering cures for herpetic diseases, which affect many people worldwide.

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Journal reference

Deng, Y., Lin, Y., Chen, S., Xiang, Y., Chen, H., Qi, S., … & Pan, D. (2024). Neuronal miR-9 promotes HSV-1 epigenetic silencing and latency by repressing Oct-1 and Onecut family genes. Nature communications15(1), 1991. https://doi.org/10.1038/s41467-024-46057-6

Dongli Pan is a Professor of Medical Microbiology and Parasitology at Zhejiang University School of Medicine. He obtained his BSc degree in Chemistry at Peking University and PhD degree in Biochemistry at the University of Pennsylvania. He underwent training in virology as a postdoctoral fellow at Harvard Medical School. His research focuses on viral pathogenesis, virus-host interactions, and the development of antiviral therapeutics.