Development of Genome Editing Approaches against Herpes Simplex Virus Infections

Abstract

Herpes simplex virus 1 (HSV-1) is a herpesvirus that may cause cold sores or keratitis in healthy or immunocompetent individuals, but can lead to severe and potentially life-threatening complications in immune-immature individuals, such as neonates or immune-compromised patients. Like all other herpesviruses, HSV-1 can engage in lytic infection as well as establish latent infection. Current anti-HSV-1 therapies effectively block viral replication and infection. However, they have little effect on viral latency and cannot completely eliminate viral infection. These issues, along with the emergence of drug-resistant viral strains, pose a need to develop new compounds and novel strategies for the treatment of HSV-1 infection. Genome editing methods represent a promising approach against viral infection by modifying or destroying the genetic material of human viruses. These editing methods include homing endonucleases (HE) and the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR associated protein (Cas) RNA-guided nuclease system. Recent studies have showed that both HE and CRISPR/Cas systems are effective in inhibiting HSV-1 infection in cultured cells in vitro and in mice in vivo. This review, which focuses on recently published progress, suggests that genome editing approaches could be used for eliminating HSV-1 latent and lytic infection and for treating HSV-1 associated diseases.

Local Immune Control of Latent Herpes Simplex Virus Type 1 in Ganglia of Mice and Man

“…This is particularly important for HSK, the leading cause of infectious corneal blindness in westernized societies ( 116 ). There has been considerable development in HSV genome targeting using CRISPR/Cas9 and meganuclease type strategies to reduce virus load and lower reactivation ( 191 ). Some progress has been made using gene editors delivered via adeno-associated virus (AAV) vectors, but the levels of gene editing were modest ( 192 ).…”

Developments in Vaccination for Herpes Simplex Virus

“…While a prophylactic vaccine would be optimal for the prevention of all complications, it might be more realistic to focus on therapeutic vaccines that would reduce disease severity (measured in recurrences, duration of clinical symptoms and viral shedding). While most therapeutic vaccines are not as effective at targeting latent virus, recent work in genome editing involving homing endonucleases and CRISPR/cas9 systems offer a bridge to complete viral clearance ( Zhang et al, 2021 ).…”

Gene Editing Technologies to Target HBV cccDNA

“…Herpesviruses are large dsDNA viruses containing 100-200 genes; they can establish lifelong infections in the host and often lead to serious diseases, especially in immunecompromised individuals. HSV-1 infection can lead to viral encephalitis or neonatal herpes in immune-immature or immune-compromised patients [66]. While both meganucleases and CRISPR/Cas systems targeting HPV genomes were efficient in inhibiting HSV-1 infection in various in vitro models, including primary neurons, in vivo delivery in a mouse model proved to be more challenging [66].…”