# Applying CRISPR Technologies for the Treatment of Human Herpesavirus Infections: A Scoping Review
## 1 Introduction  
Eight human herpesvirusiruses have been identified so far, including herpes simplex virus type 1 and 2 (HSV-1 and -2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus/HCMV), human herpesvirusirus 6 and 7 (HHV-6 and -7), and [PERSON]'s sarcoma-associated herpesvirus (KSHV) [1]. All herpesvirus viruses are widespread, with(sero)prevalences varying by herpesvirusus type and geographic region. It is highest for HSV-1, EBV, HCMV, HHV-6, and HHV-7, estimated to exceed 90% for some types [2; 3; 4; 5; 6; 7; 8]. Herpesviruses share a common virion structure composed of three major elements: (1) a nucleocapsid containing a large, linear double-stranded DNA genome encapsulated by an icosahedral capsid, (2) an envelope consisting of a host-derived lipid bilayer containing different viral glycoproteins, and (3) the tegument, a proteinaceous layer between the capsid and the envelope [9]. Another hallmark of herpesviruses is their biphasic life cycle, consisting of lytic and latent phases. The lytic replication cycle results in the production of virus particles and is orchestrated through a cascade of gene transcription. First, the expression of immediate early (IE) genes is initiated, which subsequently drives the transcription of early (E) genes involved in viral genome replication. Following DNA replication, late (L) genes are transcribed into proteins involved in virus assembly [9]. Following the lytic phase, herpesviruses establish a lifelong latent infection within host cells, either as episomal DNA or, in some cases, integrated into the host genome in a latent state [10]. The latent phase is characterized by limited viral gene expression and the absence of virion production [9; 10]. Reactivation of latent virus can be triggered by various stimuli such as ultraviolet light, physical or emotional stress, and fever, leading to the reinitiation of the lytic replication cycle and production of new virions [9; 11]. Herpesviruses infect a broad range of cells and tissues, depending on the virus and host context. Clinical manifestations vary widely and are associated with specific tissues involved during lytic replication. Infected individuals may remain asymptomatic or present with mild symptoms such as fever, malaise, and lymphadenopathy [12; 13; 14; 15; 16; 17; 18; 19; 20; 21]. Dermatological manifestations are also common. However, in immunocompromised patients, herpesvirusesvirus infection can lead to severe complications, such as encephalitis, meningitisitis, pneumonia, and various neuropathies [12; 17; 20; 22; 23; 24; 25]. Notably, two herpesviruses, EBV and KSHV, are oncogenic and have been associated with the development of malignancies such as lymphomas, nasopharyngeal, gastric, and smooth muscle carcinomas and sarcomas, following the transformation of latently infected cells [18; 19; 26; 27]. Current herpesvirus infection treatment options rely predominantly on antiviral drugs such as nucleoside-, nucleotide-, and pyrophosphate analogs, which inhibit the viral DNA polymerase and therefore virus replication and virion production [28]. Given that the viral DNA polymerase is active only during lytic replication, these antiviral drugs are only able to treat patients symptomatically without eliminating the latent virus [28]. Furthermore, multiple herpesviruses have already evolved resistance mechanisms to circumvent the action of these drugs [1]. In order to cure both active and latent herpesvirus infections, herpesviral DNA should be eliminated from infected cells. Genetic therapy would be an elegant approach to reach this goal. The discovery and subsequent development of a very precise, relatively simple, and versatile genome-editing tool known as CRISPR-Cas has boosted genetic therapy technologies over the recent years. The CRISPR-Cas9 system, short for clustered regularly inter-spaced short palindromic repeats and CRISPR-associated protein 9, was originally derived from a bacterial adaptive immune mechanism [29].