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  • CRISPR-Cas9 as a Therapeutic Strategy Against Oncogenic Viruses: Targeting HPV and EBV

  • helia lesan salmasi,1,* ali ghanbari,2 asiyeh jebelli,3
    1. Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
    2. Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
    3. Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran


  • Introduction: Human papillomavirus (HPV) and Epstein–Barr virus (EBV) are two major oncogenic DNA viruses implicated in a wide range of human malignancies. High-risk HPV types account for the majority of cervical cancers and are linked to subsets of head and neck cancers. HPV-mediated oncogenesis is primarily driven by the viral oncoproteins E6 and E7, which disrupt key tumor suppressors such as p53 and pRb, leading to uncontrolled proliferation and malignant transformation. Integration of HPV DNA into host chromosomes is a pivotal event in cervical carcinogenesis. Similarly, EBV establishes lifelong latent infection in most of the human population and is etiologically associated with several lymphoid and epithelial cancers. EBV persists episomally or integrates into host chromosomes, expressing latent proteins which drive tumorigenesis. HPV and EBV are challenging therapeutic targets due to their ability to establish latency and integrate into the host genome. Strategies that specifically target nucleotide sequences within episomal or integrated viral genomes are therefore of paramount importance for antiviral and anticancer therapeutics. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has emerged as a highly efficient and programmable genome-editing platform. CRISPR-Cas9 functions as a bacterial adaptive immune system guided by crRNA and tracrRNA to recognize sequences adjacent to a protospacer-adjacent motif (PAM). Subsequent engineering of this system enabled its adaptation for genome editing in human and mouse cells. The CRISPR-Cas9 system consists of Cas9 endonuclease and a guide RNA (gRNA) capable of inducing double-strand breaks at target sites. Repair systems enable the precise gene disruption or insertion. This versatility makes CRISPR-Cas9 a valuable therapeutic tool, especially for oncoviruses such as HPV and EBV.
  • Methods: A comprehensive literature search was undertaken in PubMed and Google Scholar. Strategically selected keywords (HPV, EBV, CRISPR–Cas9, Cancer) along with their conceptual interrelations were employed to maximize the retrieval of relevant studies. Titles and abstracts were screened to identify pertinent publications, followed by full-text review and critical appraisal of the selected papers. Six articles were ultimately chosen as the primary references for this study.
  • Results: In HPV-driven cancers, CRISPR/Cas9 has been successfully applied to disrupt E6 and E7 oncogenes. Silencing these genes reactivates p53 and Rb pathways, inducing apoptosis, senescence, and suppression of tumor growth. Experimental studies have shown that CRISPR/Cas9-mediated targeting of E6/E7 reduces viral transcript levels by over 90%, increases TP53 and p21 expression, and significantly decreases cell viability both in vitro and in vivo. In cervical cancer models, intratumoral administration of CRISPR/Cas9 constructs targeting E6/E7 has led to robust tumor growth inhibition and apoptosis induction. Delivery systems such as intratumoral injection and gRNA-liposome complexes have demonstrated potential for localized and efficient therapeutic activity, while CRISPR-mediated silencing of host factors like SIRT1 further expands its scope in HPV-driven oncogenesis. Beyond HPV, CRISPR/Cas9 has been applied to EBV-associated malignancies. In nasopharyngeal carcinoma cells, CRISPR-Cas9-mediated editing of the EBV latent transcript BART promoter reduced viral persistence, underscoring the system’s potential for eradicating latent viral reservoirs. Targeting EBV latent proteins such as EBNAs and LMPs has also been explored, providing new avenues for therapy in EBV-related cancers. Furthermore, catalytically inactive Cas9 (dCas9) fused with transcriptional effectors allows precise regulation of gene expression without DNA cleavage, expanding the scope of CRISPR-based interventions. Despite its therapeutic promise, several challenges hinder clinical translation of the CRISPR-Cas9 system. The immunogenicity of viral delivery vectors, insertional mutagenesis risks, off-target effects, and systemic delivery difficulties remain obstacles. Tumor heterogeneity further complicates consistent outcomes. Alternative delivery approaches, such as integrase-deficient lentiviruses, adeno-associated virus (AAV) vectors, nanoparticles, and exosome-mediated delivery, have shown encouraging results. For example, AAV-based CRISPR-Cas9 successfully disrupted E6 in HeLa cells, while nanoparticles encapsulating Cas9 and gRNAs demonstrated efficacy in HPV-related cervical lesion models. Overcoming these challenges in delivery, immune compatibility, and precision targeting will be crucial to realizing the full therapeutic potential of CRISPR-based antivirals.
  • Conclusion: CRISPR-Cas9 represents a transformative tool for combating viral infections and virus-associated cancers by enabling targeted genome disruption and transcriptional regulation. Preclinical studies provide compelling evidence that precise targeting of HPV and EBV oncogenes can restore tumor suppressor pathways, induce apoptosis, and inhibit tumor growth. Future advancements in delivery systems, minimization of off-target effects, and rigorous clinical validation are essential to harness its full potential in human medicine
  • Keywords: HPV, EBV, CRISPR-Cas9, Cancer

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