Potential Therapeutic Approaches Against Brain Diseases Associated with Cytomegalovirus Infections

Abstract

Cytomegalovirus (CMV) is one of the major human health threats worldwide, especially for immunologically comprised patients. CMV may cause opportunistic infections, congenital infections, and brain diseases (e.g., mental retardation and glioblastoma). The etiology of brain diseases associated with human CMV (HCMV) infections is usually complex and it is particularly difficult to treat because HCMV has a life-long infection in its hosts, high mutation rate, and latent infections. Moreover, it is almost impossible to eradicate latent viruses in humans. Although there has been progress in drug discovery recently, current drugs used for treating active CMV infections are still limited in efficacy due to side effects, toxicity, and viral resistance. Fortunately, letermovir which targets the HCMV terminase complex rather than DNA polymerase with fewer adverse reactions has been approved to treat CMV infections in humans. The researchers are focusing on developing approaches against both productive and latent infections of CMV. The gene or RNA targeting approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) are being investigated to remove acute and/or latent CMV infections. For the treatment of glioblastoma, vaccine therapy through targeting specific CMV antigens has improved patients’ survival outcomes significantly and immunotherapy has also emerged as an alternative modality. The advanced research for developing anti-CMV agents and approaches is promising to obtain significant outcomes and expecting to have a great impact on the therapy of brain diseases associated with CMV infections.

Challenges, Recent Advances and Perspectives in the Treatment of Human Cytomegalovirus Infections

“…The HCMV is a probable pathogen of brain diseases including glioblastoma (GBM). Certain malignant GBM expresses HCMV-related proteins, including the immediate early gene-1 product and the lower matrix phosphoprotein 65 (pp65) expressed by the unique long 83 (UL83) gene, indicating that HCMV may have played a role in the generation of GBM [32][33][34][35]. A certain animal study has revealed that CMV can induce GBM formation in vitro and in xenograft models and HCMV can also be detected in GBM isolated from patients, suggesting that HCMV may drive tumorigenesis or be reactivated in tumors [35].…”