**6. Adoptive Cell Therapy for CMV Infections**

It is known that the infection-related morbidity and mortality will be increased, if the T cell-mediated immune responses are impaired in transplantation recipients. Virus-specific T cells capable of targeting a variety of pathogens in patients after hematopoietic stem cell transplantation (HSCT) have demonstrated potential efficacy for multiple viruses such as CMV, Epstein-Barr Virus (EBV) and adenovirus [57]. Adoptive T cell therapy (ACT), a type of immunotherapy in which T cells are given to a patient to treat diseases, has been developed to fight against drug resistant and recurrent CMV in SOT recipients. Therefore, ACT has become one of the therapeutic strategies for CMV reactivations in patients undergoing allogeneic HSCT and SOT.

Faist et al. used the peptide specific proliferation assay (PSPA) to study CMV specific central memory T cells (TCM) repertoires and determined their functional and reproductive abilities in vitro [58]. In the animal model, the pathogen-specific TCM has demonstrated to have protective ability even at low numbers and could survive for long-term, proliferate extensively and show high plasticity after adoptive transfer. Though the clinical data showed that minimal doses of purified human CMV epitope-specific T cells are competent to remove viremia, it is still necessary to evaluate whether the human virus-specific TCM shows the same characteristic for ACT as mice. The results concluded that TCM had potential for prophylactic low-dose ACT. These good manufacturing practice (GMP)-compatible TCM could be used as a broad-spectrum antiviral T cell prophylaxis in allogeneic HSCT patients. In addition, PSPA would be a necessary tool for TCM characterization further during simultaneous immune monitoring [58].

Smith et al. applied high-throughput T cell receptor Vβ sequencing and T cell functional profiling to demonstrate the influence of ACT on T cell repertoire remodeling in the pretherapy immunity and ACT products [59]. The clinical response was consistent with significant changes in the T cell receptor Vβ landscape after therapy. This reconstitution was related to the emergence of effector memory T cells in responding patients, while nonresponding patients showed dramatic pretherapy T cell expansions with minimal change following ACT. The results revealed that immunological modulation following ACT required significant repertoire remodeling which might be damaged in nonresponding patients on account of the preexisting immune environment. Immunological interventions which controlled this environment were likely to improve clinical outcomes. ACT appears to be an advantageous strategy to restore immunological control against CMV affecting immunosuppressed patients such as SOT recipients [59].

#### **7. Conclusions**

CMV is the most frequent etiological factor for congenital infections and its infections are still global health problems of humans. Though CMV infections are often opportunistic, they sometimes cause serious diseases in healthy adults with weakened immunity and babies. Currently, no drugs are available for asymptomatic infants and for infants with CMV congenital infections to reduce related morbidity during the neonatal period. Some traditional antiviral drugs (e.g., ganciclovir, valganciclovir, cidofovir, foscarnet) are applied for the treatment of CMV acute infections, however, their efficacy is limited by side effects, cross-resistance and others. There is no effective cure for CMV infections, especially for latent infections. Promisingly, many novel antiviral drugs/agents and preventive/therapeutic strategies have been approved for clinical application (e.g., letermovir) or are being developed (e.g., maribavir, EGS-RNase, CRISPR/Cas9, TALENs, HCMV vaccine, ACT). We should investigate the interactions between CMV and hosts thoroughly to understand how antiviral agents or therapeutic strategies affect CMV infection outcomes. Moreover, the development and implications of novel antiviral agents and preventive/therapeutic strategies should be explored as extensively as possible. The future research tendency and application of these new insights should also be a highlight and could potentially become a promising milestone in the development of therapeutic strategies for CMV infections.

**Author Contributions:** S.-J.C., S.-C.W. and Y.-C.C. wrote this article. Y.-C.C. designed, organized and reviewed this article. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** We are grateful for the grant support from Mackay Memorial Hospital in publishing this article.

**Conflicts of Interest:** The authors declare no conflict of interests.
