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Review
. 2023 Nov 20:14:1321116.
doi: 10.3389/fmicb.2023.1321116. eCollection 2023.

Anti-CMV therapy, what next? A systematic review

Claire Gourin  1 , Sophie Alain  1   2 , Sébastien Hantz  1   2
Affiliations
Review

Anti-CMV therapy, what next? A systematic review

Claire Gourin et al. Front Microbiol. .

Abstract

Human cytomegalovirus (HCMV) is one of the main causes of serious complications in immunocompromised patients and after congenital infection. There are currently drugs available to treat HCMV infection, targeting viral polymerase, whose use is complicated by toxicity and the emergence of resistance. Maribavir and letermovir are the latest antivirals to have been developed with other targets. The approval of letermovir represents an important innovation for CMV prevention in hematopoietic stem cell transplant recipients, whereas maribavir allowed improving the management of refractory or resistant infections in transplant recipients. However, in case of multidrug resistance or for the prevention and treatment of congenital CMV infection, finding new antivirals or molecules able to inhibit CMV replication with the lowest toxicity remains a critical need. This review presents a range of molecules known to be effective against HCMV. Molecules with a direct action against HCMV include brincidofovir, cyclopropavir and anti-terminase benzimidazole analogs. Artemisinin derivatives, quercetin and baicalein, and anti-cyclooxygenase-2 are derived from natural molecules and are generally used for different indications. Although they have demonstrated indirect anti-CMV activity, few clinical studies were performed with these compounds. Immunomodulating molecules such as leflunomide and everolimus have also demonstrated indirect antiviral activity against HCMV and could be an interesting complement to antiviral therapy. The efficacy of anti-CMV immunoglobulins are discussed in CMV congenital infection and in association with direct antiviral therapy in heart transplanted patients. All molecules are described, with their mode of action against HCMV, preclinical tests, clinical studies and possible resistance. All these molecules have shown anti-HCMV potential as monotherapy or in combination with others. These new approaches could be interesting to validate in clinical trials.

Keywords: cytomegalovirus; direct antivirals; immunoglobulins; immunomodulatory molecules; indirect antivirals; letermovir; maribavir.

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Conflict of interest statement

SA is an expert for Takeda, MSD, Merck and Biotest with no personal link. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Antiviral targets in relication cycle of CMV. ① Virus attaches to cell. ② Entry of virus into cell and release of capsid into cytoplasm. ③ Migration of capsid to cell nucleus. ④ Release of viral genome from capsid through nuclear pore. ⑤ Replication of viral DNA by the rolling circle method using the viral polymerase pUL54. ⑥ Encapsidation of the genome into neoformed capsids via the encapsidation complex. ⑦ Nuclear exit. ⑧ Release of newly formed virions into cell cytoplasm. ⑨ Tegumentation of newly formed virions. ➉ Passage of virions through Golgi apparatus. ⑪ Acquisition of a primary envelope and transport of virions in a vesicle to the extracellular medium. ⑫ Budding, release of infectious virus particles and infection of a new cell. Indirect antivirals, direct antivirals and antivirals targeting the viral polymerase are in blue, green and pink, respectively. Created with BioRender.com
Figure 2
Figure 2
Molecule structures. Structures of chemical molecules with their corresponding order in the review. All molecules are classified as approved antivirals, molecules with direct antiviral activity or molecules with indirect antiviral activity.
Figure 3
Figure 3
Resistance mutations to letermovir in UL56, UL89 and UL51 genes. LMV resistance mutations according to EC50 values. Mutations are referenced on genes under the map of conserved and variable regions. Scaled representation.
Figure 4
Figure 4
Resistance mutations to maribavir in UL97 and UL27 genes. Mutations responsible for cross-resistance with GCV are represented in blue. Mutations are referenced on genes under the map of conserved and variable regions. Scaled representation.
Figure 5
Figure 5
Mechanism of action of brincidofovir. BCV enters the HCMV-infected cell, is cleaved and phosphorylated by cellular anabolic kinases to cidofovir diphosphate. In the nucleus, CDV-PP binds competitively to the dGTP binding site of UL54 DNA polymerase. The result is inhibition of DNA synthesis and arrest of viral replication.
Figure 6
Figure 6
Mechanism of action of cyclopropavir. CPV enters the HCMV-infected cell and is phosphorylated by a viral kinase to CPV monophosphate. Two successive phosphorylations by GMPK are required to obtain CPV triphosphate. In the nucleus, CPV-triP binds competitively to the dGTP binding site of DNA polymerase UL54 and inhibits DNA synthesis. It also inhibits the ability of the viral UL97 kinase to prevent aggresome formation. Both mechanisms lead to inhibition of viral replication. GMPK: guanosine monophosphate kinase.
Figure 7
Figure 7
Resistance mutations to cyclopropavir in UL97 and UL54 genes. CPV resistance mutations according to EC50 values. In UL97, cross-resistance mutations are represented in orange and mutations next to the ATP-binding P-loop are in pink. Mutations are referenced on genes under the map of conserved and variable regions. Scaled representation.
Figure 8
Figure 8
Mechanism of action of benzimidazol analogs. BDCRB, TCRB and tomeglovir enter the HCMV-infected cell and travel to the nucleus. They inhibit the encapsidation complex composed of pUL56, pUL89 and pUL51, and inhibit the portal protein pUL104. This mechanism leads to inhibition of DNA cleavage and concatemer recognition, or to premature cleavage. Encapsidation is interrupted and viral replication halted.
Figure 9
Figure 9
Mechanism of action of artemisinin derivatives. Artemisinin derivatives enter HCMV-infected cells and are metabolized to dihydroartemisin (DHA) by the cytochrome P-450 monooxygenase 2B6 (CYP 2B6) enzyme, which is then converted to inactive metabolites. In addition, ART moves to the cell nucleus where it inhibits the production of RelA and p65 involved in the NFκ-B pathway, which is necessary for viral replication.
Figure 10
Figure 10
Mechanism of action of quercetin and baicalein in HCMV infected cells. Quercetin enters the HCMV-infected cell and travels to the nucleus, where it inhibits early viral protein and TNF-α production. It also inhibits contact between interleukin 6 (IL-6) and STAT3, resulting in reduced ROS levels and p62 accumulation. Both mechanisms are responsible for modulating NF-κB, mitochondrial and ROS pathways. In the case of baicalein, the molecule penetrates the cell and inhibits phosphorylation of IκB-α and IKK-β, which are degraded and inhibited, respectively. Each molecular mechanism leads to a reduction in the NF-κB pathway and, consequently, in viral activity.
Figure 11
Figure 11
Antiviral effect of leflunomide in HCMV infected cell. LEF enters the HCMV-infected cell and is converted to teriflunomide (A77 1726). The metabolite inhibits protein kinase, which is unable to phosphorylate proteins. It also penetrates the nucleus to inhibit pyrimidine synthesis. These two mechanisms are involved in inhibiting tegument assembly, thereby stopping viral replication.
Figure 12
Figure 12
Indirect antiviral action of everolimus in HCMV infected T-cell. EVR binds to the interleukin-2 receptor (IL-2R) on HCMV-infected T cells. The molecule enters the cell and binds to the immunophilin FKBP12. The complex binds to mTOR, which is unable to phosphorylate the p70S6 kinase. The kinase does not phosphorylate S6, which is involved in DNA and protein synthesis. HCMV replication is inhibited by cell cycle arrest.
Figure 13
Figure 13
The four modes of action of anti-CMV immunoglobulins. In the first mechanism, HIGs neutralize the viral particle by binding its epitope to viral envelope glycoproteins. Virus adsorption and cellular penetration are inhibited. In the second mechanism, HIGs induce complement pathways leading to the formation of the membrane attack complex (MAC), which creates a hole in the cell membrane leading to cytolysis. In the third mechanism (ADCC), the Fc fraction of the HIG-neutralizing viral particle is recognized by the cytotoxic cell’s Fc receptor (FcR). This leads to the release of cytotoxic molecules that create a cytolysis signal. In the final mechanism, after neutralization of the viral particle by HIGs, macrophage FcRs recognize HIG Fc, resulting in a phagocytosis signal. The viral particle-HIG complex is phagocytosed. The phagosome fuses with the lysosome, forming a phagolysosome and destroying the complex. Created with BioRender.com
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was granted by the University of Limoges and Santé Publique France (National Reference Center for Herpesviruses).