The Cytomegalovirus, Relentless Companion of Humanity
It is one of the most common viruses present in the human body, affecting 56% to 94% of the population depending on the region of the world. Numerous diseases are associated with it, and it is highly likely that you are infected.
From the virus lurking in the shadows to opportunistic awakening
The 11 species of the cytomegalovirus genus include Human Betaherpesvirus 5 (HCMV, human cytomegalovirus, or HHV-5), the species that infects humans. Of all herpes viruses, HCMV has the largest number of genes dedicated to evading the host's innate and adaptive immunity. This means it continually finds ways to avoid detection by the human immune system and solicits it throughout life. Transmission of this virus is very easy: it spreads through saliva, urine, blood, and tears, with the most common means being through kissing and sexual intercourse. Another common transmission occurs from an infected woman to her unborn child or to an infant through breast milk. While acute HCMV infection includes the classical triad of symptoms of fever, sore throat, and swollen lymph nodes, chronic infection can often manifest without any signs or symptoms for years or even decades. In severe cases, the virus can manifest as mononucleosis, anemia, thrombocytopenia, or liver problems. After initial infection, the virus remains dormant in lymphocytes for the rest of the person's life. When an opportunity arises, such as in the case of a weakened immune system (immunocompromised), the virus begins its replication cycle and symptoms reappear. Immune suppression can be caused by another virus or bacteria, blood loss, stress, the onset of an allergy, or in more severe cases, by HIV, solid organ transplantation, or bone marrow transplantation. In such situations, HCMV is generally much more aggressive.
Figure 1: the scheme of a cytomegalovirus. It is a double-stranded DNA virus encased in a capsid, with glycoprotein I and III coating its outer shell, with which it connects to its host. By Emmanuel Boutet.
Treatment is always symptomatic
To counter HCMV, the temperature is reduced and other symptoms are treated if necessary. In cases of mononucleosis and other severe conditions, treatment is limited to specific symptoms, as antiviral drugs still carry too many risk factors and adverse reactions. Enriched hyperimmune immunoglobulin against HCMV can be used in cases of organ transplantation, as it contains a standardized number of antibodies against HCMV. It provides long-term survival benefit to transplant patients and is associated with minimal side effects. However, its use is limited. Ganciclovir and valganciclovir are antiviral drugs administered orally, with valganciclovir converting to ganciclovir in the human body. Both are given to patients with a depressed immune system and vision-related issues or in life-threatening situations. However, they have serious side effects and their administration is still complicated, with the frequent emergence of drug-resistant viral strains shortly after initial administration, and patients may need to switch to foscarnet (a broad-spectrum antiviral agent) or cidofovir (antiviral agent) as a last resort.
From minor inconvenience to major problem
The opportunistic nature of HCMV is, at worst, an inconvenience for individuals with strong immune systems and no chronic issues. However, as with all opportunistic viruses, our inability to completely cure a person of it makes their existence problematic in the most vulnerable populations: children, pregnant women, the elderly, immunocompromised individuals, and those with chronic illnesses. The impact of HCMV on these populations is greater than most other diseases. In immunocompromised individuals, such as those with HIV, it is often the opportunistic viruses that are lethal rather than HIV itself. The same goes for chronic illnesses. An outbreak of such a virus can lead to life-threatening problems and is a frequent cause of death. During pregnancy, HCMV's ability to infect the fetus can result in congenital abnormalities, affecting five live births per 1000. Symptoms include multiple disabilities, cytomegalic inclusion disease, brain calcification with dramatic decrease in IQ, deafness, and sensorineural delay. Additionally, premature infants infected with HCMV after birth may experience cognitive and motor impairments later in life. Interestingly, individuals infected with HCMV after the onset of puberty are correlated with a much higher risk of developing multiple sclerosis.
A much brighter future
Despite its relative benignity, this lifelong companion remains undesirable as it is most dangerous in moments of weakness. Several clinical trials are therefore exploring potential cures, as well as vaccination against HCMV. So far, this has proven to be a very difficult task, as nearly 75% of HCMV genes can be suppressed or destroyed (by our immune system, for example) and still result in the production of a fully functional infectious virus. Pfizer, led by their chief scientist Yuhang Liu, has achieved a major breakthrough in developing a vaccine against HCMV. The teams have succeeded in finding the exact structure of the HCMV glycoprotein responsible for fusing its membrane with the host cell membrane. Knowing the exact structure of unfused (or pre-fused) HCMV gives them the ability to immunize the human immune system against such a form, potentially developing a better vaccine against it. Another potential breakthrough is the "mRNA-1647 human cytomegalovirus vaccine candidate" in phase 3 clinical trials by Moderna Inc. It shows much better results than any other trial completed to date. Research is advancing, indeed, Moderna Inc. researchers believe the vaccine can be further improved. Several other promising vaccines in phases 1 and 2 of clinical trials are currently underway, buoyed by the success of the COVID vaccine. It's only a matter of time before such a vaccine extends to other viruses, including HCMV!
References:
1. "An Evaluation of a Cytomegalovirus (CMV) Vaccine (ASP0113) in CMV-Seropositive and CMV-Seronegative Healthy Subjects and CMV-Seronegative Dialysis Patients". ClinicalTrials.gov. 2015-07-08. Retrieved 2015-10-22.
4. Xintao Hu, Krithika P Karthigeyan, Savannah Herbek, Sarah M Valencia, Jennifer A Jenks, Helen Webster, Itzayana G Miller, Megan Connors, Justin Pollara, Caroline Andy, Linda M Gerber, Emmanuel B Walter, Kathryn M Edwards, David I Bernstein, Jacob Hou, Matthew Koch, Lori Panther, Andrea Carfi, Kai Wu, Sallie R Permar, Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses Than the gB/MF59 Vaccine, The Journal of Infectious Diseases, 2024;, jiad593, https://doi.org/10.1093/infdis/jiad593
6. https://www.cdc.gov/cmv/overview.html
7. https://www.ncbi.nlm.nih.gov/books/NBK459185/
8. https://www.mayoclinic.org/diseases-conditions/cmv/symptoms-causes/syc-20355358
9. https://www.pfizer.com/news/articles/advances_in_cytomegalovirus_vaccine_development
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