CMV & Humans Share An Ancient HistoryWhile Cytomegalovirus - Wikipedia seems to infect all mammals, each host species gets infected with a specific CMV species, suggesting an ancient association between these viruses and mammals.Given this history, it's not surprising that human CMV infection is widespread and persistent, ranging from ~40 to even 100% in different populations; while primary infection in adults can result in infectious mononucleosis-like symptoms, most infections are asymptomatic and occur before puberty, including trans-placentally as well as through breast milk (below from 1).A double-stranded DNA virus belonging to the herpes virus family, at ~235 kilobase pairs, human CMV or HHV5 is the largest genome among known human viruses (1), with signs of various strategies that help explain why it remains so persistent within human populations, strategies such as gene capture (lateral transmission), gene duplication and hypervariation (2).Even though asymptomatic CMV infection sounds innocuous in that most carriers show no adverse signs, it turns out to still have a huge impact on their immune systems.One study compared 16 monozygotic twins discordant for CMV seropositivity (positive for circulating anti-CMV antibodies; interpreted as a sign of CMV infection) with 26 CMV concordant for seronegativity. It found 119 of 204 measurements (~58%) of blood-derived immune cells and proteins to be different between CMV seropositive and seronegative monozygotic twins (3).Only Recently Have Studies Have Begun To Decipher Human CMV's Genetic Complexity & DiversityA 2021 review summarized obstacles that have prevented a better understanding of CMV biology (4),Most of the research on it has historically relied on using specific laboratory-derived CMV strains that were first isolated from clinical specimens in the 1950s (5).Decades later, an analysis found that two of the most widely used CMV lab strains lacked big chunks, ~13 to 15 kilobase pairs, chunks that had apparently been jettisoned sometime over the years of maintaining them in lab cultures (6).Such studies had concluded human CMV to be a slow growing virus that changed little and evolved slowly.Some experienced CMV researchers summarize conclusions of old experiments using such systems as (7),“the wrong virus in the wrong cell line using the wrong end point”Turns out it changes so much during replication, some now consider CMV to instead be (4),“a shape-shifting chameleon for which replication in 1 cell type results in production of virions more suited to infecting cells of other types”More recent research instead suggests a much more interesting story. Conventional wisdom holds high genetic diversity to be the purview of RNA viruses such as HIV, given their proclivity for high mutation rates. However, genomic sequencing of CMV strains isolated from plasma, saliva and urine samples of patients has shown extremely broad genomic diversity,Comparable to that seen in HIV (8, 9), andWithin patient (plasma and urine) being comparable to that between different patients (9, 10).Details of exactly how a DNA virus like CMV manages to attain such diversity is now the focus of much research.Is human CMV friend or foe?On the one hand, one study found more robust anti-flu vaccine antibodies in CMV-seropositive young adults compared to their CMV-seronegative counterparts (below from 11). The idea that CMV may help boost some immune responses in the healthy led the senior authors of this study to recently suggest it may be a “symbiote” (12).On the other hand (13, 14, 15),CMV can be lethal among the immunodeficient and immunocompromised such as HIV infected and transplant recipients.Some transplacental congenital infections can be life-threatening.It has been implicated in “inflammaging”, age-related damaging inflammation.CMV infection could somehow accelerate aging although this idea remains controversial.The Janus-faced effects of human CMV appear to turn on the ability of the immune system to hold it in check over the course of a lifetime, likely the result of an association forged over evolutionary time (see below from below from 7, 15, 16).Thus, calling CMV a “symbiote” (12) may be going a step too far. Instead, it appears to have the hallmarks of a pathobiont - Wiktionary, behaving like a symbiont under normal circumstances but remaining capable of causing serious disease and even lethality when immune function is seriously impaired.Bibliography1. Sackman, Andrew, et al. "On the demographic and selective forces shaping patterns of human cytomegalovirus variation within hosts." Pathogens 7.1 (2021): 16. On the Demographic and Selective Forces Shaping Patterns of Human Cytomegalovirus Variation within Hosts2. Davison, Andrew J. "Evolution of sexually transmitted and sexually transmissible human herpesviruses." Annals of the New York Academy of Sciences 1230.1 (2021).3. Brodin, Petter, et al. "Variation in the human immune system is largely driven by non-heritable influences." Cell 160.1-2 (2021): 37-47. ScienceDirect4. Pellett, Philip E. "Deep lessons from the uncultured." The Journal of infectious diseases (2021). Deep Lessons From the Uncultured5. Wilkinson, Gavin WG, et al. "Human cytomegalovirus: taking the strain." Medical microbiology and immunology 204.3 (2021): 273-284. Human cytomegalovirus: taking the strain6. Cha, Tai-an, et al. "Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains." Journal of virology 70.1 (1996): 78-83. Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains.7. Griffiths, Paul, Ilona Baraniak, and Matt Reeves. "The pathogenesis of human cytomegalovirus." The Journal of pathology 235.2 (2021): 288-297. The pathogenesis of human cytomegalovirus8. Renzette, Nicholas, et al. "Extensive genome-wide variability of human cytomegalovirus in congenitally infected infants." PLoS pathogens 7.5 (2021): e1001344. Extensive Genome-Wide Variability of Human Cytomegalovirus in Congenitally Infected Infants9. Renzette, Nicholas, et al. "Limits and patterns of cytomegalovirus genomic diversity in humans." Proceedings of the National Academy of Sciences 112.30 (2021): E4120-E4128. Limits and patterns of cytomegalovirus genomic diversity in humans10. Renzette, Nicholas, et al. "Rapid intrahost evolution of human cytomegalovirus is shaped by demography and positive selection." PLoS genetics 9.9 (2021): e1003735. Rapid Intrahost Evolution of Human Cytomegalovirus Is Shaped by Demography and Positive Selection11. Furman, David, et al. "Cytomegalovirus infection enhances the immune response to influenza." Science translational medicine 7.281 (2021): 281ra43-281ra43. https://pdfs.semanticscholar.org...12. Davis, Mark M., and Petter Brodin. "Rebooting human immunology." Annual review of immunology 36 (2021): 843-864.13. Sansoni, Paolo, et al. "New advances in CMV and immunosenescence." Experimental gerontology 55 (2021): 54-62. ScienceDirect14. Kaczorowski, Kevin J., et al. "Continuous immunotypes describe human immune variation and predict diverse responses." Proceedings of the National Academy of Sciences 114.30 (2021): E6097-E6106. Continuous immunotypes describe human immune variation and predict diverse responses15. Navarro, David. "Expanding role of cytomegalovirus as a human pathogen." Journal of medical virology 88.7 (2021): 1103-1112.16. Picarda, Gaëlle, and Chris A. Benedict. "Cytomegalovirus: Shape-Shifting the Immune System." The Journal of Immunology 200.12 (2021): 3881-3889. https://www.researchgate.net/pro...Thanks for the R2A, Robert Cronk.