Sofia Yeremian, Class of 2022
The Human Cytomegalovirus is one of the leading causes of congenital infection with an incidence of infection reported to be 0.2–2.5% within infants in developed countries (2). Of the 0.2-2.5% infected infants, roughly between 10–15% of affected fetuses show symptomatic congenital infection at birth (2). CMV is acquired from having direct contact with bodily fluids like urine and saliva from an individual shedding the virus (3). These forms of transmission can take place through sexual activities, blood transfusions and organ donations (3). CMV can also be transmitted from a mother to a child in utero, perinatally or postnatally through breastfeeding (3). A symptomatic congenital infection results in phenotypic variability among infants. Clinical manifestations of an infected infant may result in low birth weights, fetal growth restriction, and neurological disabilities (2). Though some infants are born with asymptomatic infections, roughly 10-15% of these newborns will develop long-term sequelae, resulting in psychomotor retardation (47-55%), visual impairments (10-20%) and sensorinueral hearing complications (50-59%) (1,2). In the United States alone, annually, approximately 40,000 children are born with a congenital CMV infection, and nearly 8,000 of these infants will experience long-term sequelae (2). When evaluating the effects of CMV on individuals greater than 60 years of age, higher levels of CMV-reactive CD4+ T-cells have shown associations with increased viral respiratory illnesses (4). Likewise, older individuals demonstrate oligoclonal expansions of CD8+ T-cells due to an increase in the frequency of reactivation of CMV (4). An increase in viral load and the immune system’s focus on controlling CMV is a costly task on the human body and an investment of resources produced by the body to target just one pathogen, thus resulting in challenged immune responses to other illness or foreign bodies (4). Though there are several other components to take into consideration, the prevalence of HCMV in elders typically leads to a shorter life span due to a weaker immune system (4).
When comparing CMV seroprevalence in developed countries against developing countries, there is a substantial difference between the infection rates (5). In developing countries like Panama, Gambia, Taiwan, and India, CMV seroprevalance is typically over 90% by adolescence and greater than 95% through early adulthood. A majority of these cases arise from non-primary maternal infections (5). When comparing this to a developed country like the United States or Canada, CMV seroprevalance over the age range of 12-40 is roughly between 40- 60%, taking into account both primary and non-primary maternal CMV infections (5). Though CMV is a prevalent virus around the world, no licensed vaccine exists for the virus (4). Currently approved anti-HCMV drugs include ganciclovir, cidofovir, valganciclovir, and foscarnet, which all serve as systematic treatments of HCMV by targeting viral DNA polymerase (6). Though these drugs are effective at preventing replication of the HCMV genome, their effectiveness is limited by renal and bone marrow toxicity and antiviral drug resistance (6).
HCMV is a double stranded DNA (dsDNA) virus and the largest virus in the Herpesviridae family (7). The incorporated HCMV genome consists of a dsDNA with roughly 230,000 base pairs in its viral core, an icosahedral capsid to encompass the genome, and the tegument protein layer between the capsid and viral envelope (7). The viral tegument is embodied with various glycoproteins that serve as mediators to enable viral entry and also function as important tools for attachment, fusion, and escaping immune responses (8). Many of these glycoproteins serve different functions to facilitate the activeness of the virus. For example, glycoprotein UL82 prevents MHC cell surface expression, thus preventing the recognition by T cells and inhibiting the destruction of the infected host cell (8). Likewise, glycoprotein UL36 prevents apoptosis, thus increasing the longevity of the host cell (8). A typical, matured viral particle has a diameter between 150 nm to 200 nm (7). HCMV, along with other enveloped viruses like herpes simplex virus type 1 (HSV-1) and influenza virus type A (H1N1), are typically less stable in their ambient environment and particularly sensitive to changes in pH, lipid solvents, and changes to temperature (9). Similar to all herpesviruses, HCMV is sensitive to heat, lipid-dissolving agents, and a low, acidic pH (7). If the phospholipid bilayer of the outer envelope is lysed or damaged, the virus may lose its functional receptors and make it less susceptible to infect cells (9). DNA viruses like HCMV have much lower mutation rates unlike RNA retroviruses like HIV, whose RNA virus polymerase lacks proofreading capabilities and whose process of reverse transcriptase increases chances for error (10).
Similar to all herpesviruses, HCMV expresses glycoproteins gB and gH/gL which are crucial for viral entry into a host cell (11). HCMV has a remarkable ability of infecting a very broad range of cells including endothelial cells, smooth muscle cells, fibroblasts and epithelial cells, and with each cell type, HCMV has a distinct path that utilizes different gH/gL complexes (11, 12). Entry into epithelial and endothelial cells typically involves macropinocytosis, fusion through the incorporation of endosomes, and protein complex gH/gL/UL128-131, while entry into fibroblasts only involves direct fusion with the plasma membrane and use of gH/gL proteins (11). Upon attachment to the host cell, the HCMV binds signaling receptors like integrin, platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR) to enable the entry of the virus into the cell and facilitate the translocation of CMV into the nucleus where it will release its DNA to initially become latent (13). The Ulb region within the genome of HCMV is unique to the HCMV strain and is proposed to be the region of the genome responsible for encoding factors incorporated in the pathogenesis, viral replication and persistence of the virus (14). In particular, the UL133-UL138 locus embedded within the ULb region of the genome is responsible for regulating a state of latency and replication of the virus, as opposed to UL138 and UL135 that have opposing regulatory functions that mediate in latency and reactivation (13, 14). UL135 plays a part in its ability to cause viral reactivation by overpowering UL138’s function of growth-suppression (14). While latency is established through transcriptional silencing enhanced by certain regions within the Ulb region of the CMV genome, reactivation is triggered through injury, inflammation, and infection (15). As a result of this relationship between the virus and its host, HCMV developed a dynamic relationship with the immune response of its host and utilizes the gene regulation of cells to establish its latency and distribute its infection in a systemic matter (15).
The cytomegalovirus fails to maintain a household name like HIV or measles due to its dual presence in a majority of individuals; however, as evident with the statistical data, it is a prevalent virus that results in a vast display of detrimental phenotypes. With the lack of a vaccine in place and the ability of the virus to be transferred with ease congenitally or through normal, everyday interactions, attention is now slowly turning towards this virus, resulting in individuals around the world focusing on ways to mitigate the effects of a virus that lies dormant in so many individuals.
References:
Image: https://www.google.com/search?q=herpes+virus&tbm=isch&ved=2ahUKEwj7u7nwyrztAhUPhFMKHY5_AvAQ2-cCegQIABAA&oq=herpes+virus&gs_lcp=CgNpbWcQAzIFCAAQsQMyAggAMgIIADICCAAyAggAMgIIADICCAAyAggAMgIIADICCAA6BAgjECc6BAgAEEM6BwgAELEDEENQ3DlYsUdgg0loAHAAeACAAZkBiAHfDJIBBDAuMTKYAQCgAQGqAQtnd3Mtd2l6LWltZ8ABAQ&sclient=img&ei=1H_OX_uBN4-IzgKO_4mADw&bih=480&biw=1079&rlz=1C1CHBF_enUS899US899&tbs=il%3Acl&hl=en#imgrc=tk0OwDeocFX-cM
When comparing CMV seroprevalence in developed countries against developing countries, there is a substantial difference between the infection rates (5). In developing countries like Panama, Gambia, Taiwan, and India, CMV seroprevalance is typically over 90% by adolescence and greater than 95% through early adulthood. A majority of these cases arise from non-primary maternal infections (5). When comparing this to a developed country like the United States or Canada, CMV seroprevalance over the age range of 12-40 is roughly between 40- 60%, taking into account both primary and non-primary maternal CMV infections (5). Though CMV is a prevalent virus around the world, no licensed vaccine exists for the virus (4). Currently approved anti-HCMV drugs include ganciclovir, cidofovir, valganciclovir, and foscarnet, which all serve as systematic treatments of HCMV by targeting viral DNA polymerase (6). Though these drugs are effective at preventing replication of the HCMV genome, their effectiveness is limited by renal and bone marrow toxicity and antiviral drug resistance (6).
HCMV is a double stranded DNA (dsDNA) virus and the largest virus in the Herpesviridae family (7). The incorporated HCMV genome consists of a dsDNA with roughly 230,000 base pairs in its viral core, an icosahedral capsid to encompass the genome, and the tegument protein layer between the capsid and viral envelope (7). The viral tegument is embodied with various glycoproteins that serve as mediators to enable viral entry and also function as important tools for attachment, fusion, and escaping immune responses (8). Many of these glycoproteins serve different functions to facilitate the activeness of the virus. For example, glycoprotein UL82 prevents MHC cell surface expression, thus preventing the recognition by T cells and inhibiting the destruction of the infected host cell (8). Likewise, glycoprotein UL36 prevents apoptosis, thus increasing the longevity of the host cell (8). A typical, matured viral particle has a diameter between 150 nm to 200 nm (7). HCMV, along with other enveloped viruses like herpes simplex virus type 1 (HSV-1) and influenza virus type A (H1N1), are typically less stable in their ambient environment and particularly sensitive to changes in pH, lipid solvents, and changes to temperature (9). Similar to all herpesviruses, HCMV is sensitive to heat, lipid-dissolving agents, and a low, acidic pH (7). If the phospholipid bilayer of the outer envelope is lysed or damaged, the virus may lose its functional receptors and make it less susceptible to infect cells (9). DNA viruses like HCMV have much lower mutation rates unlike RNA retroviruses like HIV, whose RNA virus polymerase lacks proofreading capabilities and whose process of reverse transcriptase increases chances for error (10).
Similar to all herpesviruses, HCMV expresses glycoproteins gB and gH/gL which are crucial for viral entry into a host cell (11). HCMV has a remarkable ability of infecting a very broad range of cells including endothelial cells, smooth muscle cells, fibroblasts and epithelial cells, and with each cell type, HCMV has a distinct path that utilizes different gH/gL complexes (11, 12). Entry into epithelial and endothelial cells typically involves macropinocytosis, fusion through the incorporation of endosomes, and protein complex gH/gL/UL128-131, while entry into fibroblasts only involves direct fusion with the plasma membrane and use of gH/gL proteins (11). Upon attachment to the host cell, the HCMV binds signaling receptors like integrin, platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR) to enable the entry of the virus into the cell and facilitate the translocation of CMV into the nucleus where it will release its DNA to initially become latent (13). The Ulb region within the genome of HCMV is unique to the HCMV strain and is proposed to be the region of the genome responsible for encoding factors incorporated in the pathogenesis, viral replication and persistence of the virus (14). In particular, the UL133-UL138 locus embedded within the ULb region of the genome is responsible for regulating a state of latency and replication of the virus, as opposed to UL138 and UL135 that have opposing regulatory functions that mediate in latency and reactivation (13, 14). UL135 plays a part in its ability to cause viral reactivation by overpowering UL138’s function of growth-suppression (14). While latency is established through transcriptional silencing enhanced by certain regions within the Ulb region of the CMV genome, reactivation is triggered through injury, inflammation, and infection (15). As a result of this relationship between the virus and its host, HCMV developed a dynamic relationship with the immune response of its host and utilizes the gene regulation of cells to establish its latency and distribute its infection in a systemic matter (15).
The cytomegalovirus fails to maintain a household name like HIV or measles due to its dual presence in a majority of individuals; however, as evident with the statistical data, it is a prevalent virus that results in a vast display of detrimental phenotypes. With the lack of a vaccine in place and the ability of the virus to be transferred with ease congenitally or through normal, everyday interactions, attention is now slowly turning towards this virus, resulting in individuals around the world focusing on ways to mitigate the effects of a virus that lies dormant in so many individuals.
References:
- Abate, Davide A et al. “Major human cytomegalovirus structural protein pp65 (ppUL83) prevents interferon response factor 3 activation in the interferon response.” Journal of virology vol. 78,20 (2004): 10995-1006. doi:10.1128/JVI.78.20.10995-11006.2004
- Stowell, Jennifer D et al. “Cytomegalovirus survival and transferability and the effectiveness of common hand-washing agents against cytomegalovirus on live human hands.” Applied and environmental microbiology vol. 80,2 (2014): 455-61. doi:10.1128/AEM.03262-13
- Schottstedt, Volkmar et al. “Human Cytomegalovirus (HCMV) - Revised.” Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie vol. 37,6 (2010): 365-375. doi:10.1159/000322141
- Kalejta, Robert F. “Tegument proteins of human cytomegalovirus.” Microbiology and molecular biology reviews : MMBR vol. 72,2 (2008): 249-65, table of contents. doi:10.1128/MMBR.00040-07
- Firquet, Swan et al. “Survival of Enveloped and Non-Enveloped Viruses on Inanimate Surfaces.” Microbes and environments vol. 30,2 (2015): 140-4. doi:10.1264/jsme2.ME14145
- Duffy, Siobain. “Why are RNA virus mutation rates so damn high?.” PLoS biology vol. 16,8 e3000003. 13 Aug. 2018, doi:10.1371/journal.pbio.3000003
- Vanarsdall, Adam L, and David C Johnson. “Human cytomegalovirus entry into cells.” Current opinion in virology vol. 2,1 (2012): 37-42. doi:10.1016/j.coviro.2012.01.001
- Sinzger, C et al. “Cytomegalovirus cell tropism.” Current topics in microbiology and immunology vol. 325 (2008): 63-83. doi:10.1007/978-3-540-77349-8_4
- Collins-McMillen, Donna et al. “Molecular Determinants and the Regulation of Human Cytomegalovirus Latency and Reactivation.” Viruses vol. 10,8 444. 20 Aug. 2018, doi:10.3390/v10080444
- Wang, Depeng et al. “The ULb' region of the human cytomegalovirus genome confers an increased requirement for the viral protein kinase UL97.” Journal of virology vol. 87,11 (2013): 6359-76. doi:10.1128/JVI.03477-12
- Collins-McMillen, Donna et al. “Molecular Determinants and the Regulation of Human Cytomegalovirus Latency and Reactivation.” Viruses vol. 10,8 444. 20 Aug. 2018, doi:10.3390/v10080444
- Wang, Depeng et al. “The ULb' region of the human cytomegalovirus genome confers an increased requirement for the viral protein kinase UL97.” Journal of virology vol. 87,11 (2013): 6359-76. doi:10.1128/JVI.03477-12
- Forte, Eleonora et al. “Cytomegalovirus Latency and Reactivation: An Intricate Interplay With the Host Immune Response.” Frontiers in cellular and infection microbiology vol. 10 130. 31 Mar. 2020, doi:10.3389/fcimb.2020.00130
- Mlera, Luwanika et al. “The Role of the Human Cytomegalovirus UL133-UL138 Gene Locus in Latency and Reactivation.” Viruses vol. 12,7 714. 1 Jul. 2020, doi:10.3390/v12070714
- Sedykh, Sergey E et al. “Bispecific antibodies: design, therapy, perspectives.” Drug design, development and therapy vol. 12 195-208. 22 Jan. 2018, doi:10.2147/DDDT.S151282
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