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((Short description|Species of virus))
((Redirect|HCMV|the airport with the same ICAO code|Burao Airport))
((Use dmy dates|date=December 2019))
((Infobox medical condition (new)
| name            =Human cytomegalovirus
| synonyms        =
| field           = [[Infectious disease (medical specialty)|Infectious disease]]
| symptoms        =
| complications   =
| onset           =
| duration        =
| types           =
| causes          = ''Human betaherpesvirus 5''
| risks           =
| diagnosis       =
| differential    =
| prevention      =
| treatment       =
| medication      =
| prognosis       =
| frequency       =
| deaths          =
))
((Virusbox
| image = Cytomegalovirus 01.jpg
| image_alt = CMV infection of a human lung pneumocyte
| image_caption = CMV infection of a human lung [[pneumocyte]]
| parent = Cytomegalovirus
| species = Human betaherpesvirus 5
| synonyms = *''Human herpesvirus 5''
| synonyms_ref = <ref name="2015.010aD">((cite web |last1=Davison |first1=Andrew |title=Rename species in the family ''Herpesviridae'' to incorporate a subfamily designation |url=https://ictv.global/ictv/proposals/2015.010aD.A.v2.Herpesvirales_spren.pdf |website=International Committee on Taxonomy of Viruses (ICTV) |access-date=13 March 2019 |language=en |date=27 January 2016))</ref>
| subdivision_ranks =
| subdivision =
))

'''''Human betaherpesvirus 5''''', also called '''human cytomegalovirus''' ('''HCMV''','''HHV-5'''),<ref>((Cite web|last=taxonomy|title=Taxonomy browser (Human betaherpesvirus 5)|url=https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=info&id=10359|access-date=2020-07-25|website=www.ncbi.nlm.nih.gov))</ref> is a species of [[virus]] in the genus ''[[Cytomegalovirus]]'', which in turn is a member of the viral family known as ''[[Herpesviridae]]'' or herpesviruses.  It is also commonly called '''CMV'''.<ref name=Sherris>((cite book | veditors = Ryan KJ, Ray CG | title = Sherris Medical Microbiology | edition = 4th | pages = 556; 566–9 | publisher = McGraw Hill | year = 2004 | isbn = 978-0-8385-8529-0 ))</ref> Within ''[[Herpesviridae]]'', HCMV belongs to the ''[[Betaherpesvirinae]]'' subfamily, which also includes [[cytomegalovirus]]es from other [[mammal]]s.<ref name="isbn0-521-82714-0">((cite book |author1=Koichi Yamanishi |author2=Arvin, Ann M. |author3=Gabriella Campadelli-Fiume |author4=Edward Mocarski |author5=Moore, Patrick |author6=Roizman, Bernard |author7=Whitley, Richard |title=Human herpesviruses: biology, therapy, and immunoprophylaxis |publisher=Cambridge University Press |location=Cambridge, UK |year=2007 |isbn=978-0-521-82714-0 ))</ref> CMV is a [[DNA virus#Double-stranded DNA viruses|double-stranded DNA virus]].<ref name="pmid32847820">((cite journal | vauthors=Zanella M, Cordey S, Kaiser L | title=Beyond Cytomegalovirus and Epstein-Barr Virus: a Review of Viruses Composing the Blood Virome of Solid Organ Transplant and Hematopoietic Stem Cell Transplant Recipients | journal=[[Clinical Microbiology Reviews]] | volume=33 | issue=4 | pages=e00027-20 | year=2020 | doi = 10.1128/CMR.00027-20 | pmc=7462738 | pmid=32847820))</ref>

Although they may be found throughout the body, HCMV infections are frequently associated with the [[salivary gland]]s.<ref name="isbn0-521-82714-0"/> HCMV infection is typically unnoticed in healthy people, but can be life-threatening for the [[immunocompromised]], such as [[HIV]]-infected persons, [[organ transplant]] recipients, or [[neonate|newborn infants]].<ref name=Sherris /> [[Congenital cytomegalovirus infection]] can lead to significant morbidity and even death. After infection, HCMV remains latent within the body throughout life and can be reactivated at any time. Eventually, it may cause [[mucoepidermoid carcinoma]] and possibly other malignancies<ref>((cite journal |title= Human cytomegalovirus and mucoepidermoid carcinoma of salivary glands: cell-specific localization of active viral and oncogenic signaling proteins is confirmatory of a causal relationship|date=10 November 2011 |doi=10.1016/j.yexmp.2011.10.011 |journal=Experimental and Molecular Pathology |pmid=22101257 |volume=92 |issue=1 |pages=118–25 |vauthors=Melnick M, Sedghizadeh PP, Allen CM, Jaskoll T|s2cid=41446671 ))</ref> such as [[prostate cancer]]<ref>((cite journal | pmid=68820 | volume=61 | issue=2 | title=Cytomegalovirus and cancer of the prostate: in vitro transformation of human cells | year=1977 | journal=Cancer Treat Rep | pages=139–46 |vauthors=Geder L, Sanford EJ, Rohner TJ, Rapp F ))</ref> and [[breast cancer]].<ref>((Cite journal|last1=Kumar|first1=Amit|last2=Tripathy|first2=Manoj Kumar|last3=Pasquereau|first3=Sébastien|last4=Al Moussawi|first4=Fatima|last5=Abbas|first5=Wasim|last6=Coquard|first6=Laurie|last7=Khan|first7=Kashif Aziz|last8=Russo|first8=Laetitia|last9=Algros|first9=Marie-Paule|last10=Valmary-Degano|first10=Séverine|last11=Adotevi|first11=Olivier|date=April 2018|title=The Human Cytomegalovirus Strain DB Activates Oncogenic Pathways in Mammary Epithelial Cells|journal=eBioMedicine|volume=30|pages=167–183|doi=10.1016/j.ebiom.2018.03.015|issn=2352-3964|pmc=5952350|pmid=29628341))</ref>

HCMV is found in all geographic locations and all socioeconomic groups, and infects between 60% and 70% of adults in the [[first world]] and almost 100% in the [[third world]].<ref>
((cite journal| author = T. Fülöp| author2 = A. Larbi| author3 = G. Pawelec| name-list-style=amp | title = Human T cell aging and the impact of persistent viral infections| journal = Frontiers in Immunology| volume = 4| id= article: 271| pages= 271| date = September 2013| doi=10.3389/fimmu.2013.00271 | pmid = 24062739| pmc = 3772506| doi-access = free))
</ref>
Of all herpes viruses, HCMV harbors the most genes dedicated to altering (evading) [[innate immunity|innate]] and [[adaptive immunity|adaptive host immunity]] and represents a lifelong burden of antigenic T cell surveillance and immune dysfunction.<ref>
((cite journal| author = S. Varani| author2 = M. P. Landini| name-list-style=amp | date = 2011| title = Cytomegalovirus-induced immunopathology and its clinical consequences| journal = Herpesviridae| volume = 2| issue = 6| pages = 6| doi = 10.1186/2042-4280-2-6| pmid = 21473750| pmc = 3082217| doi-access = free))
</ref>
Commonly it is indicated by the presence of [[antibodies]] in the general population.<ref name=Sherris/> [[Seroprevalence]] is age-dependent: 58.9% of individuals aged 6 and older are infected with CMV while 90.8% of individuals aged 80 and older are positive for HCMV.<ref>
((cite journal| vauthors = Staras SA, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ| title = Seroprevalence of cytomegalovirus infection in the United States, 1988–1994| journal = Clin. Infect. Dis.| volume = 43| issue = 9| pages = 1143–51|date=November 2006| pmid = 17029132| doi = 10.1086/508173| doi-access = free))</ref> HCMV is also the [[virus]] most frequently [[Vertically transmitted infection|transmitted to a developing fetus]].<ref name="asm_jov">((cite journal|last1=Britt|first1=William J.|title=Congenital Human Cytomegalovirus Infection and the Enigma of Maternal Immunity|journal=[[Journal of Virology]]|date=1 August 2017|volume=91|issue=15|pages=e02392–16|doi=10.1128/JVI.02392-16|pmid=28490582|pmc=5512250|language=en|issn=0022-538X))</ref>
HCMV [[infection]] is more widespread in [[developing countries]] and in communities with lower [[socioeconomic status]] and represents the most significant viral cause of [[birth defect]]s in industrialized countries. Congenital HCMV is the leading infectious cause of [[deafness]], [[learning disabilities]], and [[intellectual disability]] in children.<ref>((cite journal|author1=Elizabeth G. Damato |author2=Caitlin W. Winnen | title = Cytomegalovirus infection: perinatal implications| journal = J Obstet Gynecol Neonatal Nurs| volume = 31| issue = 1| pages = 86–92| year = 2006|doi = 10.1111/j.1552-6909.2002.tb00026.x| pmid = 11843023| doi-access = free))</ref>
CMV also "seems to have a large impact on immune parameters in later life and may contribute to increased [[morbidity]] and eventual [[mortality rate|mortality]]."<ref>
((cite journal| vauthors = Caruso C, Buffa S, Candore G| title = Mechanisms of immunosenescence| journal = Immun Ageing| volume = 6| pages = 10| year = 2009|doi = 10.1186/1742-4933-6-10| pmid = 19624841| pmc = 2723084| display-authors = 1| doi-access = free))</ref>

==Signs and symptoms==
''Human betaherpesvirus 5'' infection has a classic triad of symptoms: [[fever]], peaking in the late afternoon or early evening; [[pharyngitis]], usually exudative; and '''symmetrical''' [[adenopathy]].<ref>((cite web | url=https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/human-herpesvirus-5 | title=Human Herpesvirus 5 - an overview &#124; ScienceDirect Topics ))</ref><ref>((Cite journal |last1=Sarma |first1=Shohinee |last2=Little |first2=Derek |last3=Ali |first3=Tooba |last4=Jones |first4=Emily |last5=Haider |first5=Shariq |date=August 27, 2018 |title=Cytomegalovirus Primary Infection in an Immunocompetent Female with Mononucleosis Features: A Review of Mononucleosis-Like Syndromes |url=https://cjgim.ca/index.php/csim/article/download/258/877 |journal=[[Canadian Journal of General Internal Medicine]] |volume=13 |issue=3 |pages=39–43 |doi=10.22374/cjgim.v13i3.258|s2cid=80706263 |doi-access=free ))</ref><ref>((cite book | url=https://www.ncbi.nlm.nih.gov/books/NBK8157/ | isbn=9780963117212 | title=Medical Microbiology | chapter=Herpesviruses | year=1996 | publisher=University of Texas Medical Branch at Galveston | pmid=21413307 | last1=Whitley | first1=R. J. | last2=Baron | first2=S. ))</ref>

==Virology==
===Transmission===
The mode of HCMV transmission from person to person is unknown, but is presumed to occur through bodily fluids, including [[saliva]], [[urine]], [[blood]], and [[tears]].<ref name="STD Sourcebook">Larsen, Laura. ''Sexually Transmitted Diseases Sourcebook. Health Reference Series Detroit'': Omnigraphics, Inc., 2009. Online.</ref> Cytomegalovirus is most commonly transmitted through kissing and sexual intercourse. It can also be transferred from an infected mother to her unborn child.<ref name="isbn0-521-82714-0"/> Infection requires close, intimate contact with a person secreting the virus in their [[saliva]], [[urine]], or other bodily fluids. CMV can be [[sexually transmitted disease|transmitted sexually]] and via [[breastfeeding|breast milk]], and also occurs through receiving transplanted organs or [[blood transfusion]]s.<ref name="pmid12588074">((cite journal |author=Taylor GH |title=Cytomegalovirus |journal=Am Fam Physician |volume=67 |issue=3 |pages=519–24 |date=February 2003 |pmid=12588074 |url=http://www.aafp.org/link_out?pmid=12588074))</ref> Although HCMV is not highly contagious, it has been shown to spread in households and among young children in day care centers.<ref name=Sherris />

===Replication===
HCMV replicates within infected [[Endothelial cell|endothelial]] cells<ref>((Cite journal|title = Efficient Lytic Infection of Human Arterial Endothelial Cells by Human Cytomegalovirus Strains|journal = Journal of Virology|date = 1 August 2000|issn = 0022-538X|pmc = 112284|pmid = 10906217|pages = 7628–7635|volume = 74|issue = 16|first1 = M.|last1 = Kahl|first2 = D.|last2 = Siegel-Axel|first3 = S.|last3 = Stenglein|first6 = C.|last6 = Sinzger|doi=10.1128/jvi.74.16.7628-7635.2000))</ref> at a slow rate, taking about five days in [[cell culture]].<ref>((Cite journal|title = The Dynamics of Human Cytomegalovirus Replication in Vivo|journal = The Journal of Experimental Medicine|date = 19 July 1999|issn = 0022-1007|pmid = 10432281|pages = 177–182|volume = 190|issue = 2|doi = 10.1084/jem.190.2.177|first1 = Vincent C.|last1 = Emery|first2 = Alethea V.|last2 = Cope|first3 = E. Frances|last3 = Bowen|first4 = Dehila|last4 = Gor|first5 = Paul D.|last5 = Griffiths|pmc=2195570))</ref> It also infects [[fibroblasts]], which requires expression of only a trimeric viral receptor complex, rather than the full pentameric complex that is required for infection of endothelial and epithelial cells.<ref name="gerna">((cite journal |last1=Gerna |first1=Giuseppe |last2=Kabanova |first2=Anna |last3=Lilleri |first3=Daniele |title=Human Cytomegalovirus Cell Tropism and Host Cell Receptors |journal=Vaccines |year=2019 |volume=7 |issue=3 |page=70 |id=70 |doi=10.3390/vaccines7030070 |pmid=31336680 |pmc=6789482 |doi-access=free))</ref>  Like other [[Herpesviridae|herpesviruses]], HCMV expresses genes in a temporally controlled manner.<ref name=":0">((Cite journal|title = Temporal patterns of human cytomegalovirus transcription: mapping the viral RNAs synthesized at immediate early, early, and late times after infection|journal = Journal of Virology|date = 1 February 1982|issn = 0022-538X|pmc = 256775|pmid = 6281461|pages = 462–477|volume = 41|issue = 2|first1 = M. W.|last1 = Wathen|first2 = M. F.|last2 = Stinski|doi = 10.1128/JVI.41.2.462-477.1982))</ref><ref>((Cite journal|title = Decoding Human Cytomegalovirus|journal = Science|date = 23 November 2012|issn = 0036-8075|pmc = 3817102|pmid = 23180859|pages = 1088–1093|volume = 338|issue = 6110|doi = 10.1126/science.1227919|first1 = Noam|last1 = Stern-Ginossar|first2 = Ben|last2 = Weisburd|first3 = Annette|last3 = Michalski|first4 = Vu Thuy Khanh|last4 = Le|first5 = Marco Y.|last5 = Hein|first6 = Sheng-Xiong|last6 = Huang|first7 = Ming|last7 = Ma|first8 = Ben|last8 = Shen|first9 = Shu-Bing|last9 = Qian|bibcode = 2012Sci...338.1088S))</ref> [[Immediate early gene]]s (expressed 0–4 hours after infection) are involved in the regulation of [[Transcription (genetics)|transcription]], followed by early genes (expressed 4–48 hours after infection) which are involved in viral [[DNA replication]] and further [[transcriptional regulation]].<ref name=":0" /> Late genes are expressed during the remainder of infection up to viral egress and typically code for structural proteins.  While HCMV encodes for its own functional [[DNA polymerase]], the virus makes use of the host [[RNA polymerase II|RNA polymerase]] for the transcription of all of its genes.<ref>((Cite journal|title = RNA polymerase II localizes at sites of human cytomegalovirus immediate-early RNA synthesis and processing|journal = Journal of Histochemistry and Cytochemistry|date = 1 February 1999|issn = 0022-1554|pmid = 9889260|pages = 245–254|volume = 47|issue = 2|first1 = S. P.|last1 = Snaar|first2 = M.|last2 = Vincent|first3 = R. W.|last3 = Dirks|doi=10.1177/002215549904700213|doi-access = free))</ref>

In disseminated cytomegalovirus infections, as may be seen in the context of an immunosuppressed host, the virus is readily transmitted between polymorphonuclear leukocytes (PM-NLs) and endothelial cells.  Infected endothelial cells produce cytokines that attract PM-NLs, which then adhere to the endothelium by interactions between their [[CD18]]-containing cell surface [[integrins]] and the endothelial-expressed [[ICAM-1]].  Microfusions between the cells then take place in a manner dependent on expression of the viral gene locus UL128L.<ref name="gerna" />

Synthesis of the viral double-stranded DNA genome occurs at the host cell [[Cell nucleus|nucleus]] within specialized viral replication compartments.<ref>((Cite journal|title = Formation of cytomegalovirus DNA replication compartments defined by localization of viral proteins and DNA synthesis|journal = Virology|date = 8 December 1997|issn = 0042-6822|pmid = 9426445|pages = 46–61|volume = 239|issue = 1|doi = 10.1006/viro.1997.8848|first1 = M. E.|last1 = Penfold|first2 = E. S.|last2 = Mocarski|doi-access = free))</ref>

Nearly 75% of the genes encoded by HCMV strain AD169 can be deleted and still result in the production of infectious virus.<ref>((Cite journal|title = Functional profiling of a human cytomegalovirus genome|journal = Proceedings of the National Academy of Sciences|date = 25 November 2003|issn = 0027-8424|pmc = 283573|pmid = 14623981|pages = 14223–14228|volume = 100|issue = 24|doi = 10.1073/pnas.2334032100|first1 = Walter|last1 = Dunn|first2 = Cassie|last2 = Chou|first3 = Hong|last3 = Li|first4 = Rong|last4 = Hai|first5 = David|last5 = Patterson|first6 = Viktor|last6 = Stolc|first7 = Hua|last7 = Zhu|first8 = Fenyong|last8 = Liu|bibcode = 2003PNAS..10014223D|doi-access = free))</ref> This suggests that the virus focuses on avoiding the host [[immune system]] for a timely entrance into [[latency period|latency]].<ref>((cite web | url=https://www.immunology.org/public-information/bitesized-immunology/pathogens-and-disease/human-cytomegalovirus-hcmv | title=Human Cytomegalovirus (HCMV) &#124; British Society for Immunology ))</ref>

==At-risk populations==
CMV infections are most significant in the [[perinatal period]] and in people who are immunocompromised.

===Pregnancy and congenital infection===
((Main|Congenital cytomegalovirus infection))
HCMV is one of the [[vertically transmitted infection]]s that lead to congenital abnormalities. (Others are: [[Toxoplasmosis]], [[Rubella]], and [[Herpes simplex]].) [[Congenital cytomegalovirus infection|Congenital HCMV infection]] occurs when the mother has a primary infection during pregnancy.<ref>((cite web | url=https://www.cdc.gov/cmv/clinical/congenital-cmv.html | title=Congenital CMV Infection &#124; CDC | date=3 December 2021 ))</ref><ref>((cite journal | pmc=3046747 | year=2010 | last1=Carlson | first1=A. | last2=Norwitz | first2=E. R. | last3=Stiller | first3=R. J. | title=Cytomegalovirus Infection in Pregnancy: Should All Women be Screened? | journal=Reviews in Obstetrics & Gynecology | volume=3 | issue=4 | pages=172–179 | pmid=21364849 ))</ref><ref>((cite journal | pmc=6116058 | year=2018 | last1=Britt | first1=W. J. | title=Maternal Immunity and the Natural History of Congenital Human Cytomegalovirus Infection | journal=Viruses | volume=10 | issue=8 | page=405 | doi=10.3390/v10080405 | pmid=30081449 | doi-access=free ))</ref>

Up to 5 of every 1,000 live births are infected. Five percent develop multiple handicaps, and develop [[cytomegalic inclusion disease]] with nonspecific signs that resemble rubella. Another five percent later develop cerebral calcification (decreasing IQ levels dramatically and causing sensorineural deafness and psychomotor retardation).((citation needed|date=May 2021))

However, infants born preterm and infected with HCMV after birth may experience cognitive and motor impairments later in life.<ref>((Cite journal|last1=Brecht|first1=Katharina F.|last2=Goelz|first2=Rangmar|last3=Bevot|first3=Andrea|last4=Krägeloh-Mann|first4=Ingeborg|last5=Wilke|first5=Marko|last6=Lidzba|first6=Karen|date=1 April 2015|title=Postnatal Human Cytomegalovirus Infection in Preterm Infants Has Long-Term Neuropsychological Sequelae|journal=The Journal of Pediatrics|volume=166|issue=4|pages=834–839.e1|doi=10.1016/j.jpeds.2014.11.002|pmid=25466679|issn=0022-3476))</ref>

===Immunocompromised adults===
CMV infection or reactivation in people whose [[immunosuppression|immune systems are compromised]]—for example people who have received transplants or are significantly burned—causes illness and increases the risk of death.<ref name=Navarro2016/><ref name="pmid17922387">((cite journal | author=Cook CH | title=Cytomegalovirus reactivation in "immunocompetent" patients: a call for scientific prophylaxis | journal= [[The Journal of Infectious Diseases]] | volume=196 | issue=9 | pages=1273–1275 | year=2007 | doi=10.1086/522433 | pmid = 17922387 | doi-access=free ))</ref>

CMV reactivation is commonly seen in people with severe [[colitis]].<ref name="pmid25684400">((cite journal | vauthors=Sager K, Alam S, Bond A, Chinnappan L, Probert CS | title=Review article: cytomegalovirus and inflammatory bowel disease | journal= [[Alimentary Pharmacology & Therapeutics]] | volume=41 | issue=8 | pages=725–733 | year=2015 | doi=10.1111/apt.13124 | pmid = 25684400 | s2cid=5969716 | doi-access=free ))</ref>

Specific disease entities recognized in those people are
* CMV hepatitis, which may cause fulminant [[liver failure]]
* [[cytomegalovirus retinitis]] (inflammation of the [[retina]], characterised by a "pizza pie appearance" on [[ophthalmoscopy]])
* [[cytomegalovirus colitis]] (inflammation of the [[colon (anatomy)|large bowel]])
* CMV [[pneumonitis]]
* CMV [[esophagitis]]<ref name="ClassenTytgat2010">((cite book|author1=Meinhard Classen|author2=Guido N. J. Tytgat|author3=M.D. PhD|author4=Charles J. Lightdale|title=Gastroenterological Endoscopy|url=https://books.google.com/books?id=Tb2Bnn_icI0C&pg=PA490|access-date=26 June 2010|year=2010|publisher=Thieme|isbn=978-3-13-125852-6|pages=490–))</ref>
* polyradiculopathy, transverse myelitis, and subacute encephalitis

People without CMV infection who are given organ transplants from CMV-infected donors require prophylactic treatment with [[valganciclovir]] (ideally) or [[ganciclovir]], and regular serological monitoring to detect a rising CMV titre; if treated early establishment of a potentially life-threatening infection can be prevented.<ref>((cite journal | url=https://www.dovepress.com/prophylaxis-of-cytomegalovirus-infection-in-solid-organ-transplantatio-peer-reviewed-fulltext-article-TRRM | doi=10.2147/TRRM.S366213 | title=Prophylaxis of Cytomegalovirus Infection in Solid Organ Transplantation, Retrospective Evaluation | year=2022 | last1=Albekairy | first1=Abdulkareem M. | last2=Shawaqfeh | first2=Mohammad S. | last3=Alharbi | first3=Shroug H. | last4=Almuqbil | first4=Faisal | last5=Alghamdi | first5=Mesfer A. | last6=Albekairy | first6=Nataleen A. | last7=Muflih | first7=Suhaib M. | last8=Alkatheri | first8=Abdulmalik | journal=Transplant Research and Risk Management | volume=14 | pages=35–45 | s2cid=249441439 | doi-access=free ))</ref>

===Immunocompetent adults===
CMV infections can still be of clinical significance in adult immunocompetent populations.<ref>((cite journal|last1=Rafailidis|first1=PI|last2=Mourtzoukou|first2=EG|last3=Varbobitis|first3=IC|last4=Falagas|first4=ME|title=Severe cytomegalovirus infection in apparently immunocompetent patients: a systematic review.|journal=Virology Journal|date=27 March 2008|volume=5|pages=47|doi=10.1186/1743-422X-5-47|pmid=18371229|pmc=2289809 |doi-access=free ))</ref>
* CMV [[mononucleosis]] (some sources reserve "mononucleosis" for [[Epstein–Barr virus]] only). However, the mononucleosis syndrome associated with CMV typically lacks signs of enlarged [[cervical lymph nodes]] and [[splenomegaly]].<ref>((Cite journal|pmid=4316146 | volume=121 | issue=6 | title=Infectious-mononucleosis-like disease with negative heterophil agglutination test. Clinical features in relation to Epstein–Barr virus and cytomegalovirus antibodies | date=June 1970 | vauthors=Klemola E, Von Essen R, Henle G, Henle W | journal=J. Infect. Dis. | pages=608–14| doi=10.1093/infdis/121.6.608))</ref><ref name="STD Sourcebook"/>
* CMV has also been associated with [[Guillain–Barré syndrome]],<ref name="oxford_idsa">((cite journal|last1=Lunn|first1=M.|last2=Hughes|first2=R.|title=The Relationship between Cytomegalovirus Infection and Guillain-Barre Syndrome|journal=Clinical Infectious Diseases|date=1 April 2011|volume=52|issue=7|pages=845–847|doi=10.1093/cid/cir082|pmid=21427391|language=en|issn=1058-4838|doi-access=free))</ref> type 1 diabetes,<ref>((cite journal | doi=10.1016/S0140-6736(88)92941-8 | pmid=2898620 | volume=332 | issue=8601 | journal=The Lancet | pages=1–4| year=1988 | last1=Pak | first1=Chiny | title=Association of Cytomegalovirus Infection with Autoimmune Type 1 Diabetes | last2=McArthur | first2=Robertg | last3=Eun | first3=Hyone-Myong | last4=Yoon | first4=Ji-Won | s2cid=42852009 ))</ref> and type 2 diabetes.<ref>((cite journal | doi = 10.1016/0140-6736(90)92145-8 | pmid=1975850 | volume=336 | issue = 8716 | title=Detection of cytomegalovirus nucleic acid sequences in pancreas in type 2 diabetes | journal=The Lancet | pages=644–648| year = 1990 | last1 = Lohr | first1 = J.M | last2 = Oldstone | first2 = M.B.A | s2cid=9783330 ))</ref>

The question of whether latent CMV infection has any negative effects on people who are otherwise healthy has been debated; as of 2016 the answer was not clear, but discussions had focused on whether latent CMV might increase the risk of some [[cardiovascular disease]]s and [[cancer]]s.<ref name=Navarro2016>((cite journal|last1=Navarro|first1=D|title=Expanding role of cytomegalovirus as a human pathogen.|journal=Journal of Medical Virology|date=July 2016|volume=88|issue=7|pages=1103–12|doi=10.1002/jmv.24450|pmid=6681168|s2cid=2310985))</ref>

==Pathogenesis==
[[File:CMVschema.svg|thumb|right]]

Most healthy people who are infected by HCMV after birth have no symptoms.<ref name=Sherris/> Some develop a [[syndrome]] similar to [[infectious mononucleosis]] or glandular fever,<ref name=Bottieau_2006>
((cite journal|vauthors=Bottieau E, Clerinx J, Van den Enden E, etal | title = Infectious mononucleosis-like syndromes in febrile travelers returning from the tropics| journal = Journal of Travel Medicine| volume = 13| issue = 4| pages = 191–7| year = 2006| pmid = 16884400| doi = 10.1111/j.1708-8305.2006.00049.x
| doi-access = free))</ref> with prolonged [[fever]], and a mild [[hepatitis]]. A sore throat is common. After infection, the virus remains latent in [[lymphocytes]] in the body for the rest of the person's life. Overt disease rarely occurs unless [[immune system|immunity]] is suppressed either by drugs, infection or old age. Initial HCMV infection, which often is [[asymptomatic]], is followed by a prolonged, inapparent infection during which the virus resides in mononuclear cells without causing detectable damage or clinical illness.<ref>((cite web | url=https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/human-cytomegalovirus | title=Human Cytomegalovirus - an overview &#124; ScienceDirect Topics ))</ref>

Infectious CMV may be shed in the bodily fluids of any infected person, and can be found in [[urine]], [[saliva]], [[blood]], [[tears]], [[semen]], and [[breast milk]]. The [[viral shedding|shedding of virus]] can occur intermittently, without any detectable signs or symptoms.

[[File:CMV placentitis2 mini.jpg|thumb|right|[[Micrograph]] of CMV [[placentitis]].  One cell on the image (centre) has the characteristic large [[cell nucleus|nucleus]] with peri-nuclear clearing.  Two cells (centre-right) have the characteristic (cytoplasmic) viral inclusion bodies (small pink [[Antibubble|globule]]s). [[H&E stain]].]]

CMV infection can be demonstrated microscopically by the detection of intranuclear [[inclusion bodies]]. On [[H&E stain]]ing, the inclusion bodies stain dark pink and are called "owl's eye" inclusion bodies.<ref>
((cite journal| vauthors = Mattes FM, McLaughlin JE, Emery VC, Clark DA, Griffiths PD| title = Histopathological detection of owl's eye inclusions is still specific for cytomegalovirus in the era of human herpesviruses 6 and 7| journal = J. Clin. Pathol.| volume = 53| issue = 8| pages = 612–4|date=August 2000| pmid = 11002765| pmc = 1762915| doi = 10.1136/jcp.53.8.612))</ref>

HCMV infection is important to certain high-risk groups.<ref name=Bennekov_2004>
((cite journal| vauthors = Bennekov T, Spector D, Langhoff E| title = Induction of immunity against human cytomegalovirus| journal = Mt. Sinai J. Med.| volume = 71| issue = 2| pages = 86–93|date=March 2004| pmid = 15029400))</ref> Major areas of risk of infection include [[pre-natal]] or [[postnatal]] infants and [[immunocompromised]] individuals, such as [[organ transplant]] recipients, persons with [[leukemia]], or those infected with human immunodeficiency virus ([[HIV]]). In HIV infected persons, HCMV is considered an ''[[AIDS]]-defining infection'', indicating that the [[T-cell]] count has dropped to low levels.

[[Lytic cycle|Lytically replicating]] viruses disrupt the [[cytoskeleton]], causing massive cell enlargement, which is the source of the virus' name.

A study published in 2009 links infection with CMV to high blood pressure in mice, and suggests that the result of CMV infection of blood vessel [[endothelium]] in humans is a major cause of [[atherosclerosis]].<ref name=Cheng_et_al_2009>
((cite journal| vauthors = Cheng J, Ke Q, Jin Z| title = Cytomegalovirus infection causes an increase of arterial blood pressure| journal = PLOS Pathog.| volume = 5| issue = 5| pages = e1000427|date=May 2009| pmid = 19436702| pmc = 2673691| doi = 10.1371/journal.ppat.1000427| editor1-last = Früh| editor1-first = Klaus| display-authors = etal | doi-access = free))</ref> Researchers also found that when the cells were infected with CMV, they created [[renin]], a protein known to contribute to high blood pressure.

Human CMV causes [[cellular senescence]], which could contribute to [[Systemic inflammation|chronic inflammation]] ([[inflammaging]]).<ref name="pmid30078211">((cite journal | vauthors=Wei W, Ji S| title=Cellular senescence: Molecular mechanisms and pathogenicity | journal=[[Journal of Cellular Physiology]] | volume=233 | issue=12| pages=9121–9135 | year=2018 | doi = 10.1002/jcp.26956 | pmid=30078211 | s2cid=51924586 ))</ref> Human CMV is also linked to age-associated [[T cell]] dysfunction, contributing to [[immunosenescence]].<ref name="pmid30078211" /> In persons infected with CMV about 10% of  [[memory T cell]]s are CMV-specific, but these may expand to as much as 30% in the elderly,<ref name="pmid27501258">((cite journal | author=Goodrum F | title=Human Cytomegalovirus Latency: Approaching the Gordian Knot | journal=[[Annual Review of Virology]] | volume=3 | issue=1 | pages=333–357 | year=2016 | doi=  10.1146/annurev-virology-110615-042422 | pmc=5514425 | pmid=27501258))</ref> 50% or more of [[CD8]]<sup>+</sup> memory T-cells.<ref name="pmid18469829">((cite journal | author=Nikolich-Zugich J| title=Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections | journal=[[Nature Reviews Immunology]] | volume=8 | issue=7 | pages=512–522 | year=2008 | doi=  10.1038/nri2318 | pmc=5573867 | pmid=18469829))</ref>  [[COVID-19]] symptom severity is associated with CMV, although the exact mechanism has not been elucidated.<ref name="pmid34746804">((cite journal | vauthors=Bartleson JM, Radenkovic D, Verdin E | title=SARS-CoV-2, COVID-19 and the Ageing Immune System | journal=[[List of Nature Research journals#N|Nature Aging]] | volume=1 | issue=9 | pages=769–782 | year=2021 |  doi = 10.1038/s43587-021-00114-7 | pmc=8570568 | pmid=34746804 ))</ref>

CMV encodes a protein, [[UL16]], which is involved in the immune evasion of [[NK cell]] responses. It binds to ligands [[ULBP1]], [[ULBP2]] and [[MICB]] of NK cell activating receptor [[NKG2D]], which prevents their surface expression. These ligands are normally upregulated in times of cellular stress, such as in viral infection, and by preventing their upregulation, CMV can prevent its host cell from dying due to NK cells<ref name="pmid12594848">((cite journal | title = Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein | journal = European Journal of Immunology | volume = 33 | issue = 1 | pages = 194–203 | year = 2003 | pmid = 12594848 | doi = 10.1002/immu.200390022 | last1 =  Welte | first1 =  Stefan A. | last2 =  Sinzger | first2 =  Christian | last3 =  Lutz | first3 =  Stefan Z. | last4 =  Singh-Jasuja | first4 =  Harpreet | last5 =  Sampaio | first5 =  Kerstin Laib | last6 =  Eknigk | first6 =  Ute | last7 =  Rammensee | first7 =  Hans-Georg | last8 =  Steinle | first8 =  Alexander | s2cid = 20718868 | doi-access =  free ))</ref>

A substantial portion of the immune system is involved in continuously controlling CMV, which drains the resources of the immune system.<ref name="pmid16456027">((cite journal | vauthors=Hadrup SR, Strindhall J, Køllgaard T, Seremet T, Johansson B, Pawelec G, thor Straten P, Wikby A | title=Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly | journal= [[Journal of Immunology]] | volume=176 | issue=4 | pages=2645–2653 | year=2006 | pmid = 16456027 | doi=10.4049/jimmunol.176.4.2645 | doi-access=free ))</ref><ref name="pmid21813708">((cite journal | vauthors=Derhovanessian E, Maier AB, Hähnel K, Beck R, de Craen AJ, Slagboom EP, Westendorp RG, Pawelec G | title=Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4+ and CD8+ T-cells in humans | journal=[[Journal of General Virology]] | volume=92 | issue=Pt 12 | pages=2746–2756 | year=2011 | doi=10.1099/vir.0.036004-0 | pmid=21813708 | doi-access=free ))</ref> Death rates from infectious disease accelerate with age,<ref name="pmid16803971">((cite journal | vauthors=Pawelec G, Koch S, Franceschi C, Wikby A | title=Human immunosenescence: does it have an infectious component? | journal= [[Annals of the New York Academy of Sciences]] | volume=1067 | issue=1 | pages=56–65 | year=2006 | doi=10.1196/annals.1354.009 | pmid = 16803971 | bibcode=2006NYASA1067...56P | s2cid=45806175 ))</ref> and CMV infection correlates with reduced effectiveness of [[vaccination]].<ref name="pmid23196209 ">((cite journal | vauthors=Derhovanessian E, Theeten H, Hähnel K, Van Damme P, Cools N, Pawelec G | title=Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination | journal= [[Vaccine (journal)|Vaccine]] | volume=31 | issue=4 | pages=685–690 | year=2013 | url=https://pdfs.semanticscholar.org/125b/2b7579ed32de260a0e447409d4877f7bb524.pdf | archive-url=https://web.archive.org/web/20180419120521/https://pdfs.semanticscholar.org/125b/2b7579ed32de260a0e447409d4877f7bb524.pdf | url-status=dead | archive-date=2018-04-19 | doi=10.1016/j.vaccine.2012.11.041 | pmid = 23196209  | s2cid=10483363 ))</ref> Persons with the highest levels of CMV antibodies have a much higher risk of death from all causes compared with persons having few or no antibodies.<ref name="pmid20660122">((cite journal | vauthors=Roberts ET, Haan MN, Dowd JB, Aiello AE | title=Cytomegalovirus antibody levels, inflammation, and mortality among elderly Latinos over 9 years of follow-up | journal= [[American Journal of Epidemiology]] | volume=172 | issue=4 | pages=363–371 | year=2010 | doi= 10.1093/aje/kwq177 |pmc=2950794  | pmid = 20660122 | s2cid=14983626 ))</ref><ref name="pmid21379581">((cite journal | vauthors=Simanek AM, Dowd JB, Pawelec G, Melzer D, Dutta A, Aiello AE | title=Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States | journal= [[PLOS One]] | volume=6 | issue=2 | pages=e16103 | year=2011 | doi=10.1371/journal.pone.0016103 | pmc=3040745 | pmid = 21379581 | bibcode=2011PLoSO...616103S | doi-access=free ))</ref>

==Diagnosis==
((Unreferenced section|date=December 2009))
[[Image:CMV placentitis2.jpg|thumb|Micrograph of CMV placentitis.]]
Most infections with CMV go undiagnosed, as the virus usually produces few, if any, symptoms and tends to reactivate intermittently without symptoms. Persons who have been infected with CMV develop [[antibodies]] to the virus, which persist in the body for the lifetime of that individual. A number of laboratory tests that detect these antibodies to CMV have been developed to determine if infection has occurred and are widely available from commercial laboratories. In addition, the virus can be cultured from specimens obtained from urine, throat swabs, bronchial lavages and tissue samples to detect active infection. Both qualitative and quantitative [[polymerase chain reaction]] (PCR) testing for CMV are available as well, allowing physicians to monitor the [[viral load]] of people infected with CMV.

The CMV pp65 antigenemia test is an immunofluorescence-based assay which utilizes an indirect immunofluorescence technique for identifying the pp65 protein of cytomegalovirus in peripheral blood leukocytes.<ref name="PMC3730495">((cite journal|last1=Ross|first1=S.A.|last2=Novak|first2=Z.|last3=Pati|first3=S.|last4=Boppana|first4=S.B.|title=Diagnosis of Cytomegalovirus Infections|journal=Infectious Disorders Drug Targets|date=October 2011|volume=11|issue=5|pages=466–474|issn=1871-5265|doi=10.2174/187152611797636703|pmc=3730495|pmid=21827433))</ref> The CMV pp65 assay is widely used for monitoring CMV infection and its response to antiviral treatment in people who are under immunosuppressive therapy and have had renal transplantation surgery, as the antigenemia results are obtained about 5 days before the onset of symptomatic CMV disease. The advantage of this assay is the rapidity in providing results in a few hours and that the pp65 antigen determination represents a useful criterion for the physician to initiate antiviral therapy. The major disadvantage of the pp65 assay is that only a limited number of samples can be processed per test batch.

CMV should be suspected if a person has symptoms of [[infectious mononucleosis]] but has negative test results for mononucleosis and [[Epstein–Barr virus]], or if they show signs of hepatitis, but have negative test results for [[hepatitis A]], [[Hepatitis B|B]], and [[Hepatitis C|C]].

For best diagnostic results, laboratory tests for CMV antibody should be performed by using paired serum samples. One blood sample should be taken upon suspicion of CMV, and another one taken within 2 weeks. A virus culture can be performed any time the person is symptomatic. Laboratory testing for antibodies to CMV can be performed to determine if a woman has already had CMV infection. However, routine testing of all pregnant women is costly and the need for testing should therefore be evaluated on a case-by-case basis.

===Serologic testing===

The enzyme-linked immunosorbent assay (or [[ELISA]]) is the most commonly available serologic test for measuring antibody to CMV. The result can be used to determine if acute infection, prior infection, or passively acquired maternal antibody in an infant is present. Other tests include various fluorescence assays, indirect [[hemagglutination]], (PCR) and [[latex fixation test|latex agglutination]].<ref>((cite web | url=https://www.cdc.gov/cmv/clinical/lab-tests.html | title=CMV Infection Laboratory Testing &#124; CDC | date=3 December 2021 ))</ref><ref>((cite journal | pmc=126858 | year=2002 | last1=Revello | first1=M. G. | last2=Gerna | first2=G. | title=Diagnosis and Management of Human Cytomegalovirus Infection in the Mother, Fetus, and Newborn Infant | journal=Clinical Microbiology Reviews | volume=15 | issue=4 | pages=680–715 | doi=10.1128/CMR.15.4.680-715.2002 | pmid=12364375 ))</ref>

An ELISA technique for CMV-specific [[IgM]] is available, but may give [[false-positive]] results unless steps are taken to remove [[rheumatoid factor]] or most of the [[Immunoglobulin G|IgG]] [[antibody]] before the serum sample is tested. Because CMV-specific IgM may be produced in low levels in reactivated CMV infection, its presence is not always indicative of primary infection. Only virus recovered from a target organ, such as the lung, provides unequivocal evidence that the current illness is caused by acquired CMV infection. If serologic tests detect a positive or high titer of IgG, this result should not automatically be interpreted to mean that active CMV infection is present. Active CMV infection is considered to be present if antibody tests of paired serum samples show a fourfold rise in IgG antibody and a significant level of IgM antibody (equal to at least 30% of the IgG value), or if virus is cultured from a urine or throat specimen.((citation needed|date=May 2021))

===Relevance to blood donors===
Although the risks discussed above are generally low, CMV assays are part of the standard screening for non-directed [[blood donation]] (donations not specified for a particular person) in the U.S., the UK and many other countries.  CMV-negative donations are then earmarked for transfusion to infants or people who are immunocompromised. Some blood donation centers maintain lists of donors whose blood is CMV negative due to special demands.<ref name=UBS>((cite web|title=United Blood Services FAQs |url=http://www.unitedbloodservices.org/faqs.html |access-date=23 May 2007 |archive-url=https://web.archive.org/web/20070519105254/http://www.unitedbloodservices.org/faqs.html |archive-date=19 May 2007 |url-status=dead ))</ref>

===Relevance to bone marrow donors===
During allogeneic [[hematopoietic stem cell transplant]], it is generally advised to match the serostatus of donor and recipient. If the recipient is seronegative, a seropositive donor carries a risk of de novo infection. Conversely, a seropositive recipient is at risk of viral reactivation if they receive a transplant from a seronegative donor, losing their innate defenses in the process. In general, the risk is highest for CMV seropositive recipients, in which viral reactivation is a cause of significant morbidity. For these reasons, CMV serologic testing is routine for both bone marrow donors and recipients.<ref>((cite journal |last1=Ljungman |first1=Per |title=Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation |journal=Clin Infect Dis |date=15 August 2014 |volume=59 |issue=4 |pages=473–81 |doi=10.1093/cid/ciu364 |pmid=24850801 |url=https://academic.oup.com/cid/article/59/4/473/2895692 |access-date=3 September 2020|doi-access=free ))</ref><ref>((cite journal |last1=Ljungman |first1=Per |last2=Hakki |first2=Morgan |last3=Boeckh |first3=Michael |title=Cytomegalovirus in Hematopoietic Stem Cell Transplant Recipients |journal=Hematology/Oncology Clinics of North America |date=February 2011 |volume=25 |issue=1 |pages=151–169 |doi=10.1016/j.hoc.2010.11.011 |pmid=21236396 |pmc=3340426 ))</ref>

==Prevention==
===Vaccination===
((Main|Cytomegalovirus vaccine))
A [[phase 2 study]] of a CMV-vaccine published in 2009 indicated an efficacy of 50%—the protection provided was limited, and a number of subjects contracted CMV infection despite vaccination. In one case also congenital CMV was encountered.<ref>
((cite journal|vauthors=Pass RF, Zhang C, Evans A, etal | title = Vaccine prevention of maternal cytomegalovirus infection| journal = N. Engl. J. Med.| volume = 360| issue = 12| pages = 1191–9|date=March 2009| pmid = 19297572| doi = 10.1056/NEJMoa0804749| pmc=2753425
))</ref>

In 2013, [[Astellas Pharma]] started on individuals who received a hematopoietic stem cell transplant a phase 3 trial with its CMV deoxyribonucleic acid [[DNA]] cytomegalovirus vaccine ASP0113.<ref>((cite web|url=https://clinicaltrials.gov/ct2/show/NCT01877655 |title=A Study to Evaluate a Therapeutic Vaccine, ASP0113, in Cytomegalovirus (CMV)-Seropositive Recipients Undergoing Allogeneic, Hematopoietic Cell Transplant (HCT) (HELIOS) |publisher=ClinicalTrials.gov |date=12 June 2013 |access-date=26 October 2015))</ref>

In 2015, Astellas Pharma commenced on healthy volunteers a phase 1 trial with its cytomegalovirus vaccine ASP0113.<ref>((cite web|url=https://clinicaltrials.gov/ct2/show/NCT02103426 |title=An Evaluation of a Cytomegalovirus (CMV) Vaccine (ASP0113) in CMV-Seropositive and CMV-Seronegative Healthy Subjects and CMV-Seronegative Dialysis Patients |publisher=ClinicalTrials.gov |date=8 July 2015 |access-date=22 October 2015))</ref>

Further cytomegalovirus vaccines candidates are the CMV-MVA Triplex vaccine and the CMVpp65-A*0201 peptide vaccine. Both vaccine candidates are sponsored by the [[City of Hope National Medical Center]]. As of 2016, the development is in clinical phase 2 trial stage.<ref>((cite web|url=https://clinicaltrials.gov/ct2/show/NCT02506933 |title=Multi-antigen CMV-MVA Triplex Vaccine in Reducing CMV Complications in Patients Previously Infected With CMV and Undergoing Donor Hematopoietic Cell Transplant |publisher=ClinicalTrials.gov |date=21 July 2015 |access-date=23 January 2016))</ref><ref>((cite web|url=https://clinicaltrials.gov/ct2/show/NCT02396134 |title=Vaccine Therapy in Reducing the Frequency of Cytomegalovirus Events in Patients With Hematologic Malignancies Undergoing Donor Stem Cell Transplant |publisher=ClinicalTrials.gov |date=12 March 2015 |access-date=23 January 2016))</ref>

===Hygiene===
The [[Centers for Disease Control and Prevention]] (CDC) recommend regular hand washing,<ref name="cdc_handwash">((cite web|title=When & How to Wash Your Hands ((!)) Handwashing|url=https://www.cdc.gov/handwashing/when-how-handwashing.html|website=[[Centers for Disease Control and Prevention|CDC]]|access-date=16 October 2017|archive-url=https://web.archive.org/web/20170913030642/https://www.cdc.gov/handwashing/when-how-handwashing.html|archive-date=13 September 2017|language=en-us|date=7 March 2016))</ref> especially after changing diapers.<ref name="cdc_cmv_overview">((cite web|title=CMV ((!)) Overview ((!)) Cytomegalovirus and Congenital CMV Infection|url=https://www.cdc.gov/cmv/overview.html|website=CDC|access-date=16 October 2017|archive-url=https://web.archive.org/web/20171016125115/https://www.cdc.gov/cmv/overview.html|archive-date=16 October 2017|language=en-us|date=17 June 2016))</ref> Hand washing is also recommended after feeding a child, wiping a child's nose or mouth, or handling children's toys.<ref>((cite web|title=CMV Transmission|url=https://www.nationalcmv.org/overview/cmv-transmission.aspx|website=National CMV Foundation|access-date=16 October 2017|archive-url=https://web.archive.org/web/20171016125418/https://www.nationalcmv.org/overview/cmv-transmission.aspx|archive-date=16 October 2017))</ref>

==Treatment==
[[Hyperimmune globulin]] enriched for CMV (CMV-IGIV) is an immunoglobulin G (IgG) containing a standardized number of antibodies to cytomegalovirus. It may be used for the prophylaxis of cytomegalovirus disease associated with transplantation of kidney, lung, liver, pancreas, and heart. Alone or in combination with an antiviral agent, it has been shown to:
* Reduce the risk of CMV-related disease and death in some of the highest-risk transplant recipients
* Provide a measurable long-term survival benefit
* Produce minimal treatment-related side effects and adverse events.<ref>[http://www.cytogam.com/pdfs/Cytogam%20PI.pdf Cytogam Prescribing Info] ((Webarchive|url=https://web.archive.org/web/20120426020642/http://www.cytogam.com/pdfs/Cytogam%20PI.pdf |date=26 April 2012 )) CSL Behring AG</ref>

[[Ganciclovir]] (Cytovene) treatment is used for people with depressed immunity who have either sight-related or life-threatening illnesses. [[Valganciclovir]] (Valcyte) is an antiviral drug that is also effective and is given orally: it is a pro-drug that gets converted into ganciclovir in the body, but is much better absorbed orally than the latter. The therapeutic effectiveness is frequently compromised by the emergence of drug-resistant virus isolates. A variety of amino acid changes in the UL97 protein kinase and the viral DNA polymerase have been reported to cause drug resistance. [[Foscarnet]] or [[cidofovir]] are only given to people with CMV resistant to ganciclovir, because foscarnet has notable nephrotoxicity, resulting in increased or decreased Ca<sup>2+</sup> or PO<sub>4</sub><sup>3−</sup>, and decreased Mg<sup>2+</sup> levels.<ref>((cite journal | pmc=5030152 | year=2016 | last1=Avery | first1=R. K. | last2=Arav-Boger | first2=R. | last3=Marr | first3=K. A. | last4=Kraus | first4=E. | last5=Shoham | first5=S. | last6=Lees | first6=L. | last7=Trollinger | first7=B. | last8=Shah | first8=P. | last9=Ambinder | first9=R. | last10=Neofytos | first10=D. | last11=Ostrander | first11=D. | last12=Forman | first12=M. | last13=Valsamakis | first13=A. | title=Outcomes in Transplant Recipients Treated with Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection | journal=Transplantation | volume=100 | issue=10 | pages=e74–e80 | doi=10.1097/TP.0000000000001418 | pmid=27495775 ))</ref><ref>((cite journal | pmc=88918 | year=1999 | last1=Erice | first1=A. | title=Resistance of Human Cytomegalovirus to Antiviral Drugs | journal=Clinical Microbiology Reviews | volume=12 | issue=2 | pages=286–297 | doi=10.1128/CMR.12.2.286 | pmid=10194460 ))</ref>

[[Letermovir]] has been approved by the [[European Medicines Agency]]<ref>((cite web |title=Previmys EPAR summary for the public |url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/004536/WC500241681.pdf |website=European Medicines Agency |access-date=27 June 2018 |archive-url=https://web.archive.org/web/20180627141103/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/004536/WC500241681.pdf |archive-date=27 June 2018|url-status=live|language=en))</ref> and the [[FDA]]<ref>((cite web |title=Approval Package for Letermovir |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000Approv.pdf |website=FDA |access-date=27 June 2018|url-status=live|archive-url=https://web.archive.org/web/20180627141403/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000Approv.pdf |archive-date=27 June 2018))</ref> for treatment and prophylaxis of HCMV infection.

A better understanding of how HCMV supports viral latency and reactivation should allow for the development of new therapies that target the latent reservoir.<ref name="pmid34663377">((cite journal | vauthors=Smith NA, Chan GC, O'Connor CM | title=Modulation of host cell signaling during cytomegalovirus latency and reactivation | journal=[[Virology Journal]] | volume=18 | issue=1 | pages=207 | year=2021 | doi=  10.1186/s12985-021-01674-1| doi-access=free | pmc=8524946 | pmid=34663377))</ref>

===Drug resistance===
[[File:hcmvdrugs.pdf|border|Antiviral mechanisms of HCMV drugs.|left|400x400px]]
All three currently licensed anti-HCMV drugs target the viral [[DNA polymerase]], pUL54. [[Ganciclovir]] (GCV) acts as nucleoside analogue. Its antiviral activity requires phosphorylation by the HCMV protein kinase, pUL97.<ref>((cite journal| journal=Nature| title=A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells| vauthors=Sullivan V, Talarico CL, ((Stanat SCC)), Davis M, Coen DM, Biron KK |pmid= 1319560| year=1992| volume=358| pages=162–164| doi=10.1038/358162a0| issue=6382| bibcode=1992Natur.358..162S| s2cid=4309307))</ref> The second drug, [[Cidofovir]] (CDV), is a nucleotide analogue, which is already phosphorylated and thus active. Finally, [[Foscarnet]] (FOS) has a different mode of action. It directly inhibits polymerase function by blocking the [[pyrophosphate]] binding site of pUL54 (note: investigational drug [[letermovir]] acts through a mechanism that involves viral terminase).<ref>((cite journal| journal=Drugs| title=Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis|vauthors=Chrisp P, Clissold SP|pmid= 1706982 | year=1991| volume=41| pages=104–129| issue=1| doi=10.2165/00003495-199141010-00009| doi-access=free))</ref>
Two HCMV proteins are implicated in antiviral resistance against these three drugs: pUL97 and pUL54. Specific mutations in pUL97 can cause reduced phosphorylation activity of this viral protein kinase. Thus, fewer monophosphorylated – and thus active – GCV can be synthesized,<ref>((cite journal| journal=Proc. Natl. Acad. Sci. U.S.A.| title=A human cytomegalovirus mutant resistant to the nucleoside analog 9-([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine (BW B759U) induces reduced levels of BW B759U triphosphate| vauthors=Biron KK, Fyfe JA, Stanat SC, Leslie LK, Sorrell JB, Lambe CU, Coen DM |pmid=3022304| year=1986| volume=83| pages=8769–8773| issue=22| pmc=387013| doi=10.1073/pnas.83.22.8769| bibcode=1986PNAS...83.8769B| doi-access=free))</ref> leading to antiviral resistance against GCV. About 90% of all GCV resistances are caused by such mutations in UL97.<ref>((cite journal| journal= Transpl. Infect. Dis.| title=Antiviral drug resistance in human cytomegalovirus| author= Chou S|pmid=11428978| year=1999| volume=1| pages=105–114| doi=10.1034/j.1399-3062.1999.010204.x| issue= 2| s2cid=23668301))</ref> Mutations in pUL54 may have different effects leading to antiviral [[drug resistance]]: A. They can lead to decreased affinity to antiviral compounds. This resistance mechanism concerns GCV, CDV and FOS and may lead to multidrug resistance.<ref>((cite journal |journal= Antimicrob. Agents Chemother. |title= Human cytomegalovirus resistance to antiviral drugs |author=C. Gilbert |author2= G. Boivin |name-list-style=amp |pmid= 15728878 |year=2005 |volume=49 |pages= 873–883 |doi= 10.1128/AAC.49.3.873-883.2005 |issue=3 |pmc= 549271))</ref> B. Some mutations in pUL54 can increase the polymerase's [[exonuclease]] activity. This causes enhanced recognition of incorporated GCV and CDV. As a result, these dNTP analogues are excised more efficiently.
Major risk factors for HCMV drug resistance are the residual capacity of the host's immune system to control viral replication and the overall amount and duration of viral replication.<ref>((cite journal |journal= Lancet |title= Ganciclovir resistance: a matter of time and titre |author= Drew WL |pmid= 10968428 |year=2000 |volume= 356 |pages= 609–610 |doi= 10.1016/S0140-6736(00)02597-6 |issue= 9230|s2cid= 46533224 ))</ref>
HCMV antiviral drug resistance can be detected by phenotypic or by genotypic drug resistance testing. Phenotypic resistance testing involves cultivation of the virus in cell culture and testing its susceptibility using different antiviral drug concentrations in order to determine [[EC50]] values. In contrast, genotypic resistance testing means the detection of resistance associated mutations in UL97 and UL54 by [[sequencing]]. Genotypic resistance testing is becoming the method of choice because it is faster, but requires previous phenotypic characterisation of each newly found mutation. This can be performed via a [http://www.informatik.uni-ulm.de/ni/mitarbeiter/HKestler/hcmv web-based search tool] that links a person's HCMV sequence to a database containing all published UL97 and UL54 mutations and corresponding antiviral drug susceptibility phenotypes.<ref>((cite journal| journal=Antiviral Research| title=A new tool linking human cytomegalovirus drug resistance mutations to resistance phenotypes| vauthors=Chevillotte M, von Einem J, Meier BM, Lin FM, Kestler HA, Mertens T |pmid=19853628| year=2010| volume=85| pages=318–27| doi=10.1016/j.antiviral.2009.10.004| issue=2))</ref>

==Epidemiology==
In the United States, CMV infection rises with age from about 60% of people infected by 6 years of age<ref name="pmid17922387"/> leveling off at about 85–90% of the population by ages 75–80.<ref name="pmid22541724">((cite journal | vauthors=Pawelec G, McElhaney JE, Aiello AE, Derhovanessian E | title=The impact of CMV infection on survival in older humans | journal= [[Current Opinion (Elsevier)|Current Opinion in Immunology]] | volume=24 | issue=4 | pages=507–511 | year=2012 | url=https://pdfs.semanticscholar.org/2b10/8cf988b3d90ed0265be6dec8e149b5f2146a.pdf | archive-url=https://web.archive.org/web/20180419120502/https://pdfs.semanticscholar.org/2b10/8cf988b3d90ed0265be6dec8e149b5f2146a.pdf | url-status=dead | archive-date=2018-04-19 | doi=10.1016/j.coi.2012.04.002 | pmid = 22541724 | s2cid=623760 ))</ref>

== See also ==

*[[Herpesviridae]]
*[[Epstein–Barr virus]] one of the most common viruses in humans.

==References==
((Reflist))

== External links ==
((Commons category))
((Wikispecies))
* ((Curlie|Health/Conditions_and_Diseases/Infectious_Diseases/Viral/Cytomegalovirus/))
* [https://www.cdc.gov/cmv/ Cytomegalovirus (CMV)] US [[Centers for Disease Control and Prevention]] (CDC). 22 May 2009
* [http://www.informatik.uni-ulm.de/ni/mitarbeiter/HKestler/hcmv HCMV drug resistance mutations tool]
* ((cite web |title=''Human herpesvirus 5'' |work=NCBI Taxonomy Browser |url=https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10359 |id=10359))

((Medical resources
|   ICD10       = ((ICD10|B|25||b|25))
|   ICD9        = ((ICD9|078.5))
|   MeshID      = D003586
))

((Herpesvirales))
((Viral diseases))
((Diseases of maternal transmission))
((Taxonbar|from=Q6929|from2=Q24808725))
((Authority control))

[[Category:Cytomegalovirus-associated diseases]]
[[Category:Betaherpesvirinae]]
[[Category:Virus-related cutaneous conditions]]
[[Category:Viral diseases]]

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