Human Cytomegalovirus Latency: Approaching the Gordian Knot

Overview

Journal Annu Rev Virol

Publisher Annual Reviews

Specialty Microbiology

Date 2016 Aug 9

PMID 27501258

Citations 110

Authors

Felicia Goodrum

Affiliations

Soon will be listed here.

Abstract

Herpesviruses have evolved exquisite virus-host interactions that co-opt or evade a number of host pathways to enable the viruses to persist. Persistence of human cytomegalovirus (CMV), the prototypical betaherpesvirus, is particularly complex in the host organism. Depending on host physiology and the cell types infected, CMV persistence comprises latent, chronic, and productive states that may occur concurrently. Viral latency is a central strategy by which herpesviruses ensure their lifelong persistence. Although much remains to be defined about the virus-host interactions important to CMV latency, it is clear that checkpoints composed of viral and cellular factors exist to either maintain a latent state or initiate productive replication in response to host cues. CMV offers a rich platform for defining the virus-host interactions and understanding the host biology important to viral latency. This review describes current understanding of the virus-host interactions that contribute to viral latency and reactivation.

Citing Articles

Viral reactivations and fungal infections in nonresolving acute respiratory distress syndrome.

Maessen L, Boers L, Heylen J, van Someren Greve F, Wauters J, Bos L Eur Respir Rev. 2025; 34(175).

PMID: 39971398 PMC: 11836671. DOI: 10.1183/16000617.0153-2024.

Complex roles for proliferating cell nuclear antigen in restricting human cytomegalovirus replication.

Longmire P, Daigle O, Zeltzer S, Lee M, Svoboda M, Padilla-Rodriguez M bioRxiv. 2025; .

PMID: 39829879 PMC: 11741387. DOI: 10.1101/2025.01.06.631530.

Susceptibility of Mouse Brain to MCMV Infection and Neuroinflammation During Ontogeny.

Krstanovic F, Mihalic A, Sakota L, Lisnic B, Jonjic S, Brizic I Pathogens. 2025; 13(12.

PMID: 39770367 PMC: 11728524. DOI: 10.3390/pathogens13121108.

Viral microRNA regulation of Akt is necessary for reactivation of Human Cytomegalovirus from latency in CD34+ hematopoietic progenitor cells and humanized mice.

Diggins N, Pham A, Mitchell J, Parkins C, Slind L, Turner R PLoS Pathog. 2024; 20(12):e1012285.

PMID: 39661658 PMC: 11666035. DOI: 10.1371/journal.ppat.1012285.

Third intracellular loop of HCMV US28 is necessary for signaling and viral reactivation.

Medica S, Denton M, Diggins N, Kramer-Hansen O, Crawford L, Mayo A J Virol. 2024; 99(1):e0180124.

PMID: 39655954 PMC: 11784217. DOI: 10.1128/jvi.01801-24.

References

Rauwel B, Jang S, Cassano M, Kapopoulou A, Barde I, Trono D . Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch. Elife. 2015; 4. PMC: 4384640. DOI: 10.7554/eLife.06068. View

OConnor C, Murphy E . A myeloid progenitor cell line capable of supporting human cytomegalovirus latency and reactivation, resulting in infectious progeny. J Virol. 2012; 86(18):9854-65. PMC: 3446554. DOI: 10.1128/JVI.01278-12. View

Miller W, Mosialos G, Kieff E, Raab-Traub N . Epstein-Barr virus LMP1 induction of the epidermal growth factor receptor is mediated through a TRAF signaling pathway distinct from NF-kappaB activation. J Virol. 1997; 71(1):586-94. PMC: 191088. DOI: 10.1128/JVI.71.1.586-594.1997. View

Woodhall D, Groves I, Reeves M, Wilkinson G, Sinclair J . Human Daxx-mediated repression of human cytomegalovirus gene expression correlates with a repressive chromatin structure around the major immediate early promoter. J Biol Chem. 2006; 281(49):37652-60. DOI: 10.1074/jbc.M604273200. View

Ma J, Russell T, Spelman T, Carbone F, Tscharke D . Lytic gene expression is frequent in HSV-1 latent infection and correlates with the engagement of a cell-intrinsic transcriptional response. PLoS Pathog. 2014; 10(7):e1004237. PMC: 4110040. DOI: 10.1371/journal.ppat.1004237. View

Clippinger A, Maguire T, Alwine J . The changing role of mTOR kinase in the maintenance of protein synthesis during human cytomegalovirus infection. J Virol. 2011; 85(8):3930-9. PMC: 3126115. DOI: 10.1128/JVI.01913-10. View

Miller C, Eaves C . Long-term culture-initiating cell assays for human and murine cells. Methods Mol Med. 2011; 63:123-41. DOI: 10.1385/1-59259-140-X:123. View

Minton E, Tysoe C, Sinclair J, Sissons J . Human cytomegalovirus infection of the monocyte/macrophage lineage in bone marrow. J Virol. 1994; 68(6):4017-21. PMC: 236908. DOI: 10.1128/JVI.68.6.4017-4021.1994. View

Hansen S, Powers C, Richards R, Ventura A, Ford J, Siess D . Evasion of CD8+ T cells is critical for superinfection by cytomegalovirus. Science. 2010; 328(5974):102-6. PMC: 2883175. DOI: 10.1126/science.1185350. View

10.

Chan G, Nogalski M, Bentz G, Smith M, Parmater A, Yurochko A . PI3K-dependent upregulation of Mcl-1 by human cytomegalovirus is mediated by epidermal growth factor receptor and inhibits apoptosis in short-lived monocytes. J Immunol. 2010; 184(6):3213-22. PMC: 3743441. DOI: 10.4049/jimmunol.0903025. View

11.

Le V, Trilling M, Hengel H . The cytomegaloviral protein pUL138 acts as potentiator of tumor necrosis factor (TNF) receptor 1 surface density to enhance ULb'-encoded modulation of TNF-α signaling. J Virol. 2011; 85(24):13260-70. PMC: 3233134. DOI: 10.1128/JVI.06005-11. View

12.

Kramer M, Chen S, Knipe D, Coen D . Accumulation of viral transcripts and DNA during establishment of latency by herpes simplex virus. J Virol. 1998; 72(2):1177-85. PMC: 124594. DOI: 10.1128/JVI.72.2.1177-1185.1998. View

13.

Lee S, Albright E, Lee J, Jacobs D, Kalejta R . Cellular defense against latent colonization foiled by human cytomegalovirus UL138 protein. Sci Adv. 2015; 1(10):e1501164. PMC: 4681346. DOI: 10.1126/sciadv.1501164. View

14.

Price A, Luftig M . To be or not IIb: a multi-step process for Epstein-Barr virus latency establishment and consequences for B cell tumorigenesis. PLoS Pathog. 2015; 11(3):e1004656. PMC: 4366242. DOI: 10.1371/journal.ppat.1004656. View

15.

Smith W, Tomasec P, Aicheler R, Loewendorf A, Nemcovicova I, Wang E . Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses. Cell Host Microbe. 2013; 13(3):324-35. PMC: 3601332. DOI: 10.1016/j.chom.2013.02.003. View

16.

Abraham C, Kulesza C . Polycomb repressive complex 2 silences human cytomegalovirus transcription in quiescent infection models. J Virol. 2013; 87(24):13193-205. PMC: 3838248. DOI: 10.1128/JVI.02420-13. View

17.

Kung C, Raab-Traub N . Epstein-Barr virus latent membrane protein 1 modulates distinctive NF- kappaB pathways through C-terminus-activating region 1 to regulate epidermal growth factor receptor expression. J Virol. 2010; 84(13):6605-14. PMC: 2903255. DOI: 10.1128/JVI.00344-10. View

18.

Murphy E, Rigoutsos I, Shibuya T, Shenk T . Reevaluation of human cytomegalovirus coding potential. Proc Natl Acad Sci U S A. 2003; 100(23):13585-90. PMC: 263857. DOI: 10.1073/pnas.1735466100. View

19.

Weekes M, Tan S, Poole E, Talbot S, Antrobus R, Smith D . Latency-associated degradation of the MRP1 drug transporter during latent human cytomegalovirus infection. Science. 2013; 340(6129):199-202. PMC: 3683642. DOI: 10.1126/science.1235047. View

20.

Mocarski E, Bonyhadi M, Salimi S, McCune J, KANESHIMA H . Human cytomegalovirus in a SCID-hu mouse: thymic epithelial cells are prominent targets of viral replication. Proc Natl Acad Sci U S A. 1993; 90(1):104-8. PMC: 45608. DOI: 10.1073/pnas.90.1.104. View