Human Herpesviruses (HHVs) are a group of large DNA viruses that can establish lifelong infections in their hosts. They achieve this by switching between two phases: the lytic phase, where the virus actively replicates, and the latent phase, where the virus remains dormant but can reactivate later. A key factor in this process is microRNAs (miRNAs)—small, non-coding RNA molecules that regulate gene expression. In human cells, miRNAs play a crucial role in controlling various biological processes, and their disruption has been linked to diseases like cancer. Interestingly, herpesviruses have evolved ways to manipulate the host’s miRNA system to their advantage. By interfering with these regulatory pathways, the virus can evade immune detection, prevent cell death (apoptosis), and promote either viral persistence or active replication, depending on what benefits its survival. This review explores the role of viral microRNAs (v-miRNAs) in human herpesvirus infections, focusing on how they influence the virus’s lifecycle and contribute to disease. HHVs are unique in that because many of them encode their own v-miRNAs, which help them hijack the host’s cellular machinery. A key aspect of this interaction is how these viral miRNAs suppress immune responses, affecting both innate and adaptive immunity. Additionally, research has shown that herpesviruses can package their miRNAs into exosomes-tiny vesicles that can transfer viral messages between cells, altering the function of recipient cells and promoting infection. This paper specifically examines the functions of HHV-derived v-miRNAs in host-virus interactions, with a focus on how they help the virus persist in the body. Among the eight known human herpesviruses, v-miRNAs have been identified in Herpes Simplex Virus 1 & 2 (HSV-1 & HSV-2), Human Cytomegalovirus (HCMV), Human Herpesvirus-6B (HHV-6B), Epstein-Barr Virus (EBV), and Kaposi Sarcoma-Associated Herpesvirus (KSHV). Understanding how these viral miRNAs function could provide deeper insights into herpesvirus pathogenesis and potential therapeutic strategies.
References
[1]
Ryan, K., Ahmad, N., Alspaugh, J.A., Drew, W.L., Lagunoff, M., Pottinger, P., et al. (2004) Sherris Medical Microbiology. 4th Edition, McGraw Hill.
[2]
Baron, S. (1996) Medical Microbiology. 4th Edition, University of Texas Medical Branch at Gal-veston. https://www.ncbi.nlm.nih.gov/books/NBK7627/
[3]
Whitley, R.J. (1996) Herpesviruses. In Baron, S., Ed., Medical Microbiology, University of Texas Medical Branch at Galveston. https://www.ncbi.nlm.nih.gov/books/NBK8157/
[4]
Pfeffer, S., Zavolan, M., Grasser, F.A., Chien, M., Russo, J.J., Ju, J., et al. (2004) Identification of Virus-Encoded MicroRNAs. Science, 304, 734-736. https://doi.org/10.1126/science.1096781
[5]
Cullen, B.R. (2011) Herpesvirus MicroRNAs: Phenotypes and Functions. Current Opinion in Virology, 1, 211-215. https://doi.org/10.1016/j.coviro.2011.04.003
[6]
Skalsky, R.L. and Cullen, B.R. (2010) Viruses, MicroRNAs, and Host Interactions. Annual Review of Microbiology, 64, 123-141. https://doi.org/10.1146/annurev.micro.112408.134243
[7]
McGeoch, D.J., Cook, S., Dolan, A., Jamieson, F.E. and Telford, E.A.R. (1995) Molecular Phylog-eny and Evolutionary Timescale for the Family of Mammalian Herpesviruses. Journal of Molecular Biology, 247, 443-458. https://doi.org/10.1006/jmbi.1995.0152
[8]
Pellet, P. and Roizman, B. (2007) Herpesviridae: A Brief Introduction. In: Howley, P., Ed., Fields Virology, Lippincott, 2480-2499.
https://scholar.google.com/scholar_lookup?title=Fields%20Virology.
%20Philadelphia&au-thor=P%20Pellet&author=B%20Roizman&author
=DM%20Knipe&author=PM%20Howley&publication_year=2007&
[9]
Boshoff, C. and Weiss, R. (2002) Aids-Related Malignancies. Nature Reviews Cancer, 2, 373-382. https://doi.org/10.1038/nrc797
[10]
Favoreel, H.W. (2006) The Why’s of Y-Based Motifs in Alphaherpesvirus Envelope Proteins. Virus Research, 117, 202-208. https://doi.org/10.1016/j.virusres.2005.11.007
[11]
Close, W.L., Anderson, A.N. and Pellett, P.E. (2018) Betaherpesvirus Virion Assembly and Egress. In: Kawaguchi, Y., Mori, Y. and Kimura, H., Eds., Human Herpesviruses, Springer, 167-207. https://doi.org/10.1007/978-981-10-7230-7_9
[12]
Longnecker, R. and Neipel, F. (2007) Introduction to the Human γ-Herpesviruses. In: Arvin, A., Campadelli-Fiume, G., Mocarski, E., et al., Eds., Human Herpesviruses: Biology, Therapy, and Im-munoprophylaxis, Cambridge University Press. https://www.ncbi.nlm.nih.gov/books/NBK47397/
[13]
Ayoade, F.O. and Bronze, M.S. (2025) Herpes Simplex Clinical Presentation.
https://emedicine.medscape.com/article/218580-clinical?form=fpf
[14]
Knipe, H., Roizman, B. and Pellett, P.E. (2001) Herpesviridae. In: Knipe, D.M. and Howley, P., Eds., Fields Virology, Lippincott Williams & Wilkins, 2381-2397. https://www.ncbi.nlm.nih.gov/books/NBK47449/#c32tox-k1h-cc0-ef3
[15]
Koelle, D.M. (2009) HSV-1 and 2: Immunobiology and Host Response from Part III—Pathogenesis, Clinical Disease, Host Response, and Epidemiology: HSV-1 and HSV-2. Cambridge University Press.
https://www.cambridge.org/core/books/abs/human-herpesviruses/hsv1
-and-2-immunobiolo-gy-and-host-response/9F22F864B355C88BC3DB1D57B60FD59A
[16]
World Health Organization (2024) Herpes Simplex Virus. https://www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus
[17]
Mueller, N.H. (2008) Varicella Zoster Virus Infection: Clinical Feature, Molecular Patho-genesis in Disease, and Latency. National Library of Medicine.
https://pmc.ncbi.nlm.nih.gov/articles/PMC2754837/#:~:text=Varicella
%20is%20characterized%20by%20fever,after%201%20to%202%20weeks
[18]
Gupta, M. and Shorman, M. (2023) Cytomegalovirus. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK459185/
[19]
Hoover, K. and Hig-ginbotham, K. (2023) Epstein-Barr Virus. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK559285/
[20]
Yamanishi, K. (2007) HHV-6A, 6B, and 7: Pathogenesis, Host Response, and Clinical Disease. In: Arvin, A., Campadelli-Fiume, G., Mocarski, E., et al., Eds., Human Herpesviruses: Biology, Thera-py, and Immunoprophylaxis, Cambridge University Press.https://www.ncbi.nlm.nih.gov/books/NBK47394/
[21]
(2024) Human Her-pesvirus-8 Disease. https://search.app/GiywMziYGXDfHAdb6
[22]
Centres for Dis-ease Control and Prevention (n.d.) B-Virus. https://www.cdc.gov/herpes-b-virus/about/index.html
[23]
Bushati, N. and Co-hen, S.M. (2007) MicroRNA Functions. Annual Review of Cell and Developmental Biol-ogy, 23, 175-205. https://doi.org/10.1146/annurev.cellbio.23.090506.123406
[24]
Tang, S., Bertke, A.S., Patel, A., Wang, K., Cohen, J.I. and Krause, P.R. (2008) An Acutely and Latently Expressed Herpes Simplex Virus 2 Viral MicroRNA Inhibits Expression of ICP34.5, a Viral Neurovirulence Factor. Proceedings of the National Academy of Sciences, 105, 10931-10936. https://doi.org/10.1073/pnas.0801845105
[25]
Umbach, J.L. and Cullen, B.R. (2009) The Role of RNAi and MicroRNAs in Animal Virus Replication and Antiviral Immunity. Genes & Development, 23, 1151-1164. https://doi.org/10.1101/gad.1793309
[26]
Kramer, M.F., Jurak, I., Pesola, J.M., Boissel, S., Knipe, D.M. and Coen, D.M. (2011) Herpes Simplex Virus 1 MicroRNAs Expressed Abundantly during Latent Infection Are Not Essential for Latency in Mouse Trigeminal Ganglia. Virology, 417, 239-247. https://doi.org/10.1016/j.virol.2011.06.027
[27]
Stark, T.J., Arnold, J.D., Spector, D.H. and Yeo, G.W. (2012) High-Resolution Profiling and Analysis of Viral and Host Small RNAs during Human Cytomegalovirus Infection. Journal of Virology, 86, 226-235. https://doi.org/10.1128/jvi.05903-11
[28]
Cai, X., Lu, S., Zhang, Z., Gon-zalez, C.M., Damania, B. and Cullen, B.R. (2005) Kaposi’s Sarcoma-Associated Her-pesvirus Expresses an Array of Viral MicroRNAs in Latently Infected Cells. Proceed-ings of the National Academy of Sciences, 102, 5570-5575. https://doi.org/10.1073/pnas.0408192102
[29]
Barton, G.M. and Medzhitov, R. (2003) Toll-Like Receptor. Signaling Pathways. Science, 300, 1524-1525. https://doi.org/10.1126/science.1085536
[30]
Takeda, K. and Akira, S. (2015) Toll-Like Receptors. Current Protocols in Immunology, 109, 14.12.1-14.12.10. https://doi.org/10.1002/0471142735.im1412s109
[31]
Kawai, T. and Akira, S. (2009) The Roles of TLRs, RLRs and NLRs in Pathogen Recognition. International Im-munology, 21, 317-337. https://doi.org/10.1093/intimm/dxp017
[32]
Kumar, H., Kawai, T. and Akira, S. (2011) Pathogen Recognition by the Innate Immune System. International Reviews of Immunology, 30, 16-34. https://doi.org/10.3109/08830185.2010.529976
[33]
Boehme, K.W., Guerrero, M. and Compton, T. (2006) Human Cytomegalovirus Envelope Glycoproteins B and H Are Necessary for TLR2 Activation in Permissive Cells. The Journal of Immunology, 177, 7094-7102. https://doi.org/10.4049/jimmunol.177.10.7094
[34]
Landais, I., Pelton, C., Streblow, D., DeFilippis, V., McWeeney, S. and Nelson, J.A. (2015) Human Cytomegalovirus miR-Ul112-3p Targets TLR2 and Modulates the TLR2/IRAK1/NfκB Signaling Pathway. PLOS Pathogens, 11, e1004881. https://doi.org/10.1371/journal.ppat.1004881
[35]
Abend, J.R., Ramalingam, D., Kieffer-Kwon, P., Uldrick, T.S., Yarchoan, R. and Ziegelbauer, J.M. (2012) Kaposi’s Sarcoma-Associated Herpesvirus MicroRNAs Target IRAK1 and MYD88, Two Com-ponents of the Toll-Like Receptor/Interleukin-1R Signaling Cascade, to Reduce In-flammatory-Cytokine Expression. Journal of Virology, 86, 11663-11674. https://doi.org/10.1128/jvi.01147-12
[36]
Hancock, M.H., Hook, L.M., Mitchell, J. and Nelson, J.A. (2017) Human Cytomegalovirus MicroRNAs miR-US5-1 and miR-Ul112-3p Block Proinflammatory Cytokine Production in Response to NF-κB-Activating Factors through Direct Downregulation of IKKα and IKKβ. mBio, 8. https://doi.org/10.1128/mbio.00109-17
[37]
Qin, Z., Kearney, P., Plaisance, K. and Parsons, C.H. (2009) Pivotal Advance: Kaposi’s Sarcoma-Associated Herpesvirus (KSHV)-Encoded MicroRNA Specifically Induce IL-6 and IL-10 Secretion by Macro-phages and Monocytes. Journal of Leukocyte Biology, 87, 25-34. https://doi.org/10.1189/jlb.0409251
[38]
Haneklaus, M., Gerlic, M., Kurow-ska-Stolarska, M., Rainey, A., Pich, D., McInnes, I.B., et al. (2012) Cutting Edge: miR-223 and EBV miR-BART15 Regulate the NLRP3 Inflammasome and IL-1β Pro-duction. The Journal of Immunology, 189, 3795-3799. https://doi.org/10.4049/jimmunol.1200312
[39]
Hooykaas, M.J.G., van Gent, M., Soppe, J.A., Kruse, E., Boer, I.G.J., van Leenen, D., et al. (2017) EBV MicroRNA BART16 Suppresses Type I IFN Signaling. The Journal of Immunology, 198, 4062-4073. https://doi.org/10.4049/jimmunol.1501605
[40]
Devergne, O., Peuchmaur, M., Humbert, M., Navratil, E., Leger-Ravet, M.B., Crevon, M.C., et al. (1991) In vivo Expression of IL-1 Beta and IL-6 Genes during Viral Infections in Hu-man. European Cytokine Network, 2, 183-194. https://pubmed.ncbi.nlm.nih.gov/1654144/
[41]
Skinner, C.M., Ivanov, N.S., Barr, S.A., Chen, Y. and Skalsky, R.L. (2017) An Epstein-Barr Virus MicroRNA Blocks Inter-leukin-1 (IL-1) Signaling by Targeting IL-1 Receptor 1. Journal of Virology, 91. https://doi.org/10.1128/jvi.00530-17
[42]
Lau, B., Poole, E., Krishna, B., Monta-nuy, I., Wills, M.R., Murphy, E., et al. (2016) The Expression of Human Cytomegalo-virus MicroRNA miR-UL148D during Latent Infection in Primary Myeloid Cells Inhib-its Activin A-Triggered Secretion of IL-6. Scientific Reports, 6, Article No. 31205. https://doi.org/10.1038/srep31205
[43]
Wang, X., Liu, S., Zhou, Z., Yan, H. and Xiao, J. (2017) A Herpes Simplex Virus Type 2-Encoded MicroRNA Promotes Tumor Cell Metastasis by Targeting Suppressor of Cytokine Signaling 2 in Lung Cancer. Tu-mor Biology, 39. https://doi.org/10.1177/1010428317701633
[44]
Abend, J.R., Uldrick, T. and Ziegelbauer, J.M. (2010) Regulation of Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Receptor Protein (TWEAKR) Expression by Kaposi’s Sar-coma-Associated Herpesvirus MicroRNA Prevents Tweak-Induced Apoptosis and In-flammatory Cytokine Expression. Journal of Virology, 84, 12139-12151. https://doi.org/10.1128/jvi.00884-10
[45]
Blum, J.S., Wearsch, P.A. and Cresswell, P. (2013) Pathways of Antigen Processing. Annual Review of Immunology, 31, 443-473. https://doi.org/10.1146/annurev-immunol-032712-095910
[46]
Raghavan, M., Del Cid, N., Rizvi, S.M. and Peters, L.R. (2008) MHC Class I Assembly: Out and About. Trends in Immunology, 29, 436-443. https://doi.org/10.1016/j.it.2008.06.004
[47]
Tagawa, T., Albanese, M., Bouvet, M., Moosmann, A., Mautner, J., Heissmeyer, V., et al. (2016) Epstein-Barr Viral miR-NAs Inhibit Antiviral CD4 T Cell Responses Targeting IL-12 and Peptide Processing. Journal of Experimental Medicine, 213, 2065-2080. https://doi.org/10.1084/jem.20160248
[48]
Nachmani, D., Stern-Ginossar, N., Sarid, R. and Mandelboim, O. (2009) Diverse Herpesvirus MicroRNAs Target the Stress-Induced Immune Ligand MICB to Escape Recognition by Natural Killer Cells. Cell Host & Microbe, 5, 376-385. https://doi.org/10.1016/j.chom.2009.03.003
[49]
Esteso, G., Luzón, E., Sarmiento, E., Gómez-Caro, R., Steinle, A., Murphy, G., et al. (2014) Altered MicroRNA Expres-sion after Infection with Human Cytomegalovirus Leads to TIMP3 Downregulation and Increased Shedding of Metalloprotease Substrates, Including Mica. The Journal of Immunology, 193, 1344-1352. https://doi.org/10.4049/jimmunol.1303441
[50]
Lo, A.K.F., To, K.F., Lo, K.W., Lung, R.W.M., Hui, J.W.Y., Liao, G., et al. (2007) Modulation of LMP1 Protein Expres-sion by EBV-Encoded MicroRNAs. Proceedings of the National Academy of Sciences, 104, 16164-16169. https://doi.org/10.1073/pnas.0702896104
[51]
Lung, R.W., Tong, J.H., Sung, Y., Leung, P., Ng, D.C., Chau, S., et al. (2009) Modulation of LMP2A Expression by a Newly Identified Epstein-Barr Virus-Encoded MicroRNA miR-BART22. Neoplasia, 11, 1174-IN17. https://doi.org/10.1593/neo.09888
[52]
Kim, Y., Lee, S., Kim, S., Kim, D., Ahn, J. and Ahn, K. (2012) Human Cytomegalovirus Clinical Strain-Specific MicroRNA miR-Ul148d Targets the Human Chemokine RANTES during Infection. PLOS Patho-gens, 8, e1002577. https://doi.org/10.1371/journal.ppat.1002577
[53]
Xia, T., O’Hara, A., Araujo, I., Barreto, J., Carvalho, E., Sapucaia, J.B., et al. (2008) EBV Mi-croRNAs in Primary Lymphomas and Targeting of CXCL-11 by Ebv-miR-BHRF1-3. Cancer Research, 68, 1436-1442. https://doi.org/10.1158/0008-5472.can-07-5126
[54]
Colombo, M., Raposo, G. and Théry, C. (2014) Biogenesis, Secretion, and Intercellular Interactions of Exo-somes and Other Extracellular Vesicles. Annual Review of Cell and Developmental Bi-ology, 30, 255-289. https://doi.org/10.1146/annurev-cellbio-101512-122326
[55]
Valadi, H., Ekström, K., Bossios, A., Sjöstrand, M., Lee, J.J. and Lötvall, J.O. (2007) Exosome-Mediated Transfer of mRNAs and MicroRNAs Is a Novel Mechanism of Genetic Exchange be-tween Cells. Nature Cell Biology, 9, 654-659. https://doi.org/10.1038/ncb1596
[56]
Liu, J., Jennings, S.F., Tong, W. and Hong, H. (2011) Next Generation Sequencing for Profiling Expression of miRNAs: Technical Progress and Applications in Drug Development. Journal of Biomedical Science and Engineering, 4, 666-676. https://doi.org/10.4236/jbise.2011.410083
