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.
Cite this paper
Pandey, B. (2025). The Role of Human Herpesvirus-Encoded MicroRNA in Host Virus Interaction. Open Access Library Journal, 12, e3043. doi: http://dx.doi.org/10.4236/oalib.1113043.
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/
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
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
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/
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
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/
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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/
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
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
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
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
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
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
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
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
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
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
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
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
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