Expression of HCMV-Encoded miRNA in Subjects Acutely Coinfected with HIV: Correlation with Inflammation and Immune Activation
Abstract
1. Introduction
2. Results
2.1. HCMV-Encoded miRNA Expression in Lytic and Latent HCMV Infection
2.2. Expression of HCMV-Encoded miRNA During Latent Infection in Subjects Monoinfected with HCMV and Coinfected with HCMV/HIV
2.3. Inflammatory Cytokine Plasma Levels and Relationships with HCMV-Encoded miRNA Expression
3. Discussion
4. Materials and Methods
4.1. Study Population and Virological Evaluation
4.2. MiRNA Detection
4.3. Cytokine Quantification
4.4. Statistical Evaluation
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Fernández-Moreno, R.; Torre-Cisneros, J.; Cantisán, S. Human Cytomegalovirus (HCMV)-Encoded microRNAs: Potential Biomarkers and Clinical Applications. RNA Biol. 2021, 18, 2194–2202. [Google Scholar] [CrossRef] [PubMed]
- Zeng, J.; Cao, D.; Yang, S.; Jaijyan, D.K.; Liu, X.; Wu, S.; Cruz-Cosme, R.; Tang, Q.; Zhu, H. Insights into the Transcriptome of Human Cytomegalovirus: A Comprehensive Review. Viruses 2023, 15, 1703. [Google Scholar] [CrossRef]
- Diggins, N.L.; Skalsky, R.L.; Hancock, M.H. Regulation of Latency and Reactivation by Human Cytomegalovirus miRNAs. Pathogens 2021, 10, 200. [Google Scholar] [CrossRef] [PubMed]
- Meshesha, M.K.; Bentwich, Z.; Solomon, S.A.; Avni, Y.S. In Vivo Expression of Human Cytomegalovirus (HCMV) microRNAs during Latency. Gene 2016, 575, 101–107. [Google Scholar] [CrossRef]
- Tribolet, L.; Kerr, E.; Cowled, C.; Bean, A.G.D.; Stewart, C.R.; Dearnley, M.; Farr, R.J. MicroRNA Biomarkers for Infectious Diseases: From Basic Research to Biosensing. Front. Microbiol. 2020, 11, 1197. [Google Scholar] [CrossRef]
- Lichtner, M.; Cicconi, P.; Vita, S.; Cozzi-Lepri, A.; Galli, M.; Lo Caputo, S.; Saracino, A.; De Luca, A.; Moioli, M.; Maggiolo, F.; et al. Cytomegalovirus Coinfection Is Associated with an Increased Risk of Severe Non-AIDS-Defining Events in a Large Cohort of HIV-Infected Patients. J. Infect. Dis. 2015, 211, 178–186. [Google Scholar] [CrossRef]
- Lederman, M.M.; Funderburg, N.T.; Sekaly, R.P.; Klatt, N.R.; Hunt, P.W. Residual Immune Dysregulation Syndrome in Treated HIV Infection. Adv. Immunol. 2013, 119, 51–83. [Google Scholar] [CrossRef] [PubMed]
- Freeman, M.L.; Lederman, M.M.; Gianella, S. Partners in Crime: The Role of CMV in Immune Dysregulation and Clinical Outcome During HIV Infection. Curr. HIV/AIDS Rep. 2016, 13, 10–19. [Google Scholar] [CrossRef]
- Nana, B.C.; Esemu, L.F.; Besong, M.E.; Atchombat, D.H.N.; Ogai, K.; Sobgui, T.M.P.; Nana, C.M.M.; Seumko’o, R.M.N.; Awanakan, H.; Ekali, G.L.; et al. Soluble Biomarkers of HIV-1-Related Systemic Immune Activation Are Associated with High Plasma Levels of Growth Factors Implicated in the Pathogenesis of Kaposi Sarcoma in Adults. Front. Immunol. 2023, 14, 1216480. [Google Scholar] [CrossRef]
- Lurain, N.S.; Hanson, B.A.; Hotton, A.L.; Weber, K.M.; Cohen, M.H.; Landay, A.L. The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women. AIDS Res. Hum. Retroviruses 2016, 32, 134–143. [Google Scholar] [CrossRef]
- Lazzari, E.; Rozera, G.; Gagliardini, R.; Esvan, R.; Mondi, A.; Mazzotta, V.; Camici, M.; Girardi, E.; Antinori, A.; Maggi, F.; et al. Human and Viral microRNA Expression in Acute and Chronic HIV Infections. Viruses 2024, 16, 496. [Google Scholar] [CrossRef] [PubMed]
- Lussignol, M.; Esclatine, A. Herpesvirus and Autophagy: “All Right, Everybody Be Cool, This Is a Robbery!”. Viruses 2017, 9, 372. [Google Scholar] [CrossRef]
- Pandeya, A.; Khalko, R.K.; Mishra, A.; Singh, N.; Singh, S.; Saha, S.; Yadav, S.; Saxena, S.; Gosipatala, S.B. Human Cytomegalovirus miR-UL70-3p Downregulates the H2O2-Induced Apoptosis by Targeting the Modulator of Apoptosis-1 (MOAP1). Int. J. Mol. Sci. 2022, 23, 18. [Google Scholar] [CrossRef]
- Khalko, R.K.; Pandeya, A.; Saxena, S.; Gosipatala, S.B. HCMV miR-UL70-3p Downregulates the Rapamycin-Induced Autophagy by Targeting the Autophagy-Related Protein 9A (ATG9A). Int. Rev. Immunol. 2024, 43, 197–210. [Google Scholar] [CrossRef] [PubMed]
- Bates, D.O. Vascular Endothelial Growth Factors and Vascular Permeability. Cardiovasc. Res. 2010, 87, 262–271. [Google Scholar] [CrossRef] [PubMed]
- Fan, J.; Zhang, W.; Liu, Q. Human Cytomegalovirus-Encoded miR-US25-1 Aggravates the Oxidised Low Density Lipoprotein-Induced Apoptosis of Endothelial Cells. BioMed Res. Int. 2014, 2014, 531979. [Google Scholar] [CrossRef] [PubMed]
- Yu, M.; Jin, Y.; Zhang, S.; Xu, J.; Zhang, J. microRNA, a Subtle Indicator of Human Cytomegalovirus against Host Immune Cells. Vaccines 2022, 10, 144. [Google Scholar] [CrossRef]
- Zhang, L.; Yu, J.; Liu, Z. MicroRNAs Expressed by Human Cytomegalovirus. Virol. J. 2020, 17, 34. [Google Scholar] [CrossRef]
- Dong, J.; Li, S.; Lu, Z.; Du, P.; Liu, G.; Li, M.; Ma, C.; Zhou, J.; Bao, J. HCMV-miR-US33-5p Promotes Apoptosis of Aortic Vascular Smooth Muscle Cells by Targeting EPAS1/SLC3A2 Pathway. Cell. Mol. Biol. Lett. 2022, 27, 40. [Google Scholar] [CrossRef]
- Lisboa, L.F.; Egli, A.; O’Shea, D.; Åsberg, A.; Hartmann, A.; Rollag, H.; Pang, X.L.; Tyrrell, D.L.; Kumar, D.; Humar, A. Hcmv-miR-UL22A-5p: A Biomarker in Transplantation With Broad Impact on Host Gene Expression and Potential Immunological Implications. Am. J. Transplant. 2015, 15, 1893–1902. [Google Scholar] [CrossRef]
- Pan, C.; Zhu, D.; Wang, Y.; Li, L.; Li, D.; Liu, F.; Zhang, C.-Y.; Zen, K. Human Cytomegalovirus miR-UL148D Facilitates Latent Viral Infection by Targeting Host Cell Immediate Early Response Gene 5. PLOS Pathog. 2016, 12, e1006007. [Google Scholar] [CrossRef] [PubMed]
- Pandeya, A.; Khalko, R.K.; Singh, S.; Kumar, M.; Gosipatala, S.B. Hcmv-miR-UL148D Regulates the Staurosporine-Induced Apoptosis by Targeting the Endoplasmic Reticulum to Nucleus Signaling 1(ERN1). PLoS ONE 2022, 17, e0275072. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.-P.; Qi, Y.; Huang, Y.-J.; Qi, M.-L.; Ma, Y.-P.; He, R.; Ji, Y.-H.; Sun, Z.-R.; Ruan, Q. Identification of Immediate Early Gene X-1 as a Cellular Target Gene of Hcmv-Mir-UL148D. Int. J. Mol. Med. 2013, 31, 959–966. [Google Scholar] [CrossRef]
- Kim, Y.; Lee, S.; Kim, S.; Kim, D.; Ahn, J.-H.; Ahn, K. Human Cytomegalovirus Clinical Strain-Specific microRNA miR-UL148D Targets the Human Chemokine RANTES during Infection. PLOS Pathog. 2012, 8, e1002577. [Google Scholar] [CrossRef] [PubMed]
- Lau, B.; Poole, E.; Krishna, B.; Sellart, I.; Wills, M.R.; Murphy, E.; Sinclair, J. The Expression of Human Cytomegalovirus MicroRNA MiR-UL148D during Latent Infection in Primary Myeloid Cells Inhibits Activin A-Triggered Secretion of IL-6. Sci. Rep. 2016, 6, 31205. [Google Scholar] [CrossRef]
- Zhang, Y.; Tang, W.; Peng, L.; Tang, J.; Yuan, Z. Identification and Validation of microRNAs as Endogenous Controls for Quantitative Polymerase Chain Reaction in Plasma for Stable Coronary Artery Disease. Cardiol. J. 2016, 23, 694–703. [Google Scholar] [CrossRef]
A | |||||||
Sample | Age | Sex | CD4 T cells/mm3 | HCMV DNA (Log IU/mL) | HIV-1 RNA T0 (Log cp/mL) | HIV-1 RNA T1 (Log cp/mL) | HIV-1 RNA T2 (Log cp/mL) |
AHI 1 | 30 | M | 546 | ND * | 6.60 | 2.09 | NA |
AHI 2 | 49 | M | 540 | R < 2.25 ** | 6.00 | R < 1.46 ** | ND |
AHI 3 | 30 | M | 785 | ND | 3.85 | R < 1.46 | ND |
AHI 4 | 36 | M | 414 | ND | 6.37 | R < 1.46 | NA |
AHI 5 | 42 | M | 274 | ND | 7.15 | 2.16 | NA |
AHI 6 | 50 | M | 194 | ND | 7.74 | 1.58 | R < 1.46 |
AHI 7 | 29 | M | 413 | ND | 4.61 | R < 1.46 | NA |
AHI 8 | 39 | M | 425 | ND | 7.02 | R < 1.46 | R < 1.46 |
AHI 9 | 33 | M | 669 | ND | 4.68 | R < 1.46 | ND |
AHI 10 | 60 | M | 138 | ND | 6.08 | 2.00 | R < 1.46 |
AHI 11 | 46 | M | 260 | ND | 6.85 | 1.81 | R < 1.46 |
AHI 12 | 49 | M | 192 | ND | 6.69 | 1.98 | 2.54 |
AHI 13 | 33 | M | 524 | ND | 7.28 | 1.53 | R < 1.46 |
AHI 14 | 40 | M | 672 | ND | 4.84 | R < 1.46 | R < 1.46 |
AHI 15 | 55 | M | 349 | ND | 9.34 | ND | ND |
AHI 16 | 53 | M | 509 | 5.51 | 6.70 | 1.79 | R < 1.46 |
Median (IQR) | 41 (33–50) | 16 M | 420 (264–545) | 1.73 (1.73–1.73) | 6.65 (5.13–7.12) | 1.50 (1.46–1.94) | 1.46 (1.18–1.46) |
B | |||||||
CTR | Age | Sex | HCMV DNA (Log IU/mL) | ||||
CTR 1 | 47 | F | ND * | ||||
CTR 2 | 45 | F | ND | ||||
CTR 3 | 57 | F | ND | ||||
CTR 4 | 32 | F | ND | ||||
CTR 5 | 41 | M | ND | ||||
CTR 6 | 44 | F | ND | ||||
CTR 7 | 34 | F | ND | ||||
CTR 8 | 37 | F | ND | ||||
CTR 9 | 54 | F | ND | ||||
CTR 10 | 39 | F | ND | ||||
CTR 11 | 64 | M | 3.30 | ||||
CTR 12 | 63 | F | 3.67 | ||||
CTR 13 | 48 | M | 5.59 | ||||
CTR 14 | 64 | F | 3.86 | ||||
Median (IQR) | 46 (39–59) | 11 F/3 M | 1.73 (1.73–3.39) |
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Lazzari, E.; Rozera, G.; Esvan, R.; Gagliardini, R.; Mazzotta, V.; Mondi, A.; Federici, L.; Girardi, E.; Antinori, A.; Maggi, F.; et al. Expression of HCMV-Encoded miRNA in Subjects Acutely Coinfected with HIV: Correlation with Inflammation and Immune Activation. Int. J. Mol. Sci. 2025, 26, 5673. https://doi.org/10.3390/ijms26125673
Lazzari E, Rozera G, Esvan R, Gagliardini R, Mazzotta V, Mondi A, Federici L, Girardi E, Antinori A, Maggi F, et al. Expression of HCMV-Encoded miRNA in Subjects Acutely Coinfected with HIV: Correlation with Inflammation and Immune Activation. International Journal of Molecular Sciences. 2025; 26(12):5673. https://doi.org/10.3390/ijms26125673
Chicago/Turabian StyleLazzari, Elisabetta, Gabriella Rozera, Rozenn Esvan, Roberta Gagliardini, Valentina Mazzotta, Annalisa Mondi, Luigi Federici, Enrico Girardi, Andrea Antinori, Fabrizio Maggi, and et al. 2025. "Expression of HCMV-Encoded miRNA in Subjects Acutely Coinfected with HIV: Correlation with Inflammation and Immune Activation" International Journal of Molecular Sciences 26, no. 12: 5673. https://doi.org/10.3390/ijms26125673
APA StyleLazzari, E., Rozera, G., Esvan, R., Gagliardini, R., Mazzotta, V., Mondi, A., Federici, L., Girardi, E., Antinori, A., Maggi, F., & Abbate, I. (2025). Expression of HCMV-Encoded miRNA in Subjects Acutely Coinfected with HIV: Correlation with Inflammation and Immune Activation. International Journal of Molecular Sciences, 26(12), 5673. https://doi.org/10.3390/ijms26125673