Human cytomegalovirus microRNA miR-US25-1-5p inhibits viral replication by targeting multiple cellular genes during infection

Jiang, Shujuan; He, Rong; Huang, Yujing; Liu, Zhongyang; Ma, Yanping; Guo, Xin; Shao, Yiming; Sun, Zhengrong; Ruan, Qiang

doi:10.1016/j.gene.2015.06.009

Cited by 24 publications

(22 citation statements)

References 46 publications

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“…We found no difference in viral lung titers at 7 dpi when miR-155 was absent, indicating that this molecule is not necessary for acute viral replication in the lung. This is in contrast to in vitro data from EBV and other viral systems, where miRNAs have been shown to play an inhibitory role in viral replication (44)(45)(46)(47).…”

Section: Discussioncontrasting

confidence: 95%

MicroRNA miR-155 Is Necessary for Efficient Gammaherpesvirus Reactivation from Latency, but Not for Establishment of Latency

Crepeau

Zhang

Usherwood

2016

J Virol

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MicroRNA-155 (miR-155) has been shown to play significant roles in the immune response, including in the formation of germinal centers (GC) and the development and maturation of T follicular helper (Tfh) cells. There is in vitro evidence to support a critical role for cellular miR-155 and viral miR-155 homologs in the establishment of gammaherpesvirus latency in B cells. We sought to determine the contribution of miR-155 to the establishment and maintenance of latency in vivo using murine gammaherpesvirus (MHV-68) infection. MHV-68-infected mice deficient in miR-155 exhibited decreases in GC B cells and Tfh cells. However, the frequencies of spleen cells harboring latent MHV-68 genomes were the same in both miR-155-deficient and wildtype (WT) mice. Similar latent loads were also observed in mixed bone marrow chimeric mice, where B cell-extrinsic effects of miR-155 deficiency were normalized. Interestingly, we observed markedly lower efficiency of reactivation from latency in miR-155-deficient cells, indicating an important role for miR-155 in this process. These in vivo data complement previous in vitro studies and lead to the conclusion that miR-155 is not necessary for the establishment or maintenance of gammaherpesvirus latency but that it does affect reactivation efficiency. IMPORTANCEGammaherpesvirus infection leads to severe disease in immunosuppressed populations. miR-155 has been shown to play important roles in many pathological processes, including tumorigenesis and diseases caused by an overly aggressive immune response. Our work provides valuable in vivo data showing that miR-155 is dispensable for gammaherpesvirus latency but that it is critical for reactivation from latency, which is a crucial step in the viral life cycle. The herpesvirus family is a large and widely distributed family of double-stranded, enveloped DNA viruses. Their anatomical sites of latency and frequency of reactivation vary, resulting in a range of clinical manifestations. A defining feature of this virus family is the ability to establish latent infection within host cells. The gammaherpesviruses distinguish themselves by being lymphotropic, in most cases establishing latency in B cells, where coordinated programs of viral and host gene expression promote B cell differentiation to favor virus latency.Gammaherpesviruses are of clinical interest due to the two human members of this viral subfamily: Epstein-Barr virus (EBV; human herpesvirus 4 [HHV-4]) and Kaposi's sarcoma-associated herpesvirus (KSHV; HHV-8). These viruses are closely associated with the development of malignancies in immunosuppressed populations. EBV was initially recovered from an endemic form of Burkitt's lymphoma, and it has been shown to hijack the B cell differentiation pathway in order to gain access into the long-lived memory B cell compartment (1). Due to the narrow host tropism and seroprevalence of the human gammaherpesviruses, murine gammaherpesvirus (MHV-68) has become a critical model system in which to examine the in vivo immunobiology of...

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Section: Discussioncontrasting

confidence: 95%

MicroRNA miR-155 Is Necessary for Efficient Gammaherpesvirus Reactivation from Latency, but Not for Establishment of Latency

Crepeau

Zhang

Usherwood

2016

J Virol

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“…This was inconsistent with the results in this study that the level of hcmv-miR-US29-3p was signi cantly higher than that of latent infection after reactivation infection. Many results suggest that hcmv-miR-US25-1, or hcmv-miR-US25-1-5p, is involved in diverse process; not only cell cycle control, but also virus replication inhibition as well as apoptosis regulation [5,6,32]. It has been reported that hcmv-miR-US25-1-3p has the ability to downregulate CDK6 gene associated with suppress cell cycle progression [19,33].…”

Section: Discussionmentioning

confidence: 99%

Different Expression Pattern of Human Cytomegalovirus-Encoded microRNAs in Circulation from Virus Latency to Reactivation

Zhou

Wang

Ding

et al. 2020

Preprint

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Background: Human cytomegalovirus (HCMV) is a beta-hersvirinae that has a high latent infection rate worldwide and can cause serious consequences in immunocompromised patients when reactivation; however, the mechanism of how HCMV convert from latent to reactivation has rarely been investigated. In the present study, we aimed to perform a comprehensive analysis of the HCMV-encoded microRNA (miRNA) profile in serum of patients upon HCMV reactivation from latency and to further evaluate its clinical significance for the disease monitoring and preventing usefulness.Methods: Serum samples from 60 viremia patients and 60 age-gender matched controls were enrolled in this study for screening and validation of different expression of HCMV miRNAs. Serum concentrations of 22 known HCMV miRNAs were determined by a hydrolysis probe-based stem-loop quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay. HCMV DNA was measured by quantitative real-time PCR (qPCR) with the whole blood sample. Serum HCMV IgG and IgM were assessed using enzyme linked immunosorbent assay (ELISA). Another 47 samples from 5 patients at different time points were collected to evaluate the monitoring effectiveness and disease prediction ability of differential expression HCMV-miRNAs during the antiviral treatment. Results: The RT-qPCR analysis revealed that the serum levels of 16 of the 22 examined HCMV miRNAs were elevated in HCMV viremia patients compared with controls, and a profile of 8 HCMV miRNAs including hcmv-miR-US25-2-3p, hcmv-miR-US4-5p, hcmv-miR-US25-2-5p, hcmv-miR-US25-1-3p, hcmv-miR-US25-1, hcmv-miR-UL36, hcmv-miR-UL148D, hcmv-miR-US29-3p were markedly elevated (fold change > 2, P < 0.01). Receiver operating characteristic curve (ROC) analysis were performed on the selected HCMV-miRNAs in all of the patients and controls that enrolled in this study, and which ranged from 0.74 to 0.79 in the autoimmune patients. In addition, hcmv-miR-US25-1-3p levels were significantly correlated with HCMV DNA copies (r = 0.297，P = 0.022), and were obviously higher in the reactivation set than the latency set in the autoimmune patients, which could be a predictor for the monitoring of the antiviral treatment.Conclusions: HCMV miRNAs profile showed markedly shift-switch from latency to reactivation in circulation from HCMV infected patients and hcmv-miR-US25-1-3p may be served as a predictor for the switch upon reactivation from latency in patients suffered with autoimmune diseases.

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“…In previous herpesvirus studies, many viral miRNAs were found to suppress viral production by targeting the expression of viral transactivators themselves, including latency-associated transcript miRNA (miR-LAT) which is encoded by herpes simplex virus type 1 (HSV-1) and targets infected cell protein 0 (ICP0); miR-K10-6-3p, which is encoded by Kaposi’s sarcoma herpesvirus (KSHV) and targets Rta and Zta; miR-BHRF-1 and miR-BART15, which are encoded by Epstein–Barr virus (EBV) and target BZLF1 and BRLF1, respectively [16]. For HCMV, miR-UL112, miR-US25-1, and miR-US25-2 were reported to repress viral DNA synthesis and contribute to latency [13,14,17,19]. In addition, HCMV, KSHV, and EBV can also reduce virus-infected cell death by encoding miRNAs that target the natural killer (NK) cell-activating ligand MICB [24].…”

Section: Discussionmentioning

confidence: 99%

“…According to in vitro studies, CMV miRNAs play important roles in the regulation of viral replication [12,13,14,15,16,17,18,19], immune modulation [20,21], and immune evasion [22,23,24]. Recently, HCMV miR-UL22A-5p was identified as a potential biomarker for transplantation, suggesting that miRNAs encoded by HCMV are associated with specific virologic and clinical outcomes [25].…”

Section: Introductionmentioning

confidence: 99%

Manipulation of Viral MicroRNAs as a Potential Antiviral Strategy for the Treatment of Cytomegalovirus Infection

Deng¹,

Xiao

Ma³

et al. 2017

Viruses

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Cytomegalovirus (CMV) infection leads to notable morbidity and mortality in immunosuppressed patients. Current antiviral drugs are effective but seriously limited in their long-term use due to their relatively high toxicity. In the present study, we characterized the expression of murine CMV microRNAs (MCMV miRNAs) both in vitro and in vivo. Although 29 miRNAs were detectable during in vitro infection, only 11 miRNAs (classified as Group 1) were detectable during in vivo infection, and as many as 18 viral miRNAs (classified as Group 2) were less detectable (<50% of animals) in both the liver and lungs. In addition, viral miRNA profiles in the blood revealed unstable and reduced expression. We next explored the in vitro effects of viral miRNAs on MCMV replication. The inhibition of Group 1 viral miRNAs had little effect on virus production, but transfected cells overexpressing miR-m01-3-5p, miR-M23-1-5p, miR-M55-1, and miR-m107-1-5p in Group 2 showed statistically lower viral loads than those transfected with control miRNA (29%, 29%, 39%, and 43%, respectively, versus control). Finally, we performed hydrodynamic injection of viral miRNA agomirs and observed lower levels of MCMV recurrence in the livers of animals overexpressing the miR-m01-3-5p or mcmv-miR-M23-1-5p agomirs compared with those of animals transfected with control agomir, confirming the antiviral effects of viral miRNA manipulation in vivo. Therefore, the manipulation of viral miRNA expression shows great therapeutic potential and represents a novel antiviral strategy for the miRNA-based treatment of cytomegalovirus infection.

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Human cytomegalovirus microRNA miR-US25-1-5p inhibits viral replication by targeting multiple cellular genes during infection

Cited by 24 publications

References 46 publications

MicroRNA miR-155 Is Necessary for Efficient Gammaherpesvirus Reactivation from Latency, but Not for Establishment of Latency

MicroRNA miR-155 Is Necessary for Efficient Gammaherpesvirus Reactivation from Latency, but Not for Establishment of Latency

Different Expression Pattern of Human Cytomegalovirus-Encoded microRNAs in Circulation from Virus Latency to Reactivation

Manipulation of Viral MicroRNAs as a Potential Antiviral Strategy for the Treatment of Cytomegalovirus Infection

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