Oncomodulation by human cytomegalovirus: novel clinical findings open new roads

Michaelis, Martin; Baumgarten, Peter; Mittelbronn, Michel; Driever, Pablo Hernáiz; Doerr, Hans Wilhelm; Činátl, Jindřich

doi:10.1007/s00430-010-0177-7

Cited by 53 publications

(42 citation statements)

References 58 publications

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“…Consisting of miR-96, miR-182, and miR-183, this miRNA cluster has been suggested to arise from processing of a single independent primary tran- script (38,39). The upregulation of this cluster in multiple forms of cancer and tumorigenesis (31,32) is of particular interest in the debate surrounding the potential association of HCMV infection and higher risks of tumor formation (18). Furthermore, studies using mice have implicated a potential role for the murine orthologs of these miRNAs in the development of the inner ear (28).…”

Section: Discussionmentioning

confidence: 99%

High-Resolution Profiling and Analysis of Viral and Host Small RNAs during Human Cytomegalovirus Infection

Stark

Arnold

Spector

et al. 2012

J Virol

135

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Human cytomegalovirus (HCMV) contributes its own set of microRNAs (miRNAs) during lytic infection of cells, likely finetuning conditions important for viral replication. To enhance our understanding of this component of the HCMV-host transcriptome, we have conducted deep-sequencing analysis of small RNAs (smRNA-seq) from infected human fibroblast cells. We found that HCMV-encoded miRNAs accumulate to ϳ20% of the total smRNA population at late stages of infection, and our analysis led to improvements in viral miRNA annotations and identification of two novel HCMV miRNAs, miR-US22 and miRUS33as. Both of these miRNAs were capable of functionally repressing synthetic targets in transient transfection experiments. Additionally, through cross-linking and immunoprecipitation (CLIP) of Argonaute (Ago)-bound RNAs from infected cells, followed by high-throughput sequencing, we have obtained direct evidence for incorporation of all HCMV miRNAs into the endogenous host silencing machinery. Surprisingly, three HCMV miRNA precursors exhibited differential incorporation of their mature miRNA arms between Ago2 and Ago1 complexes. Host miRNA abundances were also affected by HCMV infection, with significant upregulation observed for an miRNA cluster containing miR-96, miR-182, and miR-183. In addition to miRNAs, we also identified novel forms of virus-derived smRNAs, revealing greater complexity within the smRNA population during HCMV infection. Human cytomegalovirus (HCMV), a member of the herpesvirus family, is prevalent in the majority of the global population and the main viral cause of birth defects (19). HCMV is capable of infecting a wide variety of human cell types in vivo and is known to establish a latent form of infection that persists throughout the life of the host. Immunocompromised patients are especially susceptible to problems associated with infection, further motivating HCMV studies.Expression of virus-encoded microRNAs (miRNAs) likely contributes to the molecular transformation necessary for productive infection in human cells. Since the initial discovery of viral miRNAs in 2004 (24), several viruses have been documented to express their own sets of miRNAs (4,5,7,11,12,23). These small RNAs (smRNAs) are highly attractive from a viral standpoint in that they require minimal space within the genome and potentially offer a robust mechanism for specific targeting of host defense genes. HCMV is known to encode at least 11 miRNA precursors that are expressed and processed into mature miRNAs during infection (12).High-throughput sequencing approaches have been instrumental in recent viral miRNA studies, acquiring a level of resolution that was previously unachievable through cloning efforts (17,27,36). Deep-sequencing approaches have not been extended to smRNA analysis of HCMV-infected cells, and previous microarray-based studies were limited in assessing only host miRNA levels (30,37). Thus, we set out to conduct a more comprehensive analysis by deep sequencing all smRNAs (smRNA-seq) from HCMV Towne-infected human f...

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Section: Discussionmentioning

confidence: 99%

High-Resolution Profiling and Analysis of Viral and Host Small RNAs during Human Cytomegalovirus Infection

Stark

Arnold

Spector

et al. 2012

J Virol

135

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“…Accumulating evidence indicates human cytomegalovirus (CMV) as a contributing factor to glioma progression (6,7), and CMV has been suggested as a therapeutic target (8). Although not classified as an oncogenic virus, CMV can increase cellular proliferation, angiogenesis, and immune evasion, thus enabling several hallmarks of cancer (9,10).…”

Section: Introductionmentioning

confidence: 99%

Autologous T-cell Therapy for Cytomegalovirus as a Consolidative Treatment for Recurrent Glioblastoma

Schuessler¹,

Smith²,

Beagley³

et al. 2014

Cancer Research

160

138

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Glioblastoma multiforme (GBM) is one of the most aggressive human brain malignancies. Even with optimal treatment, median survival is less than 6 months for patients with recurrent GBM. Immune-based therapies have the potential to improve patient outcome by supplementing standard treatment. Expression of human cytomegalovirus (CMV) antigens in GBM tissues provides the unique opportunity to target viral antigens for GBM therapy. Here, we report findings of a formal clinical assessment of safety and potential clinical efficacy of autologous CMV-specific T-cell therapy as a consolidative treatment for recurrent GBM. From a total of 19 patients with recurrent GBM, CMV-specific T cells were successfully expanded from 13 patients (68.4%), 11 of whom received up to four T-cell infusions. Combination therapy based on T-cell infusion and chemotherapy was well tolerated, and we detected only minor adverse events. The overall survival of these patients since first recurrence ranged from 133 to 2,428 days, with a median overall survival of 403 days. Most importantly, 4 of 10 patients that completed the treatment remained progression free during the study period. Furthermore, molecular profiling of CMV-specific T-cell therapy from these patients revealed distinct gene expression signatures, which correlated with their clinical response. Our study suggests that a combination therapy with autologous CMV-specific T cells and chemotherapy is a safe novel treatment option and may offer clinical benefit for patients with recurrent GBM. Cancer Res; 74(13); 3466–76. ©2014 AACR.

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“…In more than 50% of these tumours, HCMV proteins are highly expressed in tumor tissues. Due to this association between HCMV and cancer, an oncomodulatory role for HCMV has been proposed [31][32][33]. Stable expression of HCMV IE1 protein has been shown to differentially enhance or arrest glioblastoma cell growth and promote cell cycle entry and DNA synthesis, indicating that IE1 can modulate the oncogenic phenotype of human glioma cells and its expression in tumor cells activates signaling pathways associated with cancer.…”

Section: Introductionmentioning

confidence: 99%

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

Tseliou

Al‐Qahtani²,

Alarifi

et al. 2016

Cell Physiol Biochem

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Background/Aims: Rho GTPases are crucial regulators of the actin cytoskeleton, membrane trafficking and cell signaling and their importance in cell migration and invasion is well- established. The human cytomegalovirus (HCMV) is a widespread pathogen responsible for generally asymptomatic and persistent infections in healthy people. Recent evidence indicates that HCMV gene products are expressed in over 90% of malignant type glioblastomas (GBM). In addition, the HCMV Immediate Early-1 protein (IE1) is expressed in >90% of tumors analyzed. Methods: RhoA, RhoB and RhoC were individually depleted in U373MG glioblastoma cells as well as U373MG cells stably expressing the HCMV IE1 protein (named U373MG-IE1 cells) shRNA lentivirus vectors. Cell proliferation assays, migration as well as wound-healing assays were performed in uninfected and HCMV-infected cells. Results: The depletion of RhoA, RhoB and RhoC protein resulted in significant alterations in the morphology of the uninfected cells, which were further enhanced by the cytopathic effect caused by HCMV. Furthermore, in the absence or presence of HCMV, the knockdown of RhoB and RhoC proteins decreased the proliferation rate of the parental and the IE1-expressing glioblastoma cells, whereas the knockdown of RhoA protein in the HCMV infected cell lines restored their proliferation rate. In addition, wound healing assays in U373MG cells revealed that depletion of RhoA, RhoB and RhoC differentially reduced their migration rate, even in the presence or the absence of HCMV. Conclusion: Collectively, these data show for the first time a differential implication of Rho GTPases in morphology, proliferation rate and motility of human glioblastoma cells during HCMV infection, further supporting an oncomodulatory role of HCMV depending on the Rho isoforms' state.

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Oncomodulation by human cytomegalovirus: novel clinical findings open new roads

Cited by 53 publications

References 58 publications

High-Resolution Profiling and Analysis of Viral and Host Small RNAs during Human Cytomegalovirus Infection

High-Resolution Profiling and Analysis of Viral and Host Small RNAs during Human Cytomegalovirus Infection

Autologous T-cell Therapy for Cytomegalovirus as a Consolidative Treatment for Recurrent Glioblastoma

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

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