Molecular mechanisms of the modulatory effects of HCMV infection in tumor cell biology

Činátl, Jindřich; Scholz, Martin; Kotchetkov, Rouslan; Vogel, Jens‐Uwe; Doerr, Hans Wilhelm

doi:10.1016/j.molmed.2003.11.002

Cited by 79 publications

(80 citation statements)

References 26 publications

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“…Although HCMV is not considered to be oncogenic, its infection has been implicated in carcinogenesis by different pathways, and the concept of 'oncomodulation' emerged to explain the role of this virus in tumor progression (Cinatl et al, 1996(Cinatl et al, , 2004Michaelis et al, 2009).…”

Section: Human Cytomegalovirus and Hhv-5mentioning

confidence: 99%

Viral epigenomes in human tumorigenesis

Fernández

Esteller

2010

Oncogene

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Viruses are associated with 15-20% of human cancers worldwide. In the last century, many studies were directed towards elucidating the molecular mechanisms and genetic alterations by which viruses cause cancer. The importance of epigenetics in the regulation of gene expression has prompted the investigation of virus and host interactions not only at the genetic level but also at the epigenetic level. In this study, we summarize the published epigenetic information relating to the genomes of viruses directly or indirectly associated with the establishment of tumorigenic processes. We also review aspects such as viral replication and latency associated with epigenetic changes and summarize what is known about epigenetic alterations in host genomes and the implications of these for the tumoral process. The advances made in characterizing epigenetic features in cancer-causing viruses have improved our understanding of their functional mechanisms. Knowledge of the epigenetic changes that occur in the genome of these viruses should provide us with markers for following cancer progression, as well as new tools for cancer therapy.

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Section: Human Cytomegalovirus and Hhv-5mentioning

confidence: 99%

Viral epigenomes in human tumorigenesis

Fernández

Esteller

2010

Oncogene

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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

157

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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“…Although HCMV infection rarely causes disease in immunocompetent individuals, it can cause severe/ fatal disease in immunocompromised patients, such as congenitally infected neonates, patients with AIDS, and transplant recipients (3)(4)(5)(6). HCMV infection is also associated with the development of cardiovascular diseases, including atherosclerosis, restenosis, and transplant vascular sclerosis, as well as some cancers (7)(8)(9)(10). This wide range of pathological complications results from viral spread to multiple organs and the broad cellular tropism displayed by HCMV following infection (11).…”

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confidence: 99%

Viral binding-induced signaling drives a unique and extended intracellular trafficking pattern during infection of primary monocytes

Kim

Collins-McMillen

Caposio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We initiated experiments to examine the infection of monocytes postentry. New data show that human cytomegalovirus (HCMV) DNA is detected in the nucleus beginning only at 3 d postinfection in monocytes, compared with 30 min postinfection in fibroblasts and endothelial cells, suggesting that HCMV nuclear translocation in monocytes is distinct from that seen in other cell types. We now show that HCMV is initially retained in early endosomes and then moves sequentially to the trans-Golgi network (TGN) and recycling endosomes before nuclear translocation. HCMV is retained initially as a mature particle before deenvelopment in recycling endosomes. Disruption of the TGN significantly reduced nuclear translocation of viral DNA, and HCMV nuclear translocation in infected monocytes was observed only when correct gH/gL/UL128-131/integrin/c-Src signaling occurred. Taken together, our findings show that viral binding of the gH/gL/UL128-131 complex to integrins and the ensuing c-Src signaling drive a unique nuclear translocation pattern that promotes productive infection and avoids viral degradation, suggesting that it represents an additional viral evasion/survival strategy.monocytes | viral trafficking | gH/gL/UL128-131 complex | integrins | nuclear translocation pathway H uman cytomegalovirus (HCMV) infection usually results in an asymptomatic lifelong persistent infection in healthy individuals after primary infection (1, 2). Although HCMV infection rarely causes disease in immunocompetent individuals, it can cause severe/ fatal disease in immunocompromised patients, such as congenitally infected neonates, patients with AIDS, and transplant recipients (3-6). HCMV infection is also associated with the development of cardiovascular diseases, including atherosclerosis, restenosis, and transplant vascular sclerosis, as well as some cancers (7-10). This wide range of pathological complications results from viral spread to multiple organs and the broad cellular tropism displayed by HCMV following infection (11).Monocytes are a primary site of persistent HCMV infection, and HCMV-infected monocytes are believed to play a key role in the hematogenous dissemination of the virus to target organs following primary infection (12). For HCMV to infect primary monocytes, it must overcome several biological barriers to successfully mediate viral spread and persistence. For example, monocytes do not initially support de novo HCMV gene expression and viral replication (13), and they have a lifespan of only 1-3 d in circulation under normal homeostatic conditions (14, 15). Understanding how HCMV overcomes these biological barriers following infection may provide clues to the underlying causes of HCMV pathogenesis and persistence. Our laboratory has provided molecular evidence for how HCMV evolved to deal with these biological barriers (16)(17)(18)(19)(20)(21)(22).We have shown that the biological changes in HCMV-infected monocytes are triggered by the binding of gB to EGFR (19) and binding of the gH/gL/UL128-131 complex to β1 and β3 integri...

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Molecular mechanisms of the modulatory effects of HCMV infection in tumor cell biology

Cited by 79 publications

References 26 publications

Viral epigenomes in human tumorigenesis

Viral epigenomes in human tumorigenesis

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

Viral binding-induced signaling drives a unique and extended intracellular trafficking pattern during infection of primary monocytes

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