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Kartikasari, A. Human Cytomegalovirus Infection. Encyclopedia. Available online: https://encyclopedia.pub/entry/9279 (accessed on 18 June 2024).
Kartikasari A. Human Cytomegalovirus Infection. Encyclopedia. Available at: https://encyclopedia.pub/entry/9279. Accessed June 18, 2024.
Kartikasari, Apriliana. "Human Cytomegalovirus Infection" Encyclopedia, https://encyclopedia.pub/entry/9279 (accessed June 18, 2024).
Kartikasari, A. (2021, May 04). Human Cytomegalovirus Infection. In Encyclopedia. https://encyclopedia.pub/entry/9279
Kartikasari, Apriliana. "Human Cytomegalovirus Infection." Encyclopedia. Web. 04 May, 2021.
Human Cytomegalovirus Infection
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines9040351

Human cytomegalovirus (HCMV), also known as human herpes virus 5 (HHV-5), infects about 83% of the world’s population, approaching 100% in developing countries.

human cytomegalovirus ovarian cancer cancer progression inflammation immunosuppression

1. Introduction

Following primary infection as shown in Figure 1, HCMV establishes a life-long chronic latency in humans [1], primarily in the cluster of differentiation (CD)34+ hematopoietic progenitor cell population located in the bone marrow [2]. Latent infection is generally asymptomatic in immunocompetent individuals although symptomatic reactivation can occur, particularly in the immunocompromised or cancer patients [1]. High level circulating pro-inflammatory cytokines are the hallmark of latent HCMV reactivation, particularly when the CD34+ progenitor cells differentiate into inflammatory monocytes or infiltrating macrophages or dendritic cells, which then spread the virus to peripheral organs and body tissues thereby infecting and replicating in a broad number of cell types [2].

Figure 1. Following primary infection through contact with infected bodily fluids, HCMV replicates within host cells during which time robust immune responses are generated by the host that includes HCMV-specific neutralizing antibodies, natural killer cells and high frequencies of CD4+ T helper cells and CD8+ cytotoxic T cells. These responses subsequently control viral replication thereby resolving primary infection. However, HCMV has the potential to replicate and spread resulting in infection of CD34+ myeloid cells in the bone marrow and establishment of latency. Differentiation of HCMV-infected CD34+ cells into dendritic cells and macrophages contributes to new HCMV replication during which a secondary immune response induced that helps to inhibit HCMV replication spread. HCMV, human cytomegalovirus. Figure created with BioRender.com.

2. HCMV Infection in Ovarian Cancer

Although HCMV infection is rarely associated with OC, a study by Shanmughapriya et al. [3] detected HCMV-gB by polymerase chain reaction (PCR) in approximately 50% of OC tissues, of which 80% were late stage invasive tumours, suggesting that HCMV infection in the TME may promote cancer progression or metastasis. More recently, another study assessed the presence of HCMV within OC tissue specimens obtained from diagnostic excisional biopsy pre-chemotherapy (DEBPC) and interval debulking surgery (IDS) after neoadjuvant chemotherapy (4–5 times Taxol/Paraplatin). In this study, OC patients with high levels of HCMV-IE and tegument pp65 proteins in their tumours had lower median overall survival compared to those with lower levels or no detectable HCMV proteins [4]. A second recent study by Radestad et al. [5] also investigated the prevalence of HCMV in ovarian cancer and its relation to clinical outcome. In their study, HCMV-IgG levels, HCMV-IE proteins, and pp65 proteins were all shown to be higher in OC patients with malignant or benign cystadenoma (benign ovarian epithelial tumour) compared with age-matched controls. Additionally, OC patients with focal HCMV-pp65 expression in their tumours accompanied with high IgG levels against HCMV were found to live longer when compared with patients showing high expression of HCMV-pp65 protein in their tumours [5]. These findings suggest a possible impact of HCMV infection on immune responses to ovarian tumours. It is important to highlight that the existence of an active HCMV infection with protein production is a rare occurrence in tissues of healthy individuals. Therefore, the presence of an active HCMV infection with HCMV-pp65 and HCMV-IE proteins on ovarian tumours is quite intriguing and needs further investigation in a larger cohorts of OC patients. This would help justify whether administering anti-HCMV treatment to OC patients experiencing active HCMV reactivation in their TME is needed in future personalised treatment approaches for such patients.

HCMV and Inflammation, a Possible Link for Ovarian Cancer Progression

HCMV infection in monocytes may leads to monocyte activation via activation of NF-κB, the transcription factor that controls cytokine production, and phosphoinositide-3-kinase (PI3K), an enzyme involved in cell differentiation pathways [6][7]. The polarisation and activation of monocytes due to HCMV infection or reactivation leads to high systemic levels of inflammatory cytokines, particularly tumour necrosis factor (TNF) and IL-6, as well as diminished immune function [8][9][10][11][12]. Such an augmented production of proinflammatory cytokines following HCMV infection or reactivation may induce cancer progression directly by promoting undesirable inflammatory conditions in the TME of OC leading to cancer development or suppressed immune function [4][13][14]. Indeed, previous studies have inferred a potential role of inflammatory factors in OC progression as observed in OC patients who have experienced pelvic inflammatory disease [15][16][17][18]. Although clinical HCMV disease is classically manifested only in immunocompromised individuals, there is substantial evidence also that HCMV reactivation occurs frequently in healthy seropositive individuals [12]. Such frequent HCMV reactivation may also exacerbate chronic conditions such as OC.

In OC, approximately one-third of patients present with ascites, a bulging accumulation of fluid in the peritoneal cavity, that is usually associated with resistance to platinum-based chemotherapy, disease recurrence, and poor survival outcomes [19][20]. Studies have shown that OC ascites suppresses the effector functions of both CTLs and NK cells, as it contains abundant immunosuppressive cells, soluble inflammatory mediators and growth factors, all of which helps to promote growth or proliferation of the ovarian tumour [21][22]. A study by Govindaraj et al. [23] showed that CD4+ Tregs, particularly those expressing tumour necrosis factor (TNF) receptor 2 (TNFR2), from OC-associated ascites exert more suppressive capacity on effector CTLs than peripheral blood-derived TNFR2+ Tregs. Interestingly, the increased frequencies of TNFR2+ Tregs within the total CD4+ T cell pool present in OC ascites was shown to be driven by the presence of pro-inflammatory IL-6 within the ascitic fluid as blockade of IL-6 resulted in reduced frequencies of CD4+TNFR2+ Tregs [22]. Since HCMV reactivation in the TME could lead to increased IL-6 production, these data suggest that active HCMV infection in the TME may also drive the expansion of highly suppressive CD4+TNFR2+ Tregs. Together, these data point towards a potential for an OC immunotherapy targeting IL-6 blockade or anti-HCMV for OC patients presenting with ascites or HCMV in order to improve survival outcomes.

3. Conclusions

Presently, there is an overwhelming research interest into personalised medicine, not only in OC but for many other cancers. Both HCMV and OC share similar disease mechanisms through impairment of CTL and NK cell responses thereby promoting their survival or progression. Previous studies have demonstrated that HCMV infects many cell types; promotes tumour growth and induces a pro-inflammatory environment. Furthermore, active HCMV infection creates an immunosuppressive TME that suppress tumour-specific immune responses. To-date, no clinical study has investigated the use of an anti-HCMV approach to treat OC patients infected with HCMV. In GBM patients, however, the use of anti-HCMV targeted T cell therapy has provided some beneficial treatment outcomes, especially in recurrent GBM patients. Therefore, it is reasonable to rationalise that personalised anti-HCMV treatment could potentially help improve the survival outcomes of OC, particularly in patients with active HCMV infection in their TME. Future studies are needed to evaluate the use of anti-HCMV therapy in combination with current established 1st line and 2nd line therapies and evaluate if this combination approach is efficient at improving the survival outcomes of patients with HCMV positive ovarian tumours.

References

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  2. Geisler, J.; Touma, J.; Rahbar, A.; Söderberg-Nauclér, C.; Vetvik, K. A Review of the Potential Role of Human Cytomegalovirus (HCMV) Infections in Breast Cancer Carcinogenesis and Abnormal Immunity. Cancers 2019, 11, 1842.
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  12. Forte, E.; Zhang, Z.; Thorp, E.B.; Hummel, M. Cytomegalovirus Latency and Reactivation: An Intricate Interplay With the Host Immune Response. Front. Cell. Infect. Microbiol. 2020, 10, 130.
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