Juliet V. Spencer

Background: Hormone receptor-positive breast cancer depends on estrogen and progesterone signaling, yet factors that modulate hormone receptor expression within tumors remain incompletely understood. Human cytomegalovirus (HCMV), a widespread herpesvirus detected in breast tumors, has been associated with reduced expression of estrogen receptor-α (ERα) and progesterone receptor (PR), but a direct causal relationship has not been established. Methods: ER+/PR+ breast cancer cell lines MCF-7 and T47D were infected with HCMV in vitro. ERα and PR protein levels were assessed by immunoblotting, and transcript levels of ESR1 and PGR were quantified by qPCR. To determine whether virus replication was required, parallel experiments used UV-inactivated HCMV. Results: HCMV infection resulted in a marked reduction in ERα and PR protein levels in both cell lines, accompanied by decreased ESR1 and PGR transcript levels by 48 h post-infection. Notably, UV-inactivated HCMV produced a comparable suppression of hormone receptor expression, indicating that viral gene expression and productive replication are not required for this effect. Conclusions: These findings indicate that HCMV exposure suppresses ERα and PR expression in breast cancer cells through a replication-independent mechanism. This effect suggests that viral components or host responses to infection may alter hormone receptor signaling within tumors, with potential implications for hormone receptor signaling and endocrine therapy responsiveness that warrant further investigation. Together, these results identify HCMV as a previously underrecognized modulator of hormone receptor pathways in breast cancer.

Human cytomegalovirus (HCMV) is a complex pathogen that encodes a diverse array of proteins essential for its survival and replication within host organisms. Among these proteins, a noteworthy group comprises four chemokine-like G protein-coupled receptors (cellular GPCRs), which play pivotal roles in the virus’s evasion of the host immune response and the establishment of persistent infections. Of particular interest is pUS28, recognized as one of the most extensively studied viral GPCRs (vGPCRs). This receptor has attracted significant attention for its potential as a target for innovative antiviral therapies aimed at addressing HCMV-related diseases. In contrast, pUS27 has not been as thoroughly characterized, presenting a potentially promising avenue for antiviral intervention. The relative scarcity of research surrounding pUS27 underscores an exciting opportunity for further exploration, as a deeper understanding of its functions and mechanisms may reveal novel strategies for combating HCMV infections. This review seeks to synthesize recent advancements in our understanding of pUS27, elucidating its biological roles, interactions, and potential implications for therapeutic development. We will also highlight critical gaps in the existing literature that warrant further investigation, underscoring the need for a more comprehensive understanding of this understudied receptor. By delving into the complexities of pUS27, we aim to inspire future research initiatives that could lead to the development of novel antiviral treatments, thereby enhancing our overall understanding of HCMV pathogenesis. Importance: The study of vGPCRs is essential for understanding how viruses like HCMV manipulate host cell signaling and evade immune responses. While pUS28 has been extensively studied due to its broad chemokine binding and signaling activity, its lesser-known homolog, pUS27, warrants closer attention. Likely arising from a gene duplication event, pUS27 shares approximately 31% sequence identity with pUS28 and is conserved across HCMV strains, suggesting an important functional role. By focusing on pUS27, we may uncover shared mechanisms that allow therapies to effectively target both pUS28 and pUS27, potentially leading to more potent antiviral treatments. The implications of studying pUS27 are profound, as it could play a pivotal role in improving our approaches to combating HCMV and enhancing our overall understanding of immune evasion strategies.

Cytomegalovirus (CMV) is the leading infectious cause of birth defects and has been linked to increased risk of preterm birth (PTB). CMV establishes lifelong latency and is more prevalent among Black and Hispanic/Latina women, populations already at higher risk for adverse pregnancy outcomes. Vitamin D deficiency, also common in these groups, has been linked to impaired immune function and increased susceptibility to infections, including CMV. In this cross–sectional study of 63 pregnant minority women (50 CMV+, 13 CMV−), we evaluated associations among serum 25(OH)D levels, CMV serostatus, and cmvIL–10, the CMV–encoded interleukin–10 homolog that modulates host immune responses. While vitamin D insufficiency and CMV seropositivity were both highly prevalent, we found no statistically significant associations between 25(OH)D levels and CMV serostatus or cmvIL–10 levels. These findings highlight the need for further investigation into how vitamin D deficiency and CMV infection may independently or synergistically contribute to maternal and neonatal health disparities.

Purpose: Breast cancer accounts for 30% of all female cancers in the US. Cytomegalovirus (CMV), a herpesvirus that establishes lifelong infection, may play a role in breast cancer. CMV is not oncogenic, yet viral DNA and proteins have been detected in breast tumors, indicating possible contribution to tumor development. CMV encodes cmvIL-10, a homolog of human cellular IL-10 (cIL-10) with potent immunosuppressive activities. We investigated the relationship between CMV infection, cytokines, and breast cancer. Methods: We evaluated CMV serostatus and cytokine levels in plasma of women with benign breast disease (n = 38), in situ carcinoma (n = 41), invasive carcinoma, no lymph node involvement (Inv/LN−; n = 41), and invasive with lymph node involvement (Inv/LN+; n = 37). Results: Fifty percent of the patient samples (n = 79) were CMV seropositive. There was no correlation between CMV status and diagnosis (p = 0.75). For CMV+ patients, there was a trend toward higher CMV IgG levels in invasive disease (p = 0.172). CmvIL-10 levels were higher in CMV+ in situ patients compared to the Inv/LN− and Inv/LN+ groups (p = 0.020). Similarly, cIL-10 levels were higher in CMV+ in situ patients compared to the Inv/LN− and Inv/LN+ groups (p = 0.043). The results were quite different in CMV− patients where cIL-10 levels were highest in Inv/LN− compared to benign, in situ, or Inv/LN+ (p = 0.019). African American patients were significantly associated with CMV+ status (p = 0.001) and had lower cmvIL-10 levels than Caucasian patients (p = 0.046). Conclusion: No association was observed between CMV IgG and diagnosis, but CMV infection influences cytokine production and contributes to altered cytokine profiles in breast cancer.

Breast cancer is the leading cause of cancer deaths among women worldwide. There are many known risk factors for breast cancer, but the role of infectious disease remains unclear. Human cytomegalovirus (HCMV) is a widespread herpesvirus that usually causes little disease. Because HCMV has been detected in breast tumor biopsy samples and is frequently transmitted via human breast milk, we investigated HCMV replication in breast tumor cells. Four human breast cancer cell lines with different expression profiles for the key diagnostic markers of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), were infected with a bacterial artificial chromosome-derived HCMV clinical strain TB40/E tagged with green fluorescent protein (GFP). Fluorescence microscopy confirmed that all four breast cancer cell lines supported virus entry. RNA was isolated from infected cells and the expression of immediate early (UL123), early (UL54), and late (UL111A) genes was confirmed using PCR. Viral proteins were detected by immunoblotting, and viral progeny were produced during the infection of breast tumor cells, as evidenced by subsequent infection of fibroblasts with culture supernatants. These results demonstrate that breast tumor cells support productive HCMV infection and could indicate that HCMV replication may play a role in breast cancer progression.

Since its introduction in 1971, the enzyme-linked immunosorbent assay (ELISA) has revolutionized medicine by enabling detection of both antigens and antibodies in a variety of samples. We describe here a customized sandwich ELISA developed for the detection of Human Cytomegalovirus interleukin-10 (cmvIL-10). CmvIL-10 is a virally encoded cytokine and ortholog of human interleukin 10 (hIL-10). While cmvIL-10 and hIL-10 are similar in structure and function, overall amino acid sequence identity is only 27%, resulting in antigenically distinct proteins. The cmvIL-10 ELISA is specific and does not detect hIL-10. The assay is sensitive enough to detect cmvIL-10 in both culture supernatants and patient serum. The ability to quantify cmvIL-10 levels during HCMV infection could provide valuable information about immune evasion strategies and viral control of host signaling pathways.

Human cytomegalovirus (HCMV) has evolved a number of mechanisms for long-term co-existence within its host. HCMV infects a wide range of cell types, including fibroblasts, epithelial cells, monocytes, macrophages, dendritic cells, and myeloid progenitor cells. Lytic infection, with the production of infectious progeny virions, occurs in differentiated cell types, while undifferentiated myeloid precursor cells are the primary site of latent infection. The outcome of HCMV infection depends partly on the cell type and differentiation state but is also influenced by the composition of the immune environment. In this review, we discuss the role of early interactions between HCMV and the host immune system, particularly cytokine and chemokine networks, that facilitate the establishment of lifelong latent infection. A better understanding of these cytokine signaling pathways could lead to novel therapeutic targets that might prevent latency or eradicate latently infected cells.

Herpesviruses are prevalent throughout the animal kingdom, and they have coexisted and coevolved along with their host species for millions of years. Herpesviruses carry a large (120-230 kb) double-stranded DNA genome surrounded by a protein capsid, a tegument layer consisting of viral and host proteins, and a lipid bilayer envelope with surface glycoproteins. A key characteristic of these viruses is their ability to enter a latent state following primary infection, allowing them to evade the host’s immune system and persist permanently. Herpesviruses can reactivate from their dormant state, usually during times of stress or when the host’s immune responses are impaired. While herpesviruses can cause complications with severe disease in immune-compromised people, most of the population experiences few ill effects from herpesvirus infections. Indeed, herpes simplex virus 1 (HSV-1) in particular has several features that make it an attractive tool for therapeutic gene delivery. Herpes simplex virus 1 targets and infects specific cell types, such as epithelial cells and neurons. The HSV-1 genome can also accommodate large insertions of up to 14 kb. The HSV-1-based vectors have already achieved success for the oncolytic treatment of melanoma. In addition to serving as a vehicle for therapeutic gene delivery and targeted cell lysis, comparative genomics of herpesviruses HSV-1 and 2 has revealed valuable information about the evolutionary history of both viruses and their hosts. This review focuses on the adaptability of HSV-1 as an instrument for gene delivery and an evolutionary marker. Overall, HSV-1 shows great promise as a tool for treating human disease and studying human migration patterns, disease outbreaks, and evolution.