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Viruses
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Human Betaretrovirus and Related Diseases
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Human Betaretrovirus and Related Diseases

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 29643

Special Issue Editor

Prof. Dr. Andrew L. Mason

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Guest Editor
Center of Excellence for Gastrointestinal Inflammation and Immunity Research, Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
Interests: human betaretrovirus; mouse mammary tumor virus induction of autoimmune liver disease in mouse models; repurposing antiretroviral therapy for HBRV; viral pathogenesis; virus–host interactions; proviral integration; viral diagnostics with ELISA and cellular immune assays
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Human betaretrovirus (HBRV, also referred to as HMTV – human mammary tumor virus) is the only characterized exogenous betaretrovirus in humans. Evidence for HBRV infection has been found in patients with breast cancer, lymphoma, and primary biliary cholangitis, an autoimmune liver disease. Paleontological studies provide the earliest documentation of human infection dating back to the copper age. Original infection likely arose as a result of zoonosis, as suggested by marked genomic similarity of HBRV with the mouse mammary tumor virus (MMTV) studies and because different strains of MMTV can infect human cells. However, the route of HBRV transmission is unknown. The presence of viral sequences in human saliva indicates the possibility of microdroplet spread, whereas the demonstration of betaretrovirus particles and nucleic acid in breast milk are suggestive of neonatal passage. To date, the lack of readily available, reproducible diagnostic assays for HBRV has hindered clinical research. Nevertheless, the derivation of HBRV isolates from patient samples and the detection of proviral HBRV integration sites in human genomic DNA have documented human betaretrovirus infection. The low level of viral burden and close genomic relatedness of mouse and human viral sequences has limited firm conclusions from PCR studies. However, the construction of an interferon-g release assay to detect HBRV cellular immunity is providing more prevalence data. Translational studies have been performed on MMTV mouse models of breast cancer, lymphoma, and autoimmune biliary disease. These have provided useful tools to better understand viral pathogenesis, induction of autoimmunity, and virus–host interactions. The repurposing of HIV antiretroviral therapy in mouse models with MMTV cholangitis has identified regimens that block HBRV and provide durable clinical responses for patients with PBC. Attenuating murine cancer using both passive immunization and active vaccination with specific MMTV proteins provides further avenues for translational approaches to treat human disease. In this Special Issue, we will directly address controversies surrounding HBRV and focus on new developments in HBRV epidemiology and diagnostics, viral pathogenesis, and translational therapies to combat human disease.

Prof. Dr. Andrew L. Mason
Guest Editor

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Keywords

  • human betaretrovirus
  • mouse mammary tumor virus
  • breast cancer
  • primary biliary cholangitis
  • HBRV pathogenesis
  • HBRV diagnosis
  • HBRV epidemiology
  • HBRV oncogenesis
  • proviral integration
  • antiviral cellular immune responses

Related Special Issue

Published Papers (9 papers)

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Editorial

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2 pages, 165 KiB  
Editorial
Special Issue “Human Betaretrovirus and Related Diseases”
by Andrew L. Mason
Viruses 2022, 14(12), 2792; https://doi.org/10.3390/v14122792 - 15 Dec 2022
Cited by 1 | Viewed by 1082
Abstract
A betaretrovirus resembling mouse mammary tumor virus (MMTV) was first linked with human breast cancer over 50 years ago [...] Full article
(This article belongs to the Special Issue Human Betaretrovirus and Related Diseases)

Research

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17 pages, 3725 KiB  
Article
Isolation of a Human Betaretrovirus from Patients with Primary Biliary Cholangitis
by Mariam Goubran, Weiwei Wang, Stanislav Indik, Alexander Faschinger, Shawn T. Wasilenko, Jasper Bintner, Eric J. Carpenter, Guangzhi Zhang, Paulo Nuin, Georgina Macintyre, Gane K.-S. Wong and Andrew L. Mason
Viruses 2022, 14(5), 886; https://doi.org/10.3390/v14050886 - 24 Apr 2022
Cited by 7 | Viewed by 3085
Abstract
A human betaretrovirus (HBRV) has been linked with the autoimmune liver disease, primary biliary cholangitis (PBC), and various cancers, including breast cancer and lymphoma. HBRV is closely related to the mouse mammary tumor virus, and represents the only exogenous betaretrovirus characterized in humans [...] Read more.
A human betaretrovirus (HBRV) has been linked with the autoimmune liver disease, primary biliary cholangitis (PBC), and various cancers, including breast cancer and lymphoma. HBRV is closely related to the mouse mammary tumor virus, and represents the only exogenous betaretrovirus characterized in humans to date. Evidence of infection in patients with PBC has been demonstrated through the identification of proviral integration sites in lymphoid tissue, the major reservoir of infection, as well as biliary epithelium, which is the site of the disease process. Accordingly, we tested the hypothesis that patients with PBC harbor a transmissible betaretrovirus by co-cultivation of PBC patients’ lymph node homogenates with the HS578T breast cancer line. Because of the low level of HBRV replication, betaretrovirus producing cells were subcloned to optimize viral isolation and production. Evidence of infection was provided by electron microscopy, RT-PCR, in situ hybridization, cloning of the HBRV proviral genome and demonstration of more than 3400 integration sites. Further evidence of viral transmissibility was demonstrated by infection of biliary epithelial cells. While HBRV did not show a preference for integration proximal to specific genomic features, analyses of common insertion sites revealed evidence of integration proximal to cancer associated genes. These studies demonstrate the isolation of HBRV with features similar to mouse mammary tumor virus and confirm that patients with PBC display evidence of a transmissible viral infection. Full article
(This article belongs to the Special Issue Human Betaretrovirus and Related Diseases)
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12 pages, 907 KiB  
Article
Revisiting the MMTV Zoonotic Hypothesis to Account for Geographic Variation in Breast Cancer Incidence
by Alexandre F. R. Stewart and Hsiao-Huei Chen
Viruses 2022, 14(3), 559; https://doi.org/10.3390/v14030559 - 9 Mar 2022
Cited by 12 | Viewed by 3308
Abstract
Human breast cancer incidence varies by geographic location. More than 20 years ago, we proposed that zoonotic transmission of the mouse mammary tumor virus (MMTV) from the western European house mouse, Mus musculus domesticus, might account for the regional differences in breast [...] Read more.
Human breast cancer incidence varies by geographic location. More than 20 years ago, we proposed that zoonotic transmission of the mouse mammary tumor virus (MMTV) from the western European house mouse, Mus musculus domesticus, might account for the regional differences in breast cancer incidence. In the intervening years, several developments provide additional support for this hypothesis, including the limited impact of genetic factors for breast cancer susceptibility revealed by genome-wide association studies and the strong effect of antiretroviral therapy to reduce breast cancer incidence. At the same time, economic globalization has further expanded the distribution of M. m. domesticus to Asia, leading to a significant increase in breast cancer incidence in this region. Here, we revisit this evidence and provide an update to the MMTV zoonotic hypothesis for human breast cancer at a time when the world is recovering from the global COVID-19 zoonotic pandemic. We present evidence that mouse population outbreaks are correlated with spikes in breast cancer incidence in Australia and New Zealand and that globalization has increased the range of M. m. domesticus and MMTV. Given the success of global vaccination campaigns for HPV to eradicate cervical cancer, a similar strategy for MMTV may be warranted. Until breast cancer incidence is reduced by such an approach, zoonotic transmission of MMTV from mice to humans as an etiologic factor for breast cancer will remain controversial. Full article
(This article belongs to the Special Issue Human Betaretrovirus and Related Diseases)
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Review

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15 pages, 2921 KiB  
Review
Life after Cleavage: The Story of a β-Retroviral (MMTV) Signal Peptide—From Murine Lymphoma to Human Breast Cancer
by Jacob Hochman and Ori Braitbard
Viruses 2022, 14(11), 2435; https://doi.org/10.3390/v14112435 - 2 Nov 2022
Cited by 2 | Viewed by 2116
Abstract
An increasing body of evidence in recent years supports an association of the betaretrovirus mouse mammary tumor virus (MMTV) with human breast cancer. This is an issue that still raises heated controversy. We have come to address this association using the signal peptide [...] Read more.
An increasing body of evidence in recent years supports an association of the betaretrovirus mouse mammary tumor virus (MMTV) with human breast cancer. This is an issue that still raises heated controversy. We have come to address this association using the signal peptide p14 of the MMTV envelope precursor protein as a key element of our strategy. In addition to its signal peptide function, p14 has some significant post endoplasmic reticulum (ER)-targeting characteristics: (1) it localizes to nucleoli where it binds key proteins (RPL5 and B23) involved (among other activities) in the regulation of nucleolar stress response, ribosome biogenesis and p53 stabilization; (2) p14 is a nuclear export factor; (3) it is expressed on the cell surface of infected cells, and as such, is amenable to, and successfully used, in preventive vaccination against experimental tumors that harbor MMTV; (4) the growth of such tumors is impaired in vivo using a combination of monoclonal anti-p14 antibodies or adoptive T-cell transfer treatments; (5) p14 is a phospho-protein endogenously phosphorylated by two different serine kinases. The phosphorylation status of the two sites determines whether p14 will function in an oncogenic or tumor-suppressing capacity; (6) transcriptional activation of genes (RPL5, ErbB4) correlates with the oncogenic potential of MMTV; (7) finally, polyclonal anti-p14 antibodies have been applied in immune histochemistry analyses of breast cancer cases using formalin fixed paraffin-embedded sections, supporting the associations of MMTV with the disease. Taken together, the above findings constitute a road map towards the diagnosis and possible prevention and treatment of MMTV-associated breast cancer. Full article
(This article belongs to the Special Issue Human Betaretrovirus and Related Diseases)
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25 pages, 2579 KiB  
Review
Linking Human Betaretrovirus with Autoimmunity and Liver Disease in Patients with Primary Biliary Cholangitis
by Hussain Syed, Tara Penner and Andrew L. Mason
Viruses 2022, 14(9), 1941; https://doi.org/10.3390/v14091941 - 31 Aug 2022
Cited by 3 | Viewed by 3000
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the production of diagnostic antimitochondrial antibodies (AMA) reactive to the pyruvate dehydrogenase complex. A human betaretrovirus (HBRV) resembling mouse mammary tumor virus has been characterized in patients with PBC. However, linking the [...] Read more.
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the production of diagnostic antimitochondrial antibodies (AMA) reactive to the pyruvate dehydrogenase complex. A human betaretrovirus (HBRV) resembling mouse mammary tumor virus has been characterized in patients with PBC. However, linking the viral infection with the disease is not a straight-forward process because PBC is a complex multifactorial disease influenced by genetic, hormonal, autoimmune, environmental, and other factors. Currently, PBC is assumed to have an autoimmune etiology, but the evidence is lacking to support this conjecture. In this review, we describe different approaches connecting HBRV with PBC. Initially, we used co-cultivation of HBRV with biliary epithelial cells to trigger the PBC-specific phenotype with cell surface expression of cryptic mitochondrial autoantigens linked with antimitochondrial antibody expression. Subsequently, we have derived layers of proof to support the role of betaretrovirus infection in mouse models of autoimmune biliary disease with spontaneous AMA production and in patients with PBC. Using Hill’s criteria, we provide an overview of how betaretrovirus infection may trigger autoimmunity and propagate biliary disease. Ultimately, the demonstration that disease can be cured with antiviral therapy may sway the argument toward an infectious disease etiology in an analogous fashion that was used to link H. pylori with peptic ulcer disease. Full article
(This article belongs to the Special Issue Human Betaretrovirus and Related Diseases)
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44 pages, 901 KiB  
Review
The Viral Origin of Human Breast Cancer: From the Mouse Mammary Tumor Virus (MMTV) to the Human Betaretrovirus (HBRV)
by Generoso Bevilacqua
Viruses 2022, 14(8), 1704; https://doi.org/10.3390/v14081704 - 1 Aug 2022
Cited by 8 | Viewed by 3830
Abstract
A Human Betaretrovirus (HBRV) has been identified in humans, dating as far back as about 4500 years ago, with a high probability of it being acquired by our species around 10,000 years ago, following a species jump from mice to humans. HBRV is [...] Read more.
A Human Betaretrovirus (HBRV) has been identified in humans, dating as far back as about 4500 years ago, with a high probability of it being acquired by our species around 10,000 years ago, following a species jump from mice to humans. HBRV is the human homolog of the MMTV (mouse mammary tumor virus), which is the etiological agent of murine mammary tumors. The hypothesis of a HMTV (human mammary tumor virus) was proposed about 50 years ago, and has acquired a solid scientific basis during the last 30 years, with the demonstration of a robust link with breast cancer and with PBC, primary biliary cholangitis. This article summarizes most of what is known about MMTV/HMTV/HBRV since the discovery of MMTV at the beginning of last century, to make evident both the quantity and the quality of the research supporting the existence of HBRV and its pathogenic role. Here, it is sufficient to mention that scientific evidence includes that viral sequences have been identified in breast-cancer samples in a worldwide distribution, that the complete proviral genome has been cloned from breast cancer and patients with PBC, and that saliva contains HBRV, as a possible route of inter-human infection. Controversies that have arisen concerning results obtained from human tissues, many of them outdated by new scientific evidence, are critically discussed and confuted. Full article
(This article belongs to the Special Issue Human Betaretrovirus and Related Diseases)
22 pages, 1477 KiB  
Review
Mouse Mammary Tumor Virus (MMTV) and MMTV-like Viruses: An In-depth Look at a Controversial Issue
by Francesca Parisi, Giulia Freer, Chiara Maria Mazzanti, Mauro Pistello and Alessandro Poli
Viruses 2022, 14(5), 977; https://doi.org/10.3390/v14050977 - 6 May 2022
Cited by 14 | Viewed by 5123
Abstract
Since its discovery as a milk factor, mouse mammary tumor virus (MMTV) has been shown to cause mammary carcinoma and lymphoma in mice. MMTV infection depends upon a viral superantigen (sag)-induced immune response and exploits the immune system to establish infection in mammary [...] Read more.
Since its discovery as a milk factor, mouse mammary tumor virus (MMTV) has been shown to cause mammary carcinoma and lymphoma in mice. MMTV infection depends upon a viral superantigen (sag)-induced immune response and exploits the immune system to establish infection in mammary epithelial cells when they actively divide. Simultaneously, it avoids immune responses, causing tumors through insertional mutagenesis and clonal expansion. Early studies identified antigens and sequences belonging to a virus homologous to MMTV in human samples. Several pieces of evidence fulfill a criterion for a possible causal role for the MMTV-like virus in human breast cancer (BC), though the controversy about whether this virus was linked to BC has raged for over 40 years in the literature. In this review, the most important issues related to MMTV, from its discovery to the present days, are retraced to fully explore such a controversial issue. Furthermore, the hypothesis of an MMTV-like virus raised the question of a potential zoonotic mouse–man transmission. Several studies investigate the role of an MMTV-like virus in companion animals, suggesting their possible role as mediators. Finally, the possibility of an MMTV-like virus as a cause of human BC opens a new era for prevention and therapy. Full article
(This article belongs to the Special Issue Human Betaretrovirus and Related Diseases)
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20 pages, 831 KiB  
Review
Mouse Mammary Tumour Virus (MMTV) in Human Breast Cancer—The Value of Bradford Hill Criteria
by James S. Lawson and Wendy K. Glenn
Viruses 2022, 14(4), 721; https://doi.org/10.3390/v14040721 - 30 Mar 2022
Cited by 12 | Viewed by 4132
Abstract
For many decades, the betaretrovirus, mouse mammary tumour virus (MMTV), has been a causal suspect for human breast cancer. In recent years, substantial new evidence has been developed. Based on this evidence, we hypothesise that MMTV has a causal role. We have used [...] Read more.
For many decades, the betaretrovirus, mouse mammary tumour virus (MMTV), has been a causal suspect for human breast cancer. In recent years, substantial new evidence has been developed. Based on this evidence, we hypothesise that MMTV has a causal role. We have used an extended version of the classic A. Bradford Hill causal criteria to assess the evidence. 1. Identification of MMTV in human breast cancers: The MMTV 9.9 kb genome in breast cancer cells has been identified. The MMTV genome in human breast cancer is up to 98% identical to MMTV in mice. 2. Epidemiology: The prevalence of MMTV positive human breast cancer is about 35 to 40% of breast cancers in Western countries and 15 to 20% in China and Japan. 3. Strength of the association between MMTV and human breast cancer: Consistency—MMTV env gene sequences are consistently five-fold higher in human breast cancer as compared to benign and normal breast controls. 4. Temporality (timing) of the association: MMTV has been identified in benign and normal breast tissues up to 10 years before the development of MMTV positive breast cancer in the same patient. 5. Exposure: Exposure of humans to MMTV leads to development of MMTV positive human breast cancer. 6. Experimental evidence: MMTVs can infect human breast cells in culture; MMTV proteins are capable of malignantly transforming normal human breast epithelial cells; MMTV is a likely cause of biliary cirrhosis, which suggests a link between MMTV and the disease in humans. 7. Coherence—analogy: The life cycle and biology of MMTV in humans is almost the same as in experimental and feral mice. 8. MMTV Transmission: MMTV has been identified in human sputum and human milk. Cereals contaminated with mouse fecal material may transmit MMTV. These are potential means of transmission. 9. Biological plausibility: Retroviruses are the established cause of human cancers. Human T cell leukaemia virus type I (HTLV-1) causes adult T cell leukaemia, and human immunodeficiency virus infection (HIV) is associated with lymphoma and Kaposi sarcoma. 10. Oncogenic mechanisms: MMTV oncogenesis in humans probably differs from mice and may involve the enzyme APOBEC3B. Conclusion: In our view, the evidence is compelling that MMTV has a probable causal role in a subset of approximately 40% of human breast cancers. Full article
(This article belongs to the Special Issue Human Betaretrovirus and Related Diseases)
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3 pages, 183 KiB  
Commentary
The Role of a Betaretrovirus in Human Breast Cancer: Enveloping a Conundrum
by Walter H. Gunzburg and Brian Salmons
Viruses 2022, 14(11), 2342; https://doi.org/10.3390/v14112342 - 25 Oct 2022
Cited by 1 | Viewed by 1542
Abstract
Most of the evidence that a human betaretrovirus (HBRV/HMTV) highly related to mouse mammary tumour virus (MMTV) has an etiological role in breast cancer has been summarized in a recent comprehensive Special Issue of “Viruses” entitled “Human Betaretrovirus (HBRV) and Related Diseases”. Shortly [...] Read more.
Most of the evidence that a human betaretrovirus (HBRV/HMTV) highly related to mouse mammary tumour virus (MMTV) has an etiological role in breast cancer has been summarized in a recent comprehensive Special Issue of “Viruses” entitled “Human Betaretrovirus (HBRV) and Related Diseases”. Shortly after publication of this special issue, a detailed analysis of aligned env sequences was published and concluded that (i) MMTV and HBRV/HMTV cannot be distinguished on the basis of aligned env sequences and (ii) more sequence data covering the full-length env or HBRV/HMTV genomes from multiple isolates is needed. Although productive infection of human cells by MMTV (and presumably HBRV/HMTV) has been shown, it is imperative that the receptor(s) enabling HBRV/HMTV to infect human cells are defined. Moreover, there is currently no compelling data for common integration sites, in contrast to MMTV induced mammary tumorigenesis in mice, suggesting that other mechanisms of tumorigenesis are associated with HBRV/HMTV infection. These issues need to be resolved before a clear link between MMTV/HBRV/HMTV and human breast cancer can be concluded. Full article
(This article belongs to the Special Issue Human Betaretrovirus and Related Diseases)
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