Human betaretrovirus (HBRV), also known as Human mammary tumor virus, or Mouse mammary tumor-like virus is the human homologue of the Mouse mammary tumor virus (MMTV). The nomenclature for Human betaretrovirus was introduced following characterization of infection in patient with autoimmune liver disease suggesting the virus is not solely found in mice nor exclusively implicated in the development of neoplastic disease. Evidence of HBRV has been documented in humans dating back at least 4500 years ago, and it stands as the only identified exogenous betaretrovirus affecting humans to date. The existence of this virus was suspected for decades. Nucleotide sequences identifying a whole proviral betarerovirus were first reported in human breast cancer in 2001 and lymphoid tissues of patients with autoimmune liver disease in 2003. Viral particles were isolated several years later.
Virology
The HBRV encodes an approximately 9 kilobase single-stranded RNA genome, and shares significant virological similarities with MMTV. The human and mouse betaretrovirus are difficult to distinguish genetically, and structural proteins share 93% to 99% amino acid sequence similarity with each other and less than 35% with other betaretroviruses and the human endogenous betaretroviruses (HERV-K). By electron microscopy, both human betaretrovirus and MMTV have comparable morphological features and form 80-100 nm spherical and pleomorphic structures with eccentric nucleocapsid cores. Previously, these betaretroviruses were considered simple retroviruses encoding gag, pol and env genes but are now considered complex with the characterization of the regulator of MMTV expression (Rem) protein that acts as a nuclear export of the unspliced RNA. The HBRV genome encodes five possible open reading frames (ORFs) that correspond with the Gag, protease (Pro), polymerase (Pol), envelope (Env), regulator of MMTV expression (Rem) and superantigen (Sag) proteins found in MMTV. The viral superantigen is the most variable region within the betaretrovirus genome. The viral superantigen mechanism is required to stimulate lymphocyte proliferation and enable viral replication within dividing cells; demonstration of superantigen activity is used to demonstrate MMTV infection in mice.
Transmission
Cross-species transmission The similarity of MMTV with HBRV suggests a zoonosis from mice to humans. The discovery of HBRV in humans, dating back thousands of years, indicates an interspecies transmission of the virus between mice and humans coinciding with the development of agriculture. This transmission process may have resulted in the adaptation of MMTV to humans, ultimately evolving into HBRV. MMTV can infect human cells, as demonstrated in co-cultivation studies using 293 human kidney, and HeLa human cervical adenocarcinoma, and Hs578T breast epithelial cells.
HBRV transmission in humans The route of HBRV transmission in humans remains unknown. However, some evidence suggests the possibility of microdroplet transmission, as viral sequences have been found in human saliva. It has been suggested that HBRV may be transmitted through saliva, as the virus can potentially reach the Waldeyer's ring structures in the throat. Similar to observations in mice, both betaretrovirus particles and nucleic acid have been documented in human breast milk. However, human milk has been shown to have a destructive effect on MMTV particles, and this route of transmission is not consistent with the epidemiological data concerning breast feeding.
Tropism While contemporary understanding of tropism remains limited, recent studies have provided insights into HBRV's ability to infect biliary epithelial cells and replicate within lymphoid tissue.
Human betaretrovirus and linked diseases Human betaretrovirus has been associated with various cancers and autoimmune conditions, such as primary biliary cholangitis. While HBRV may be a contributing factor, it is not the accepted cause at present, or the sole agent triggering these diseases. Other factors, such as genetic predisposition and other environmental exposures, are thought to play a contributary role in disease development. Nevertheless, several criteria used for linking environmental agents with disease have been firmly established for HBRV. The over-expression in human MCF7 cells of both WNT1 and FGF3 genes, main integration sites (INT) of MMTV in mouse, induces the synthesis of epithelial mesenchymal transition markers, mitochondrial proteins, glycolytic enzymes, and protein machinery synthesis. Many of these proteins are found transcriptionally overexpressed in human breast cancer cells in vivo.
Human betaretrovirus and cancer The potential association between human mammary tumor virus (HBRV) and breast cancer has been a subject of interest for approximately 50 years since betaretrovirus particles resembling MMTV were observed in breast milk derived from close relatives of patients with breast cancer. Over the past three decades, numerous studies have provided substantial support to link a human mammary tumor virus with sporadic breast cancer and more recent research has identified viral sequences of HBRV in breast cancer samples from different regions, indicating the presence of the virus in breast cancer tissues.
Invasive sporadic carcinoma More than 40 studies worldwide report evidence of HBRV infection in human sporadic breast cancer tissue ranging from ~30% to 40% of patients as compared to ~2% frequency in control samples.
Ductal carcinoma in situ The rate of HBRV infection in DCIS has been found double than in invasive forms (80%). This finding indicates that HBRV plays a role in cancer initiation rather than in cancer progression, in line with what is known in the murine model.
Hereditary carcinoma In contrast, hereditary breast carcinoma occurs as a result of etiopathogenetic factors unassociated with HBRV and this form of cancer has a very low frequency of HBRV ranging from 2-4%. The mounting evidence regarding the potential similarity in pathogenic mechanisms between HBRV and MMTV has further strengthened the hypothesis that the virus could be relevant in understanding sporadic breast cancer development and progression.
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