Human betaretrovirus

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Human betaretrovirus
Virus classification OOjs UI icon edit-ltr.svg
(unranked): Virus
Realm: Riboviria
Kingdom: Pararnavirae
Phylum: Artverviricota
Class: Revtraviricetes
Order: Ortervirales
Family: Retroviridae
Genus: Betaretrovirus
Species:
Human betaretrovirus

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. [1] [2] [3] Evidence of HBRV has been documented in humans dating back at least 4500 years ago, [4] [5] and it stands as the only identified exogenous betaretrovirus affecting humans to date. [6]

Contents

The existence of this virus was suspected for decades. [7] Nucleotide sequences identifying a whole proviral betarerovirus were first reported in human breast cancer in 2001 [8] and lymphoid tissues of patients with autoimmune liver disease in 2003. Viral particles were isolated several years later. [9]

Virology

Human betaretretrovirus particle isolated in co-culture with Hs578T cells from a lymph node derived from a patient with primary biliary cholangitis. The negative stained transmission electron microscopy shows a betaretrovirus-like morphology with an eccentric core and membrane spikes (Hitachi H-7650 Transmission Electron Microscope). Human betaretretrovirus particle isolated in co-culture with Hs578T cells from a lymph node.png
Human betaretretrovirus particle isolated in co-culture with Hs578T cells from a lymph node derived from a patient with primary biliary cholangitis. The negative stained transmission electron microscopy shows a betaretrovirus-like morphology with an eccentric core and membrane spikes (Hitachi H-7650 Transmission Electron Microscope).

The HBRV encodes an approximately 9 kilobase single-stranded RNA genome, and shares significant virological similarities with MMTV. [1] [6] 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). [1] [6] 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. [10] [2] [6]

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. [11] [12] 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. [1] [6] [11] [12] The viral superantigen is the most variable region within the betaretrovirus genome. [1] 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. [13]

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, [5] 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. [4] 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. [14] [15]

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. [4] [16] 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. [4] Similar to observations in mice, both betaretrovirus particles and nucleic acid have been documented in human breast milk. [17] [10] 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. [18] [19] [20]

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. [6] [21] [10]

Human betaretrovirus and linked diseases

Human betaretrovirus has been associated with various cancers [4] and autoimmune conditions, such as primary biliary cholangitis. [22] 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. [3] [23] 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. [24]

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. [10] 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. [25] [26] [27] [28]

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. [4] [23]

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. [29] [30]

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%. [31] 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. [4] [32] [23]

Human betaretrovirus and autoimmune diseases

Human betaretrovirus (HBRV) has been extensively studied in its connection to the autoimmune liver disease, primary biliary cholangitis (PBC). [3] Various research approaches have been employed, including in vitro HBRV co-cultivation studies using biliary epithelium, the use of autoimmune biliary disease mouse models with MMTV infection and the study of patient samples. [3] These studies have provided valuable insights into the link between HBRV and PBC. For example, HBRV infection leads to the expression of autoantigens linked with the development of the anti-mitochondrial antibodies used to diagnose PBC, [10] [33] and MMTV infection in mice is also linked with mitochondrial antigen expression and antimitochondrial antibody production. [34] [35]

Using PBC patient samples, researchers have isolated HBRV and identified up to 3000 viral integration sites within the human genome, providing strong evidence of a transmissible betaretrovirus infection in patients diagnosed with PBC. [6] [21] Furthermore, HBRV insertions and betaretrovirus RNA were commonly observed at the site of disease in the biliary epithelia of patients with PBC, and also in patients with autoimmune hepatitis.

Diagnosis of human betaretrovirus infection

The diagnosis of human betaretrovirus virus infection remains a challenging task due to the lack of widely available, sensitive, and reproducible diagnostic tests. One serological ELISA assay using the HBRV Env protein was positive in 10% of breast cancer and PBC patients as compared to ~2% of healthy subjects. [36] Accordingly, this serological assay was less sensitive than the gold standard for demonstrating retroviral infection with proviral integrations. However, demonstration of genomic insertions is a research tool that is not readily adaptable for clinical use. HBRV is not readily detectable in blood by the polymerase chain reaction methodology and therefore a tissue diagnosis is required. However, this assay may be compromised by contamination. Further development of cellular immune assays using characterized HBRV Gag and Env peptides can be employed for diagnostic purposes by quantifying interferon-gamma production following stimulation of lymphocytes, providing a more sensitive assay than the ELISA. [37]

Treatment of human betaretrovirus infection

Although there is currently no approved treatment specifically targeted for human betaretrovirus infection, some studies have demonstrated efficacy of repurposed HIV antiretroviral therapy. [38] A randomized controlled trial using combination reverse transcriptase inhibitors, lamivudine and zidovudine, did not meet the study endpoints but showed a significant improvement in alkaline phosphatase, a biliary enzyme used to gauge disease activity in PBC patients. [39] Another randomized controlled trial using the combination of tenofovir, emtricitabine, and lopinavir, was stopped early due to gastrointestinal side effects. [40] However, patients able to tolerate long-term treatment demonstrated both biochemical and histological improvement. [41] [38]

The potential for immunotherapy of cancers exhibiting immunodominant betaretrovirus antigens has been studied in animal models. Using either a combination of monoclonal anti-MMTV p14 antibodies or adoptive T-cell transfer treatments, tumour growth was reduced in vivo. [42] This may have translational relevance, as related p14 antigens can be detected in benign hyperplasia patient samples predating the development of breast cancer, and in a proportion of human breast cancer samples. [43] Accordingly, the animal studies may provide a pathway for the future development of passive or active vaccination strategies to treat and possibly prevent human betaretrovirus-associated cancers.

Related Research Articles

<span class="mw-page-title-main">Retrovirus</span> Family of viruses

A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. After invading a host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backward). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus. Many retroviruses cause serious diseases in humans, other mammals, and birds.

<span class="mw-page-title-main">Primary biliary cholangitis</span> Autoimmune disease of the liver

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.

<i>Polyomaviridae</i> Family of viruses

Polyomaviridae is a family of viruses whose natural hosts are primarily mammals and birds. As of 2024, there are eight recognized genera. 14 species are known to infect humans, while others, such as Simian Virus 40, have been identified in humans to a lesser extent. Most of these viruses are very common and typically asymptomatic in most human populations studied. BK virus is associated with nephropathy in renal transplant and non-renal solid organ transplant patients, JC virus with progressive multifocal leukoencephalopathy, and Merkel cell virus with Merkel cell cancer.

Mouse mammary tumor virus (MMTV) is a milk-transmitted retrovirus like the HTL viruses, HI viruses, and BLV. It belongs to the genus Betaretrovirus. MMTV was formerly known as Bittner virus, and previously the "milk factor", referring to the extra-chromosomal vertical transmission of murine breast cancer by adoptive nursing, demonstrated in 1936, by John Joseph Bittner while working at the Jackson Laboratory in Bar Harbor, Maine. Bittner established the theory that a cancerous agent, or "milk factor", could be transmitted by cancerous mothers to young mice from a virus in their mother's milk. The majority of mammary tumors in mice are caused by mouse mammary tumor virus.

<span class="mw-page-title-main">Liver disease</span> Medical condition

Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.

<span class="mw-page-title-main">Cholangiocarcinoma</span> Cancer of the bile ducts

Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts. Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever. Light colored stool or dark urine may also occur. Other biliary tract cancers include gallbladder cancer and cancer of the ampulla of Vater.

<span class="mw-page-title-main">Oncovirus</span> Viruses that can cause cancer

An oncovirus or oncogenic virus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term oncornaviruses was used to denote their RNA virus origin. With the letters RNA removed, it now refers to any virus with a DNA or RNA genome causing cancer and is synonymous with tumor virus or cancer virus. The vast majority of human and animal viruses do not cause cancer, probably because of longstanding co-evolution between the virus and its host. Oncoviruses have been important not only in epidemiology, but also in investigations of cell cycle control mechanisms such as the retinoblastoma protein.

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<i>Jaagsiekte sheep retrovirus</i> Species of virus

Jaagsiekte sheep retrovirus (JSRV) is a betaretrovirus which is the causative agent of a contagious lung cancer in sheep, called ovine pulmonary adenocarcinoma.

<span class="mw-page-title-main">Ascending cholangitis</span> Medical condition

Ascending cholangitis, also known as acute cholangitis or simply cholangitis, is inflammation of the bile duct, usually caused by bacteria ascending from its junction with the duodenum. It tends to occur if the bile duct is already partially obstructed by gallstones.

<i>Murine respirovirus</i> Sendai virus, virus of rodents

Murine respirovirus, formerly Sendai virus (SeV) and previously also known as murine parainfluenza virus type 1 or hemagglutinating virus of Japan (HVJ), is an enveloped, 150-200 nm–diameter, negative sense, single-stranded RNA virus of the family Paramyxoviridae. It typically infects rodents and it is not pathogenic for humans or domestic animals.

Env is a viral gene that encodes the protein forming the viral envelope. The expression of the env gene enables retroviruses to target and attach to specific cell types, and to infiltrate the target cell membrane.

<span class="mw-page-title-main">Liver cancer</span> Medical condition

Liver cancer, also known as hepatic cancer, primary hepatic cancer, or primary hepatic malignancy, is cancer that starts in the liver. Liver cancer can be primary in which the cancer starts in the liver, or it can be liver metastasis, or secondary, in which the cancer spreads from elsewhere in the body to the liver. Liver metastasis is the more common of the two liver cancers. Instances of liver cancer are increasing globally.

<span class="mw-page-title-main">Toll-like receptor 9</span> Protein found in humans

Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. TLR9 has also been designated as CD289. It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expressed in immune system cells including dendritic cells, macrophages, natural killer cells, and other antigen presenting cells. TLR9 is expressed on endosomes internalized from the plasma membrane, binds DNA, and triggers signaling cascades that lead to a pro-inflammatory cytokine response. Cancer, infection, and tissue damage can all modulate TLR9 expression and activation. TLR9 is also an important factor in autoimmune diseases, and there is active research into synthetic TLR9 agonists and antagonists that help regulate autoimmune inflammation.

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<span class="mw-page-title-main">James Lawson (Australian doctor)</span> Australian public health doctor and scientist

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<span class="mw-page-title-main">Murine polyomavirus</span> Species of virus

Murine polyomavirus is an unenveloped double-stranded DNA virus of the polyomavirus family. The first member of the family discovered, it was originally identified by accident in the 1950s. A component of mouse leukemia extract capable of causing tumors, particularly in the parotid gland, in newborn mice was reported by Ludwik Gross in 1953 and identified as a virus by Sarah Stewart and Bernice Eddy at the National Cancer Institute, after whom it was once called "SE polyoma". Stewart and Eddy would go on to study related polyomaviruses such as SV40 that infect primates, including humans. These discoveries were widely reported at the time and formed the early stages of understanding of oncoviruses.

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References

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