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Science (New York, N.Y.) Oct 2022Endogenous retroviruses are abundant components of mammalian genomes descended from ancient germline infections. In several mammals, the envelope proteins encoded by...
Endogenous retroviruses are abundant components of mammalian genomes descended from ancient germline infections. In several mammals, the envelope proteins encoded by these elements protect against exogenous viruses, but this activity has not been documented with endogenously expressed envelopes in humans. We report that the human genome harbors a large pool of envelope-derived sequences with the potential to restrict retroviral infection. To test this, we characterized an envelope-derived protein, Suppressyn. We found that is expressed in human preimplantation embryos and developing placenta using its ancestral retroviral promoter. Cell culture assays showed that , and its hominoid orthologs, could restrict infection by extant mammalian type D retroviruses. Our data support a generalizable model of retroviral envelope co-option for host immunity and genome defense.
Topics: Animals; Female; Humans; Pregnancy; Betaretrovirus; Gene Products, env; Genome, Human; Placenta; Placentation; Pregnancy Proteins; Evolution, Molecular
PubMed: 36302021
DOI: 10.1126/science.abq7871 -
Viruses Dec 2022
Topics: Animals; Mice; Humans; Female; Betaretrovirus; Mammary Tumor Virus, Mouse; Breast Neoplasms
PubMed: 36560796
DOI: 10.3390/v14122792 -
Viruses Aug 2022Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the production of diagnostic antimitochondrial antibodies (AMA) reactive to the... (Review)
Review
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 with peptic ulcer disease.
Topics: Animals; Antiviral Agents; Autoantibodies; Autoantigens; Autoimmunity; Betaretrovirus; Humans; Liver Cirrhosis, Biliary; Liver Diseases; Mice; Pyruvate Dehydrogenase Complex
PubMed: 36146750
DOI: 10.3390/v14091941 -
Retrovirology Dec 2021The majority of emerging infectious diseases in humans are of animal origin, and many of them are caused by neuropathogenic viruses. Many cases of neurological disease...
BACKGROUND
The majority of emerging infectious diseases in humans are of animal origin, and many of them are caused by neuropathogenic viruses. Many cases of neurological disease and encephalitis in livestock remain etiologically unresolved, posing a constant threat to animal and human health. Thus, continuous extension of our knowledge of the repertoire of viruses prone to infect the central nervous system (CNS) is vital for pathogen monitoring and the early detection of emerging viruses. Using high-throughput sequencing (HTS) and bioinformatics, we discovered a new retrovirus, bovine retrovirus CH15 (BoRV CH15), in the CNS of a cow with non-suppurative encephalitis. Phylogenetic analysis revealed the affiliation of BoRV CH15 to the genus Betaretrovirus.
RESULTS
BoRV CH15 genomes were identified prospectively and retrospectively by PCR, RT-PCR, and HTS, with targeting of viral RNA and proviral DNA, in six additional diseased cows investigated over a period of > 20 years and of different geographical origins. The virus was not found in brain samples from healthy slaughtered control animals (n = 130). We determined the full-length proviral genomes from six of the seven investigated animals and, using in situ hybridization, identified viral RNA in the cytoplasm of cells morphologically compatible with neurons in diseased brains.
CONCLUSIONS
Further screening of brain samples, virus isolation, and infection studies are needed to estimate the significance of these findings and the causative association of BoRV CH15 with neurological disease and encephalitis in cattle. However, with the full-length proviral sequences of BoRV CH15 genomes, we provide the basis for a molecular clone and further in vitro investigation.
Topics: Animals; Betaretrovirus; Cattle; Encephalitis; Female; Phylogeny; Retrospective Studies; Viruses
PubMed: 34930327
DOI: 10.1186/s12977-021-00585-x -
Viruses Apr 2022A human betaretrovirus (HBRV) has been linked with the autoimmune liver disease, primary biliary cholangitis (PBC), and various cancers, including breast cancer and...
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.
Topics: Animals; Betaretrovirus; Breast Neoplasms; Female; Humans; Liver Cirrhosis, Biliary; Mammary Tumor Virus, Mouse; Mice; Proviruses
PubMed: 35632628
DOI: 10.3390/v14050886 -
Viruses Oct 2022Most 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...
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.
Topics: Humans; Mice; Animals; Female; Betaretrovirus; Breast Neoplasms; Mammary Tumor Virus, Mouse; Carcinogenesis
PubMed: 36366440
DOI: 10.3390/v14112342 -
Veterinary Medicine and Science May 2022Retroviral infections have been reported in many species of animals, especially cattle, sheep and goats. However, there are no available reports about retrovirus...
BACKGROUND
Retroviral infections have been reported in many species of animals, especially cattle, sheep and goats. However, there are no available reports about retrovirus infection in dromedary camels. Several dromedary camels showed visible tumor-like lesions on and around the nostrils as well as around the eyes.
OBJECTIVES
Following are the objectives: to identify the causative agents of these identified tumours in dromedary camels and to perform molecular characterization of the detected strains of the causative agent.
METHODS
We extracted the nucleic acids from some fresh lesions out of these animals, and then amplified some key retrovirus genes. We amplified several regions of the rotavirus genome using the PCR technique. The obtained sequences were assembled and the phylogenetic trees were conducted per each target retrovirus gene.
RESULTS
Our results revealed a high degree of identity to some retroviruses of sheep. Phylogenetic analysis based on some retrovirus genes revealed that the causative agents of these lesions are closely related to sheep retroviruses, particularly the Jaagsiekte sheep Retrovirus (JSRV) and the ENTV.
CONCLUSIONS
To the best of our knowledge, this is the first report of retrovirus infections in dromedary camels in the Arabian Peninsula. This highlights the possible species jump for the retrovirus from sheep and goats to the dromedary camels, which live in close proximity with these animals in many parts of the world, especially the Arabian Peninsula.
Topics: Animals; Betaretrovirus; Camelus; Cattle; Cattle Diseases; Goat Diseases; Goats; Phylogeny; Retroviridae Infections; Saudi Arabia; Sheep; Sheep Diseases
PubMed: 35114072
DOI: 10.1002/vms3.760 -
Viruses Jan 2022Endogenous retroviruses (ERVs) are the remnants of past retroviral infections that once invaded the host's germline and were vertically transmitted. ERV sequences have...
Endogenous retroviruses (ERVs) are the remnants of past retroviral infections that once invaded the host's germline and were vertically transmitted. ERV sequences have been reported in mammals, but their distribution and diversity in cervids are unclear. Using next-generation sequencing, we identified a nearly complete genome of an endogenous betaretrovirus in fallow deer (). Further genomic analysis showed that this provirus, tentatively named cervid endogenous betaretrovirus 1 (CERV β1), has typical betaretroviral genome features (---) and the betaretrovirus-specific dUTPase domain. In addition, CERV β1 sequences were detected by PCR in the six non-native deer species with wild populations in Australia. Phylogenetic analyses demonstrated that CERV β1 sequences from subfamily clustered as sister taxa to ERV-like sequences in species of subfamily . These findings, therefore, suggest that CERV β1 endogenisation occurred after the split of these two subfamilies (between 3.3 and 5 million years ago). Our results provide important insights into the evolution of betaretroviruses in cervids.
Topics: Animals; Animals, Wild; Australia; Betaretrovirus; Deer; Endogenous Retroviruses; Evolution, Molecular; Genome; Genome, Viral; Open Reading Frames; Phylogeny; Proviruses
PubMed: 35215845
DOI: 10.3390/v14020252 -
World Journal of Gastroenterology Jan 2016Following the characterization of a human betaretrovirus in patients with primary biliary cirrhosis (PBC), pilot studies using antiretroviral therapy have been conducted... (Review)
Review
Following the characterization of a human betaretrovirus in patients with primary biliary cirrhosis (PBC), pilot studies using antiretroviral therapy have been conducted as proof of principal to establish a link of virus with disease and with the eventual aim to find better adjunct therapies for patients unresponsive to ursodeoxycholic acid. In the first open label pilot study, the reverse transcriptase inhibitor lamivudine had little demonstrable biochemical or histological effect after 1 year. Whereas, lamivudine in combination with zidovudine was associated with a significant reduction in alkaline phosphatase as well as improvement in necroinflammatory score, cholangitis and ductopenia over a 12 mo period. A double blind, multi-center randomized controlled trial using lamivudine with zidovudine for 6 mo confirmed a significant reduction in alkaline phosphatase, ALT and AST in patients on antiviral therapy. However, none of the patients achieved the stringent endpoint criteria for normalization of alkaline phosphatase. Furthermore, some patients developed biochemical rebound consistent with drug resistance. A major fault of these studies has been the inability to measure the viral load in peripheral blood and therefore, provide a direct correlation between improvement of hepatic biochemistry and reduction in viral load. Nevertheless, viral mutants to lamivudine with zidovudine were later characterized in the NOD.c3c4 mouse model of PBC that has been used to test other antiretroviral regimens to betaretrovirus. The combination of tenofovir and emtricitabine reverse transcriptase inhibitors and the HIV protease inhibitor, lopinavir were found to abrogate cholangitis in the NOD.c3c4 mouse model and the same regimen normalized the liver tests in a PBC patient with HIV and human betaretrovirus infection. This combination antiretroviral therapy has now been used in a double blind randomized controlled crossover study for patients with PBC followed by an open label extension study. Only a third of the PBC patients were able to tolerate the lopinavir but those maintained on tenofovir, emtricitabine and lopinavir experienced sustained and clinically meaningful reduction in hepatic biochemistry. While we await the histological and virological evaluation, it is clear that better tolerated regimens of antiretroviral treatment will be required in future clinical trials.
Topics: Animals; Anti-Retroviral Agents; Betaretrovirus; Clinical Trials as Topic; Drug Therapy, Combination; Emtricitabine; Humans; Lamivudine; Liver Cirrhosis, Biliary; Lopinavir; Mammary Tumor Virus, Mouse; Mice; Tenofovir; Zidovudine
PubMed: 26755881
DOI: 10.3748/wjg.v22.i1.349 -
Frontiers in Cellular and Infection... 2021Mouse mammary tumor virus (MMTV) is a virus that induces breast cancer in mice. During lactation, MMTV can transmit from mother to offspring through milk, and Peyer's... (Review)
Review
Mouse mammary tumor virus (MMTV) is a virus that induces breast cancer in mice. During lactation, MMTV can transmit from mother to offspring through milk, and Peyer's patches (PPs) in mouse intestine are the first and specific target organ. MMTV can be transported into PPs by microfold cells and then activate antigen-presenting cells (APCs) by directly binding with Toll-like receptors (TLRs) whereas infect them through mouse transferrin receptor 1 (mTfR1). After being endocytosed, MMTV is reversely transcribed and the cDNA inserts into the host genome. Superantigen (SAg) expressed by provirus is presented by APCs to cognate CD4 T cells MHCII molecules to induce SAg response, which leads to substantial proliferation and recruitment of related immune cells. Both APCs and T cells can be infected by MMTV and these extensively proliferated lymphocytes and recruited dendritic cells act as hotbeds for viral replication and amplification. In this case, intestinal lymphatic tissues can actually become the source of infection for the transmission of MMTV , which results in mammary gland infection by MMTV and eventually lead to the occurrence of breast cancer.
Topics: Animals; Female; Intestines; Mammary Tumor Virus, Mouse; Mice; Mice, Inbred BALB C; Retroviridae Infections; Superantigens; T-Lymphocytes; Tumor Virus Infections
PubMed: 35096654
DOI: 10.3389/fcimb.2021.807462