Human betaretrovirus

The HBRV encodes an approximately 9 kilobase single-stranded RNA genome, and shares significant virological similarities with MMTV. 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. ==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, 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. ==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 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. 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. 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. and MMTV infection in mice is also linked with mitochondrial antigen expression and antimitochondrial antibody production. 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. 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. 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. ==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. 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. Another randomized controlled trial using the combination of tenofovir, emtricitabine, and lopinavir, was stopped early due to gastrointestinal side effects. However, patients able to tolerate long-term treatment demonstrated both biochemical and histological improvement. 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. 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. ==References==