Evolutionary journey of the retroviral restriction gene <i>Fv1</i>

Proceedings of the National Academy of Sciences

Both exogenous and endogenous retroviruses have long been studied in mice, and some of the earliest mouse studies focused on the heritability of genetic factors influencing permissivity and resistance to infection. The prototypic retroviral restriction factor,Fv1, is now understood to exhibit a degree of control across multiple retroviral genera and is highly diverse withinMus. To better understand the age and evolutionary history ofFv1, a comprehensive survey of the Muroidea was conducted, allowing the progenitor integration to be dated to ∼45 million years. Intact coding potential is visible beyondMus, and sequence analysis reveals strong signatures of positive selection also within field mice,Apodemus.Fv1’s survival for such a period implies a recurring and shifting retroviral burden imparting the necessary selective pressures—an influence likely also common to analogous factors. Regions ofFv1adapt cooperatively, highlighting its preference for repeated structures and suggesting ...

2019

Viruses and their hosts are locked in an evolutionary race where resistance to infection is acquired by the hosts while viruses develop strategies to circumvent these host defenses. Forming one arm of the host defense armory are cell autonomous restriction factors like Fv1. Originally described as protecting laboratory mice from infection by murine leukemia virus (MLV), Fv1s from some wild mice have also been found to restrict non-MLV retroviruses, suggesting an important role in the protection against viruses in nature. To begin to understand how restriction factors evolve, we surveyed the Fv1 genes of wild mice trapped in Thailand and characterized their restriction activities against a panel of retroviruses. An extra copy of the Fv1 gene, named Fv7, was found on chromosome 6 of three closely related Asian species of mice ( Mus caroli , M. cervicolor and M. cookii ). The presence of flanking repeats suggested it arose by LINE-mediated retrotransposition. A high degree of natural v...

Revue Scientifique et Technique de l'OIE, 1998

A number of genes which affect the susceptibility of mice to infection by retroviruses have been described. One of the most interesting of these genes is Fvl (Friend virus susceptibility 1), which acts at a stage in the retroviral life-cycle following virus entry into the cell but prior to integration and formation of proviral structures. A detailed understanding of the mode of action of Fv1 might be expected to shed fresh light on early steps of the retroviral replication, although progress has been slow in this area due to uncertainty about the nature of the Fv1 gene. The recent cloning of Fvl by a positional approach fills this gap in current knowledge. Fv1 appears to be derived from a fragment of a retroviral genome, an observation that may suggest novel approaches to the control of retroviral replication.

Proceedings of the National Academy of Sciences, 2000

The murine Fv1 gene restricts infection by N-or B-tropic murine leukemia viruses at a postentry, preintegration stage. The Fv1sensitive viruses previously used for the study of Fv1 encode an ecotropic envelope gene and thus only infect rodent cells. Consequently, the study of Fv1 restriction has been carried out solely in mice and murine cell lines. By infection with retroviral vectors containing N-or B-tropic core and pantropic vesicular stomatitis virus-G envelope protein, we now demonstrate that cell lines derived from various mammalian species, including humans, have an Fv1-like retrovirus restriction function, preventing N-tropic vector infection. Like Fv1, restriction is directed at amino acid 110 of the viral capsid protein. In contrast to Fv1, the novel restriction is characterized by the absence of reverse-transcribed viral DNA. We speculate that these activities have been selected for by retroviral epidemics in the distant past.

Fv1 is the prototypic restriction factor that protects against infection by the murine leukemia virus (MLV). It was first identified in cells that were derived from laboratory mice and was found to be homologous to the gag gene of an endogenous retrovirus (ERV). To understand the evolution of the host restriction gene from its retroviral origins, Fv1s from wild mice were isolated and characterized. Most of these possess intact open reading frames but not all restricted N-, B-, NR-or NB-tropic MLVs, suggesting that other viruses could have played a role in the selection of the gene. The Fv1s from Mus spretus and Mus caroli were found to restrict equine infectious anemia virus (EIAV) and feline foamy virus (FFV) respectively, indicating that Fv1 could have a broader target range than previously thought, including activity against lentiviruses and spumaviruses. Analyses of the Fv1 sequences revealed a number of residues in the C-terminal region that had evolved under positive selection. Four of these selected residues were found to be involved in the novel restriction by mapping studies. These results strengthen the similarities between the two capsid binding restriction factors, Fv1 and TRIM5a, which support the hypothesis that Fv1 defended mice against waves of retroviral infection possibly including non-MLVs as well as MLVs.

Annual Review of Genetics, 2008

For millions of years, retroviral infections have challenged vertebrates, occasionally leading to germline integration and inheritance as ERVs, genetic parasites whose remnants today constitute some 7% to 8% of the human genome. Although they have had significant evolutionary side effects, it is useful to view ERVs as fossil representatives of retroviruses extant at the time of their insertion into the germline and not as direct players in the evolutionary process itself. Expression of particular ERVs is associated with several positive physiological functions as well as certain diseases, although their roles in human disease as etiological agents, possible contributing factors, or disease markers—well demonstrated in animal models—remain to be established. Here we discuss ERV contributions to host genome structure and function, including their ability to mediate recombination, and physiological effects on the host transcriptome resulting from their integration, expression, and othe...

Philosophical Transactions of the Royal Society B: Biological Sciences, 2013

PLOS Genetics, 2020

Viruses and their hosts are locked in an evolutionary race where resistance to infection is acquired by the hosts while viruses develop strategies to circumvent these host defenses. Forming one arm of the host defense armory are cell autonomous restriction factors like Fv1. Originally described as protecting laboratory mice from infection by murine leukemia virus (MLV), Fv1s from some wild mice have also been found to restrict non-MLV retroviruses, suggesting an important role in the protection against viruses in nature. We surveyed the Fv1 genes of wild mice trapped in Thailand and characterized their restriction activities against a panel of retroviruses. An extra copy of the Fv1 gene, named Fv7, was found on chromosome 6 of three closely related Asian species of mice: Mus caroli, M. cervicolor, and M. cookii. The presence of flanking repeats suggested it arose by LINE-mediated retroduplication within their most recent common ancestor. A high degree of natural variation was observed in both Fv1 and Fv7 and, on top of positive selection at certain residues, insertions and deletions were present that changed the length of the reading frames. These genes exhibited a range of restriction phenotypes, with activities directed against gamma-, spuma-, and lentiviruses. It seems likely, at least in the case of M. caroli, that the observed gene duplication may expand the breadth of restriction beyond the capacity of Fv1 alone and that one or more such viruses have recently driven or continue to drive the evolution of the Fv1 and Fv7 genes.

Trends in Microbiology, 1997

Nature Reviews Microbiology, 2012

Capable of forming tumours. Some but not all retroviruses are capable of changing cell growth properties, resulting in cancer. The kinds of tumours seen include carcinomas, sarcomas and leukaemias.