Although the existence of endogenous retroviruses in the genomes of vertebrate species, including mice and humans, has been known for many years, it was not until the sequencing of the human and mouse genomes that the extent to which we harbor endogenous retroviral sequences was fully appreciated. It has been estimated that our germ line has incurred about 40,000 infections by retroviruses over the course of evolution and that retroviral sequences account for 8 to 10% of our total DNA (20
). Most of these retrovirus elements are defective, and many consist only of solo long terminal repeats (LTRs) generated by recombination between the two LTRs generated during the integration process. Others that retain coding sequences are often transcriptionally silent; however, some of the sequences are expressed in a very controlled manner throughout the lifetime of the host and appear to be modulated under various physiological and pathological circumstances (4
). There are an increasing number of studies indicating that many of these elements have been utilized for a number of physiological processes. These include processes at the genomic level, such as transcriptional control of several genes (3
), at the transcript level, by interaction of viral RNAs with proteins (35
), and at the protein level, such as the role of endogenous retrovirus envelope proteins in the fusion of placental trophoblasts (6
). The observations that endogenous retrovirus sequences are expressed during the lifetimes of animals may reflect requirements for the transcription and translation of some of the endogenous retroviruses, even though the expression of these viruses may have deleterious consequences. Thus, some restriction factors likely reflect mechanisms evolved by the host to control endogenous viruses that are obliged to be transcribed due to a physiological role.
Among the most extensively studied groups of endogenous retroviruses are the endogenous polytropic retroviruses of mice (11
). These viruses, like some human retroviruses, are expressed in a tightly controlled fashion during the lifetime of the host and have not been found to produce infectious viruses, even though some of them possess intact env
genes and are transcribed (1
). They do, however, interact with exogenous viruses that have infected the mouse. Upon infection, the exogenous viruses recombine with the env
gene sequences of the endogenous polytropic MuLVs to generate host range variants that utilize a different cell surface receptor for infectious entry (11
). The generation of such recombinant viruses is instrumental in the induction of disease by a number of exogenous retroviruses.
Recombination between the exogenous and endogenous retrovirus genomes requires transcription of a complete endogenous provirus to an RNA strand that is copackaged with an exogenous murine leukemia virus (MuLV) transcript as a heterodimeric virion RNA. Upon subsequent infection, the heterodimer can undergo recombination during reverse transcription (RT) (16
). Although the endogenous polytropic proviruses are transcribed, replication of the endogenous polytropic viruses in the absence of recombination has not been observed. This may, in many cases, reflect defects, such as point mutations or deletions, in the endogenous viral genome but may also be influenced by the activities of various restriction factors (14
). The fact that exogenous MuLVs are capable of replicating in mice indicates that they have evolved mechanisms to circumvent the activities of at least some of the restriction factors. Thus, exogenous retroviruses might facilitate, through complementation, active replication of endogenous retroviruses.
In this report, we present evidence that infection of mice by an exogenous virus results in the mobilization of complete endogenous retroviruses. This includes proviruses that are severely defective and possess large deletions, as well as proviruses that are full length. Furthermore, the transferred sequences are transcribed and packaged into virions released from the newly infected cells.