It is estimated that humans as well as mice have acquired approximately 40,000 copies of retroviruses over the course of evolution such that approximately 8% of their genomic sequences are retroviral in origin. The majority of these retroviruses are no longer full length and do not encode functional retroviruses. However, several endogenous retroviral elements function in important physiological roles such as transcriptional regulation of host genes or the induction of placenta-trophoblast fusion during embryogenesis. In humans, the HERV-K (HLM-2) group of endogenous retroviruses are the most recently acquired and are polymorphic in the population. The expression of these viruses have been associated with a number of diseases but have yet to be established as causative. A group of endogenous retroviruses of mice, termed the polytropic viruses, like the HERV-K (HLM-2), are the most recently acquired endogenous retroviruses in mice. They are polymorphic among mouse strains and are associated with a number of pathogenic processes. Upon infection of susceptible mice by ecotropic murine leukemia viruses (MuLVs) endogenous polytropic transcripts can recombine with incoming ecotropic murine leukemia viruses. This results in the generation of replication-competent polytropic MuLVs that utilize a different cellular receptor for entry and exhibit an altered host range. The generation of recombinant polytropic MuLVs is associated with the development of fatal proliferative diseases. Furthermore, some recombinant polytropic viruses induce severe neurological diseases, and the expression of endogenous polytropic envelope sequences in certain mouse strains correlates with the development of murine lupus nephritis, a severe immunological disorder. Although the endogenous polytropic proviruses are transcribed; replication of the endogenous polytropic viruses in the absence of recombination has not been observed. This may reflect defects in the endogenous viral genome but may also be influenced by the activity of various restriction factors. The fact that exogenous MuLVs are capable of replicating in mice indicates that they have evolved mechanisms to circumvent the activity of at least some of the restriction factors such as the murine APOBEC3 (mA3). Thus, exogenous retroviruses might facilitate, through complementation, active replication of endogenous retroviruses. We have shown in mice infected with the exogenous ecotropic Friend MuLV (F-MuLV) that endogenous polytropic transcripts not only recombine with F-MuLV but are mobilized by packaging of complete transcripts within F-MuLV virions in the absence of recombination. These pseudotyped endogenous polytropic transcripts, consisting of severely deleted as well as nearly complete genomes, are transferred by infection and integration into the genome of new cells. The newly infected cells are also infected by F-MuLV which enables the packaging and release of infectious progeny virions containing genomes transcribed from the newly integrated defective mobilized proviruses. More recently we demonstrated the mobilization of endogenous polytropic genomes from F-MuLV-infected NFS/N mice as early as one day after infection corresponding to a single replication cycle. Thereafter, the level of mobilized viruses increased throughout the course of disease and remained a major component of the viral load. The mobilized viruses identified were limited to endogenous polytropic proviral transcripts at the exclusion of other endogenous retroviral elements such as intracisternal-A particles (IAPs) or mouse mammary tumor viruses. The endogenous polytropic proviruses are comprised of two structural subclasses termed Polytropic (PT) and Modified Polytropic (mPT). We observed a distinct shift in the subclass of proviruses from the mPT subclass to the PT subclass of polytropic proviruses detected during the course of infection. Studies conducted in 2016 further characterized the mobilized polytropic proviruses. Some of the mobilized proviruses exhibited nearly identical sequences to proviruses identified in the mouse genomic reference sequence. Others exhibited definitive evidence of recombination events that occurred prior to the derivation of inbred mouse strains. Furthermore, some of the endogenous proviruses exhibit identical lethal mutations strongly suggesting that they entered the germline as defective passengers of infectious viruses through mobilization. The mobilization of intact endogenous retroviruses is unprecedented and may have important implications for the involvement of endogenous retroviruses in disease processes. Further, mobilization of proviruses may have played an important role in the acquisition of endogenous proviruses during evolution. Exogenous mouse retroviruses encode a glycosylated gag protein (gGag) originating from an alternate translation start site upstream of the methionine site of the gag structural polyproteins. Mutations that eliminate the synthesis of gGag impede in vivo replication of the virus with little effect on replication in fibroblastic cell lines. APOBEC3 proteins have evolved as innate defenses against retroviral infections. Both mice and humans express APOBEC3 proteins that have cytidine deaminase activity leading to hypermutation of viral transcripts and inactivation of infecting retroviruses. HIV encodes the VIF protein to evade human APOBEC3G (hA3G), however mouse retroviruses do not encode a VIF homologue and it has not been understood how they evade mouse APOBEC3 (mA3). We have found that a mouse retrovirus utilizes the gGag protein to evade APOBEC3. gGag is critical for infection of in vitro cell lines in the presence of APOBEC3. Furthermore, a gGag-deficient virus restricted for replication in wild-type mice replicates efficiently in APOBEC3 knockout mice implicating a novel role of gGag in circumventing the action of APOBEC3 in vivo. We have found that mA3 packaged at very high levels in wild-type virions results in a loss of specific infectivity and a loss in the specific enzymatic activity of the viral polymerase. This is accompanied by a substantial increase in the overall mutation rate. However we did not observe G to A hypermutation in either the wild-type or gGag-deficient MuLVs. Thus, the inhibitory action of mA3 on the MuLVs is unlikely to involve cytidine deamination. It has been reported by one group that the ecotropic MuLV, AKV, in contrast to other MuLVs, undergoes G to A hypermutation when mA3 is packaged within AKV virions in human 293T cells. We have found that hypermutation of AKV occurs in mouse 3T3 cells in the absence of detectable mA3. Furthermore, hypermutation occurs in only a portion of the virus transcripts suggesting that a restriction factor is present in only a portion of the virions. Identical results were observed in NIH 3T3 cells that were engineered to express mA3, indicating that its expression did not augment the mutagenic activity. This results suggests that a restriction factor other than mA3 may be involved. Studies conducted in 2016 continued to examine hypermutation of the ecotropic MuLV AKV and the involvement of mA3. We have found that AKV harvested from M. dunni cells does not undergo hypermutation on 3T3 cells during an initial infection. However, AKV virions harvested from the initial infection undergo hypermutation upon further infection. This result indicates that AKV virions have acquired a factor from the NIH 3T3 cells that induces G to A hypermutation. Other studies in which AKV infected M. dunni cells were transfected with mA3 or human APOBEC3G (hA3G) indicated that the restriction factors were incorporated into virions. However, hA3G but not mA3 induced G to A hypermutation. These results further suggest that mA3 may not induce hypermutation of AKV in mice.