Approximately 8% of the genomes of mammals, including humans and mice, are comprised of retroviral elements acquired by infection of germ line cells during the course of evolution. Retroviral insertions in our genome number about 40,000 and are in the same range as the total number of genes encoded by our DNA. Most endogenous retrovirus elements are defective for replication however several contain one or more viral genes that are expressed during development and certain physiological or pathological conditions. Little is known about the control of retrovirus expression or the influence of such expression on the physiology or pathology of the host. An extensively investigated group of endogenous retroviruses are those giving rise to recombinant murine leukemia viruses (MuLVs) in mice. Upon infection of mice with exogenous ecotropic MuLVs, members of this group undergo recombination to generate new MuLVs with an altered infectious host range. Recombination requires transcription of the endogenous retroviruses. 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 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. Thus, exogenous retroviruses might facilitate through complementation, active replication of endogenous retroviruses. We have found that infection of mice by an exogenous virus results in the infectious transfer of complete endogenous proviral genetic sequences. This includes proviruses which 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. At early times after infection with the Friend MuLV, packaging and transfer of intact endogenous retroviruses is much more prevalent than recombination. In 2010 our studies have been extended to show that transfer of endogenous retroviruses can be observed as early as one day after infection indicating that packaging occurs after a single replication cycle in the initially infected cells of the host. In addition, we have found that other endogenous viruses, distinct from polytropic MuLVs, are also mobilized from infected mice. These include the Mus D and the IAP mouse transposable elements. Notably, endogenous MMTV elements were not detected suggesting a degree of specificity. The mobilization of intact endogenous retroviruses is unprecedented and may have important implications for the involvement of endogenous retroviruses in disease processes. This may be particularly important considering recent reports that mouse retroviruses similar to those we have described have been detected in humans. Exogenous mouse retroviruses as well as some other gamma retroviruses, encode a glycosylated gag protein (gGag) originating from an alternate translation start site upstream of the methionine start site of the gag structural polyproteins. The functions of gGag remain unclear, but mutations that eliminate its synthesis severely impede in vivo replication of the virus with little, if any, effect on replication in fibroblastic cell lines. APOBEC proteins have evolved as innate defenses against retroviral infections. HIV encodes the VIF protein to evade human APOBEC3G, however mouse retroviruses do not encode a VIF homologue and it has not been understood how they evade mouse APOBEC3. In 2010 we have found that a mouse retrovirus utilizes its glycosylated gag protein (gGag) 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. Current studies are focused on the elucidation of the mechanism by which the gGag protein abrogates the action of APOBEC3. The endogenous retroviral envelope glycoprotein, gp70 is implicated in murine lupus nephritis. This protein is secreted by hepatocytes as an acute phase protein and has been believed to be a product of an endogenous xenotropic virus. However, since endogenous polytropic viruses encode gp70s that are closely related to xenotropic gp70, these viruses could be additional sources of serum gp70. To better understand the genetic basis of the expression of serum gp70, we analyzed the abundance of xenotropic and polytropic gp70 RNAs in livers and the genomic composition of corresponding endogenous proviruses in various strains of mice, including two different Sgp (serum gp70 production) congenic mice (Sgp3 and Sgp4). These studies revealed a significant contribution of polytropic gp70s to serum gp70. These studies were extended to show that expression levels of a subclass of polytropic MuLVs, termed, modified polytropic (mPT), are highly elevated in mice which develop systemic lupus erythematosus. This elevated expression appears specific for this class of endogenous viruses and under the control of the Sgp3 locus. In 2010 our studies have focused on the influence of TLR7 or TLR9 agonist on the expression of serum gp70s. Serum levels of gp70 were up-regulated in lupus-prone NZB mice injected with TLR7 or TLR9 agonist at levels comparable to those induced by injection of IL-1, IL-6 or TNF. These results suggest an additional pathogenic role of TLR7 and TLR9 in murine lupus nephritis by promoting the expression of nephritogenic gp70 autoantigen. Studies of C57BL/6 Sgp3 and/or Sgp4 congenic mice defined the major roles of these two loci in up-regulated production of serum gp70 during acute phase responses. The analysis of Sgp3 congenic mice strongly suggests the presence of at least two distinct genetic factors in the Sgp3 interval, one of which controls the basal-level expression of serum gp70s and the other which controls the up-regulated production of gp70s during acute phase responses
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