Several host genes control retroviral replication and pathogenesis through the regulation of immune responses to viral antigens. The Rfv3 gene influences the persistence of viremia and production of virusneutralizing antibodies in mice infected with Friend mouse retrovirus complex (FV). This locus has been mapped within a narrow segment of mouse chromosome 15 harboring the APOBEC3 and BAFF-R loci, both of which show functional polymorphisms among different strains of mice. The exon 5-lacking product of the APOBEC3 allele expressed in FV-resistant C57BL/6 (B6) mice directly restricts viral replication, and mice lacking the B6-derived APOBEC3 exhibit exaggerated pathology and reduced production of neutralizing antibodies. However, the mechanisms by which the polymorphisms at the APOBEC3 locus affect the production of neutralizing antibodies remain unclear. Here we show that the APOBEC3 genotypes do not directly affect the B-cell repertoire, and mice lacking B6-derived APOBEC3 still produce FV-neutralizing antibodies in the presence of primed T helper cells. Instead, higher viral loads at a very early stage of FV infection caused by either a lack of the B6-derived APOBEC3 or a lack of the wild-type BAFF-R resulted in slower production of neutralizing antibodies. Indeed, B cells were hyperactivated soon after infection in the APOBEC3-or BAFF-R-deficient mice. In contrast to mice deficient in the B6-derived APOBEC3, which cleared viremia by 4 weeks after FV infection, mice lacking the functional BAFF-R allele exhibited sustained viremia, indicating that the polymorphisms at the BAFF-R locus may better explain the Rfv3-defining phenotype of persistent viremia.Several host genetic factors control retroviral replication and pathogenesis through the regulation of immune responses to viral antigens. The recovery from Friend virus 3 gene (Rfv3) was identified as a host gene locus that affects the persistence of viremia and development of virus-specific antibody (Ab) responses upon Friend virus (FV) infection (5). FV is the pathogenic retrovirus complex composed of replication-competent Friend murine leukemia virus (F-MuLV) and the defective spleen focus-forming virus (SFFV). The product of the SFFV env gene, gp55, forms a complex with the erythropoietin receptor and the short form of the hematopoietic-cell-specific receptor tyrosine kinase (STK), and this interaction induces the growth and terminal differentiation of erythroid progenitor cells, causing increased hematocrit values and massive splenomegaly. The resultant increase in targets of FV integration consequently causes the emergence of mono-or oligoclonal erythroleukemia through insertional activation of transcription factors or disruption of a tumor suppressor gene (15,29,34). Mice of the C57BL background possess mutations in the intron of the Stk gene and lack expression of the short-form STK, resulting in resistance to SFFV-induced splenomegaly (37).This host factor was first described as polymorphisms at the Fv2 locus, with the resistance allele found in C57BL m...

Background:The mechanism whereby the circadian clock regulates phosphate metabolism remains elusive. Results: Fgf23 expression is regulated by the time of food intake which involves the alteration in circadian profile of sympathetic activity. Conclusion:The circadian network plays important roles in phosphate metabolism. Significance: The sympathetic regulation of Fgf23 expression may shed light on new regulatory networks that could be important for phosphate homeostasis.

Background:The role of elevated FGF23 in the development of growth retardation associated with X-linked hypophosphatemic rickets (XLH) remains elusive. Results: FGF23 suppresses chondrocyte proliferation in cooperation with soluble ␣-Klotho. Conclusion: Elevated FGF23 could have a causative role in the development of growth retardation in XLH. Significance: This may provide insights into the unrecognized function of FGF23 signaling in chondrocyte biology.

Inorganic phosphate (Pi) has been implicated in the pathogenesis of accelerated aging; however, the underlying mechanisms remain elusive. Herein, we demonstrated in cultured cells and in vivo that increased levels of extracellular Pi activated the AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway by suppressing membrane-bound phosphatase and tensin homolog (PTEN) levels in a manner requiring the sodium-dependent Pi transporter PiT-1. High levels of extracellular Pi also led to phosphorylation of Ser/Thr clusters in the C-terminal tail of PTEN, which has been shown to dissociate PTEN from the membrane. Notably, blockade of mTORC1 activity by rapamycin treatment prolonged the life span of hyperphosphatemic a-Klotho-deficient (Kl 2/2 ) mice. Dietary correction of hyperphosphatemia or treatment with rapamycin also rescued the brown adipose tissue dysfunction and oxidative damage observed in Kl 2/2 mice. Furthermore, rapamycin treatment partially rescued these effects and extended the life span when Kl 2/2 mice were maintained on a high-phosphate diet. Finally, rapamycin reduced circulating Pi levels in Kl 2/2 mice, apparently by decreasing the localization of sodium-dependent Pi transport protein 2a at the renal brush border membrane. Therefore, the activation of mTORC1 may create a vicious loop that exacerbates the retention of Pi, which in turn may enhance oxidative damage and ultimately shorten the life span of Kl 2/2 mice. These results demonstrate that Pi has important roles in the aging process, and the blockade of mTORC1 may have therapeutic potential for premature aging-like symptoms associated with hyperphosphatemia.

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