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Published on: October 14, 2016
Mouse APOBEC3 restricts friend leukemia virus infection and pathogenesis in vivo
Eri Takeda1, Sachiyo Tsuji-Kawahara, Mayumi Sakamoto
1Department of Immunology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan. masaaki@med.kindai.ac.jp
Abstract:
Several members of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like complex 3 (APOBEC3) family in primates act as potent inhibitors of retroviral replication. However, lentiviruses have evolved mechanisms to specifically evade host APOBEC3. Likewise, murine leukemia viruses (MuLV) exclude mouse APOBEC3 from the virions and cleave virion-incorporated APOBEC3. Although the betaretrovirus mouse mammary tumor virus has been shown to be susceptible to mouse APOBEC3, it is not known if APOBEC3 has a physiological role in restricting more widely distributed and long-coevolved mouse gammaretroviruses. The pathogenicity of Friend MuLV (F-MuLV) is influenced by several host genes: some directly restrict the cell entry or integration of the virus, while others influence the host immune responses. Among the latter, the Rfv3 gene has been mapped to chromosome 15 in the vicinity of the APOBEC3 locus. Here we have shown that polymorphisms at the mouse APOBEC3 locus indeed influence F-MuLV replication and pathogenesis: the APOBEC3 alleles of F-MuLV-resistant C57BL/6 and -susceptible BALB/c mice differ in their sequences and expression levels in the hematopoietic tissues and in their abilities to restrict F-MuLV replication both in vitro and in vivo. Furthermore, upon infection with the pathogenic Friend virus complex, (BALB/c x C57BL/6)F(1) mice displayed an exacerbated erythroid cell proliferation when the mice carried a targeted disruption of the C57BL/6-derived APOBEC3 allele. These results indicate, for the first time, that mouse APOBEC3 is a physiologically functioning restriction factor to mouse gammaretroviruses.
Insights
Mouse apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) restricts mouse gammaretroviruses. Genetic variations in mouse APOBEC3 influence Friend MuLV replication and disease, establishing its physiological role in innate immunity.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- The apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) family inhibits retroviral replication in primates.
- Lentiviruses and murine leukemia viruses (MuLV) possess mechanisms to evade or exclude host APOBEC3.
- The role of mouse APOBEC3 in restricting gammaretroviruses, particularly Friend MuLV (F-MuLV), remained unclear.
Purpose of the Study:
- To investigate the physiological role of mouse APOBEC3 in restricting mouse gammaretroviruses.
- To determine if polymorphisms in the mouse APOBEC3 locus affect F-MuLV replication and pathogenesis.
Main Methods:
- Comparative sequence and expression analysis of APOBEC3 alleles from F-MuLV-resistant (C57BL/6) and susceptible (BALB/c) mice.
- In vitro and in vivo assays to assess the restriction capabilities of different APOBEC3 alleles against F-MuLV.
- Analysis of erythroid cell proliferation in F1 hybrid mice with targeted APOBEC3 disruption after F-MuLV infection.
Main Results:
- Polymorphisms in mouse APOBEC3 alleles correlate with F-MuLV replication and pathogenesis.
- APOBEC3 alleles from resistant mice exhibit differential sequence and expression levels in hematopoietic tissues.
- APOBEC3 alleles demonstrate varying abilities to restrict F-MuLV replication in vitro and in vivo.
- Disruption of the C57BL/6 APOBEC3 allele in F1 mice led to exacerbated erythroid cell proliferation upon pathogenic Friend virus complex infection.
Conclusions:
- Mouse APOBEC3 functions as a physiological restriction factor against mouse gammaretroviruses.
- Genetic variations in mouse APOBEC3 significantly impact F-MuLV pathogenesis.
- These findings highlight the importance of APOBEC3 in innate antiviral defense against gammaretroviruses.
