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The AKV murine leukemia virus is restricted and hypermutated by mouse APOBEC3
Marc-André Langlois1, Kristin Kemmerich, Cristina Rada
1Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge, United Kingdom CB2 0QH. langlois@uottawa.ca
Abstract:
APOBEC3 proteins are potent restriction factors against retroviral infection in primates. This restriction is accompanied by hypermutations in the retroviral genome that are attributable to the cytidine deaminase activity of the APOBEC3 proteins. Studies of nucleotide sequence diversity among endogenous gammaretroviruses suggest that the evolution of endogenous retroelements could have been shaped by the mutagenic cytidine deaminase activity of APOBEC3. In mice, however, APOBEC3 appears to restrict exogenous murine retroviruses in the absence of detectable levels of deamination. AKV is an endogenous retrovirus that is involved in causing a high incidence of thymic lymphoma in AKR mice. A comparative analysis of several mouse strains revealed a relatively low level of APOBEC3 expression in AKR mice. Here we show that endogenous mouse APOBEC3 restricts AKV infection and that this restriction likely reflects polymorphisms affecting APOBEC3 abundance rather than differences in the APOBEC3 isoforms expressed. We also observe that restriction of AKV by APOBEC3 is accompanied by G-->A hypermutations in the viral genome. Our findings demonstrate that APOBEC3 acts as a restriction factor in rodents affecting the strain tropism of AKV, and they provide good support for the proposal that APOBEC3-mediated hypermutation contributed to the evolution of endogenous rodent retroviral genomes.
Insights
APOBEC3 proteins restrict retroviral infections in mice, with AKV infection limited by APOBEC3 abundance. This restriction involves G-to-A hypermutations, suggesting APOBEC3
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- APOBEC3 proteins are primate restriction factors against retroviruses, causing genome hypermutation via cytidine deaminase activity.
- Endogenous retroviral evolution may be shaped by APOBEC3's mutagenic activity.
- In mice, APOBEC3 restricts exogenous retroviruses without detectable deamination.
Purpose of the Study:
- To investigate the role of endogenous mouse APOBEC3 in restricting AKV (a murine retrovirus).
- To determine if APOBEC3 restriction of AKV involves deamination and if polymorphisms in APOBEC3 affect its expression.
- To explore the impact of APOBEC3 on AKV strain tropism and retroviral genome evolution in rodents.
Main Methods:
- Comparative analysis of APOBEC3 expression levels across different mouse strains.
- Assessing the restriction of AKV infection by endogenous mouse APOBEC3.
- Analyzing viral genomes for G-->A hypermutations following APOBEC3 restriction.
- Investigating the role of APOBEC3 abundance versus isoform differences in restriction.
Main Results:
- Endogenous mouse APOBEC3 restricts AKV infection.
- Restriction is linked to APOBEC3 abundance polymorphisms, not isoform differences.
- AKV restriction by APOBEC3 is accompanied by G-->A hypermutations in the viral genome.
- AKR mice exhibit relatively low APOBEC3 expression, correlating with AKV involvement in thymic lymphoma.
Conclusions:
- APOBEC3 functions as a restriction factor in rodents, influencing AKV strain tropism.
- APOBEC3-mediated hypermutation likely contributed to the evolution of endogenous rodent retroviral genomes.
- APOBEC3's role in restricting retroviral infections and shaping genome evolution is conserved across species.
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