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bioRxiv · 10.1101/2023.11.02.565355

Apobec-Mediated Retroviral Hypermutation In Vivo is Dependent on Mouse Strain

Byun, H.·Singh, G. B.·Xu, W. K.·Das, P.·Reyes, A.·Battenhouse, A.·Wylie, D. C.·Lozano, M. M.·Dudley, J. P.
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Abstract

Replication of the complex retrovirus mouse mammary tumor virus (MMTV) is antagonized by murine Apobec3 (mA3), a member of the Apobec family of cytidine deaminases. We have shown that MMTV-encoded Rem protein inhibits proviral mutagenesis by the Apobec enzyme, activation-induced cytidine deaminase (AID) during viral replication in BALB/c mice. To further study the role of Rem in vivo, we have infected C57BL/6 (B6) mice with a superantigen-independent lymphomagenic strain of MMTV (TBLV-WT) or a mutant strain (TBLV-SD) that is defective in Rem and its cleavage product Rem-CT. Unlike MMTV, TBLV induced T-cell tumors in {micro}MT mice, indicating that mature B cells, which express the highest AID levels, are not required for TBLV replication. Compared to BALB/c, B6 mice were more susceptible to TBLV infection and tumorigenesis. The lack of Rem expression accelerated B6 tumorigenesis at limiting doses compared to TBLV-WT in either wild-type B6 or AID-deficient mice. However, unlike proviruses from BALB/c mice, high-throughput sequencing indicated that proviral G-to-A or C-to-T changes did not significantly differ in the presence and absence of Rem expression. Ex vivo stimulation showed higher levels of mA3 relative to AID in B6 compared to BALB/c splenocytes, but effects of agonists differed in the two strains. RNA-Seq revealed increased transcripts related to growth factor and cytokine signaling in TBLV-SD-induced tumors relative to those from TBLV-WT, consistent with a third Rem function. Thus, Rem-mediated effects on tumorigenesis in B6 mice are independent of Apobec-mediated proviral hypermutation.

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Byun, H., Singh, G. B., Xu, W. K., Das, P., Reyes, A., Battenhouse, A., Wylie, D. C., Lozano, M. M., Dudley, J. P.. 2023-11-02. Apobec-Mediated Retroviral Hypermutation In Vivo is Dependent on Mouse Strain. https://doi.org/10.1101/2023.11.02.565355

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