Journal Article

Apobec-mediated retroviral hypermutation in vivo is dependent on mouse strain

Das, Poulami, Battenhouse, Anna, Reyes, Alejandro, Byun, Hyewon, Wylie, Dennis C., Xu, Wendy Kaichun, Santiago, Mario L., Dudley, Jaquelin P., Singh, Gurvani B., Lozano, Mary M.

2024

Overview

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 that is defective in Rem and its cleavage product Rem-CT (TBLV-SD). Compared to BALB/c, B6 mice were more susceptible to TBLV infection and tumorigenesis. Furthermore, unlike MMTV, TBLV induced T-cell tumors in B6 μMT mice, which lack membrane-bound IgM and conventional B-2 cells. At limiting viral doses, loss of Rem expression in TBLV-SD-infected B6 mice accelerated tumorigenesis compared to TBLV-WT in either wild-type B6 or AID-knockout mice. Unlike BALB/c results, high-throughput sequencing indicated that proviral G-to-A or C-to-T mutations were unchanged regardless of Rem expression in B6 tumors. However, knockout of both AID and mA3 reduced G-to-A mutations. Ex vivo stimulation showed higher levels of mA3 relative to AID in B6 compared to BALB/c splenocytes, and 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 TBLV-WT-induced tumors, consistent with another Rem function. Thus, Rem-mediated effects on tumorigenesis in B6 mice are independent of Apobec-mediated proviral hypermutation.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation-induced cytidine deaminase / AICDA (Activation-Induced Cytidine Deaminase) / Analysis / Animals / APOBEC Deaminases - genetics / APOBEC Deaminases - metabolism / Biology and Life Sciences / Carcinogenesis - genetics / Care and treatment / Complications and side effects / Cytidine deaminase / Cytidine Deaminase - genetics / Cytidine Deaminase - metabolism / Enzymes / Experiments / Female / Genes / Genetic aspects / Genetic engineering / Genomes / Growth factors / Health aspects / HIV / Human immunodeficiency virus / Immune response / Immunoglobulin M / In vivo methods and tests / Infections / Lymphocytes T / Lymphoma / Mammary Tumor Virus, Mouse - genetics / Medicine and Health Sciences / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Knockout / Mutagenesis / Mutation / Next-generation sequencing / Proteins / Replication / Research and Analysis Methods / Retroviridae Infections - genetics / Retroviridae Infections - immunology / Retroviridae Infections - virology / Retrovirus infections / RNA sequencing / Splenocytes / Tumor Virus Infections - genetics / Tumor Virus Infections - immunology / Tumor Virus Infections - virology / Tumorigenesis / Tumors / Virus Replication / Viruses