复杂逆转录病毒小鼠乳腺肿瘤病毒 (MMTV) 的复制受到胞苷脱氨酶 Apobec 家族成员鼠 Apobec3 (mA3) 的拮抗作用。我们已经证明，MMTV 编码的 Rem 蛋白可抑制 BALB/c 小鼠病毒复制过程中 Apobec 酶（激活诱导的胞苷脱氨酶 (AID)）引起的前病毒诱变。为了进一步研究 Rem 在体内的作用，我们用 MMTV 的超抗原非依赖性淋巴瘤发生株 (TBLV-WT) 或 Rem 及其裂解产物 Rem-CT 缺陷的突变株感染 C57BL/6 (B6) 小鼠（TBLV-SD）。与BALB/c相比，B6小鼠更容易受到TBLV感染和肿瘤发生。此外，与 MMTV 不同，TBLV 在缺乏膜结合 IgM 和传统 B-2 细胞的 B6 μMT 小鼠中诱导 T 细胞肿瘤。在限制病毒剂量下，与野生型 B6 或 AID 敲除小鼠中的 TBLV-WT 相比，TBLV-SD 感染的 B6 小鼠中 Rem 表达的丧失加速了肿瘤发生。与 BALB/c 结果不同，高通量测序表明，无论 B6 肿瘤中 Rem 表达如何，前病毒 G 至 A 或 C 至 T 突变均未改变。然而，AID 和 mA3 的敲除减少了 G 到 A 的突变。与 BALB/c 脾细胞相比，离体刺激显示 B6 中的 mA3 水平高于 AID，并且两种菌株中激动剂的作用不同。 RNA-Seq 显示，相对于 TBLV-WT 诱导的肿瘤，TBLV-SD 诱导的肿瘤中与生长因子和细胞因子信号转导相关的转录物增加，这与另一个 Rem 功能一致。因此，Rem 介导的 B6 小鼠肿瘤发生作用与 Apobec 介导的原病毒超突变无关。版权所有：© 2024 Byun 等人。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

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.Copyright: © 2024 Byun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.