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 及其缺陷的突变株 (TBLV-SD) 感染了 C57BL/6 (B6) 小鼠。裂解产物Rem-CT。与 MMTV 不同，TBLV 在 µMT 小鼠中诱导 T 细胞肿瘤，这表明表达最高 AID 水平的成熟 B 细胞并不是 TBLV 复制所必需的。与BALB/c相比，B6小鼠更容易受到TBLV感染和肿瘤发生。与野生型 B6 或 AID 缺陷小鼠中的 TBLV-WT 相比，Rem 表达的缺乏在有限剂量下加速了 B6 肿瘤的发生。然而，与来自 BALB/c 小鼠的原病毒不同，高通量测序表明，原病毒 G 到 A 或 C 到 T 的变化在 Rem 表达存在和不存在时没有显着差异。与 BALB/c 脾细胞相比，离体刺激显示 B6 中 mA3 水平高于 AID，但激动剂的作用在两种菌株中不同。 RNA-Seq 显示，与 TBLV-WT 相比，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本有所增加，这与第三个 Rem 功能一致。因此，Rem 介导的 B6 小鼠肿瘤发生作用与 Apobec 介导的前病毒超突变无关。

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 µMT 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.