Background Non-Hodgkin lymphoma is of high prevalence among HIV-infected people. In particular, the incidence of HIV-associated Burkitt lymphoma (BL) remains high despite the advent of Highly Active Anti-Retroviral Therapy. Recent evidence shows that serum-soluble HIV proteins can enhance oncogenesis, particularly in lymphoid tissues. This study sought to define the role of HIV protein Negative regulatory factor (Nef) in BL development by assessing its effect on key lymphoma driver genes. Methods A recombinant Nef protein was used to assess changes in expressions of activation-induced cytidine deaminase ( AICDA /AID) and c-MYC in B lymphocytes exposed extracellularly to the protein. Additionally, changes in the promoter activities of these genes were measured using a Nef-expressing cellular model and reporter assays. Confocal microscopy was used to observe c-MYC and AID expression and localization, and genomic integrity via the recruitment of phosphorylated γ-H2AX, in Nef-exposed cells. Results mRNA transcription of c-MYC and AICDA were significantly enhanced in lymphoma cells, up to 2-fold for c-MYC and up to 4-fold for AICDA , when exposed to varying concentrations of Nef (0–1000 ng/ml) and for different periods of time (3, 6 and 12 h). The protein expressions of AID and c-MYC followed a similar pattern and these effects were specific to BL but not lymphoblastoid cells. While the promoter activity of c-MYC was enhanced in the presence of Nef in a dose-dependent manner, the same was not observed for AICDA . Both AID and c-MYC accumulated within the cytoplasmic and nuclear spaces of Nef-exposed lymphoma cells, with a concomitant increase in DNA double strand breaks within the genome. Conclusions Exposure to HIV Nef leads to significant increases in AID and c-MYC, leading to genomic instability, potentially enhancing the oncogenic potential of Burkitt lymphoma. Our findings align with that of others to show that HIV proteins can directly contribute to the development and pathogenesis of HIV-associated lymphoma and accounts for the elevated incidence of BL observed in the HIV-infected population.

中文翻译：

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HIV Nef 增强 Burkitt 淋巴瘤细胞中致癌 c-MYC 和活化诱导的胞苷脱氨酶的表达，促进基因组不稳定性

背景 非霍奇金淋巴瘤在 HIV 感染者中的患病率很高。特别是，尽管出现了高效抗逆转录病毒疗法，但 HIV 相关伯基特淋巴瘤 (BL) 的发病率仍然很高。最近的证据表明，血清可溶性 HIV 蛋白可以增强肿瘤发生，特别是在淋巴组织中。本研究旨在通过评估 HIV 蛋白负调节因子 (Nef) 对关键淋巴瘤驱动基因的影响来确定其在 BL 发展中的作用。方法 使用重组 Nef 蛋白评估细胞外暴露于该蛋白的 B 淋巴细胞中活化诱导的胞苷脱氨酶 (AICDA /AID) 和 c-MYC 表达的变化。此外，使用表达 Nef 的细胞模型和报告基因测定法测量了这些基因启动子活性的变化。在 Nef 暴露的细胞中，共聚焦显微镜用于观察 c-MYC 和 AID 的表达和定位，以及通过募集磷酸化 γ-H2AX 的基因组完整性。结果当暴露于不同浓度的 Nef (0–1000 ng/ml) 和不同浓度的 Nef 时，c-MYC 和 AICDA 的 mRNA 转录在淋巴瘤细胞中显着增强，c-MYC 高达 2 倍，AICDA 高达 4 倍。不同的时间段（3、6 和 12 小时）。AID 和 c-MYC 的蛋白质表达遵循相似的模式，这些效应对 BL 具有特异性，但对淋巴母细胞没有特异性。虽然在 Nef 存在下 c-MYC 的启动子活性以剂量依赖性方式增强，但在 AICDA 中没有观察到相同的情况。AID 和 c-MYC 都在 Nef 暴露的淋巴瘤细胞的细胞质和核空间内积累，伴随着基因组内 DNA 双链断裂的增加。结论 暴露于 HIV Nef 会导致 AID 和 c-MYC 显着增加，导致基因组不稳定，从而可能增强伯基特淋巴瘤的致癌潜力。我们的研究结果与其他研究结果一致，表明 HIV 蛋白可以直接促进 HIV 相关淋巴瘤的发展和发病机制，并解释了在 HIV 感染人群中观察到的 BL 发病率升高。