Unité Virus et Immunité, Institut Pasteur, 75724 Paris cedex 15, France.
J Exp Med. 2010 Jan 18;207(1):39-49. doi: 10.1084/jem.20091933. Epub 2009 Dec 28.
The cytidine deaminase APOBEC3G (A3G) enzyme exerts an intrinsic anti-human immunodeficiency virus (HIV) defense by introducing lethal G-to-A hypermutations in the viral genome. The HIV-1 viral infectivity factor (Vif) protein triggers degradation of A3G and counteracts this antiviral effect. The impact of A3G on the adaptive cellular immune response has not been characterized. We examined whether A3G-edited defective viruses, which are known to express truncated or misfolded viral proteins, activate HIV-1-specific (HS) CD8+ cytotoxic T lymphocytes (CTLs). To this end, we compared the immunogenicity of cells infected with wild-type or Vif-deleted viruses in the presence or absence of the cytidine deaminase. The inhibitory effect of A3G on HIV replication was associated with a strong activation of cocultivated HS-CTLs. CTL activation was particularly marked with Vif-deleted HIV and with viruses harboring A3G. Enzymatically inactive A3G mutants failed to enhance CTL activation. We also engineered proviruses bearing premature stop codons in their genome as scars of A3G editing. These viruses were not infectious but potently activated HS-CTLs. Therefore, the pool of defective viruses generated by A3G represents an underestimated source of viral antigens. Our results reveal a novel function for A3G, acting not only as an intrinsic antiviral factor but also as an inducer of the adaptive immune system.
胞苷脱氨酶 APOBEC3G（A3G）通过在病毒基因组中引入致命的 G 到 A 超突变，发挥内在的抗人类免疫缺陷病毒（HIV）防御作用。HIV-1 病毒感染力因子（Vif）蛋白触发 A3G 的降解，从而抵消这种抗病毒作用。A3G 对适应性细胞免疫反应的影响尚未得到表征。我们研究了是否 A3G 编辑的缺陷病毒，已知这些病毒表达截短或错误折叠的病毒蛋白，会激活 HIV-1 特异性（HS）CD8+细胞毒性 T 淋巴细胞（CTL）。为此，我们比较了在存在或不存在胞苷脱氨酶的情况下，用野生型或 Vif 缺失病毒感染的细胞的免疫原性。A3G 对 HIV 复制的抑制作用与共培养的 HS-CTL 的强烈激活有关。Vif 缺失的 HIV 和携带 A3G 的病毒的 CTL 激活尤其明显。无酶活性的 A3G 突变体不能增强 CTL 激活。我们还在其基因组中带有提前终止密码子的前病毒作为 A3G 编辑的痕迹进行了工程改造。这些病毒没有感染性，但能强烈激活 HS-CTL。因此，A3G 产生的缺陷病毒池是一种被低估的病毒抗原来源。我们的结果揭示了 A3G 的一个新功能，它不仅作为内在的抗病毒因子，而且作为适应性免疫系统的诱导剂发挥作用。
